Remarkable advances have been reached in the understanding of the genetic basis of Parkinson’s disease (PD), with the identification of monogenic causes (mPD) and a plethora of gene loci leading to an increased risk for idiopathic PD. The expanding knowledge and subsequent identification of genetic contributions fosters the understanding of molecular mechanisms leading to disease development and progression. Distinct pathways involved in mitochondrial dysfunction, oxidative stress, and lysosomal function have been identified and open a unique window of opportunity for individualized treatment approaches. These genetic findings have led to an imminent progress towards pathophysiology-targeted clinical trials and potentially disease-modifying treatments in the future.In this review article we will summarize known genetic contributors to the pathophysiology of Parkinson’s disease, the molecular mechanisms leading to disease development, and discuss challenges and opportunities in clinical trial designs.The future success of clinical trials in PD is mainly dependent on reliable biomarker development and extensive genetic testing to identify genetic cases. Whether genotype-dependent stratification of study participants will extend the potential application of new drugs will be one major challenge in conceptualizing clinical trials. However, the latest developments in genotype-driven treatments will pave the road to individualized pathophysiology-based therapies in the future. Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized by the progressive degeneration of nigrostriatal dopaminergic neurons and extranigral brain regions due to the accumulation of certain α-synuclein species , LRRK2 (Leucine Rich Repeat Kinase 2), and VPS35 (VPS35 Retromer Complex Component) cause an autosomal dominant form of mPD whereas mutations in PRKN (Parkin), PINK1 (PTEN-induced kinase 1), and PARK7 (oncogene DJ-1) (among others) are associated with autosomal-recessive mPD  gene are an unequivocal and frequent risk factor for the development of PD and a promising future drug target.PD is caused by complex interactions between genetic and environmental factors. Mutations in mPD Lill . Althoug Cookson . The ideGBA converge to distinct molecular mechanisms and can be divided into (i) α-synuclein aggregation  resulting in the formation of Lewy bodies  has already been proven useful in in-vitro, rodent, and primate models  against GBA gene encodes the protein glucocerebrosidase (GCase), a lysosomal hydrolase, which converts glucosylceramide to ceramide and glucose . Interestingly, GD patients have a higher incidence of parkinsonism, and heterozygous mutations in the GBA gene increase the risk of developing PD  and ‘PD risk factor’ GBA variants, which show an association with PD risk but are not considered causative for GD   are comparable with IPD whereas carriers of severe GBA variants (sGBA-PD) have a clearly increased risk of dementia with an earlier onset and a more rapid cognitive decline  substrate reduction (as often considered for the treatment of GD), (ii) external GCase augmentation, and (iii) the enhancement of GCase activity . Substrate reduction can be achieved by different mechanisms: Glucosylceramide synthase inhibitors decrease glycosphingolipid levels and are used to treat the hematological and visceral presentations of GD patients. The clinical trial GZ/SAR402671 (NCT02906020) showed that the glucosylceramide synthase inhibitor venglustat sufficiently crossed the blood brain barrier (BBB) in humans  and R15-006 (NCT02914366) tested the safety, efficacy, and tolerability of ambroxol in PD  phenotype, but show a relatively mild cognitive and motor decline during the overall disease course  with an increase of LRRK2 kinase activity. The LRRK2 protein has a complex multidomain structure and belongs to the family of protein kinases, which play a fundamental role in the control and regulation of complex cellular processes by transferring phosphate groups to target proteins. The kinase domain of LRRK2 shares similarities with mitogen-activated protein (MAP) kinases, which play a central role in mediating cellular stress. Even though the precise mechanism of LRRK2 is poorly understood, the disease-causing GOF mutations allows heuristic treatments by inhibition of its activity. Currently, two main strategies exist for LRRK2-targeted treatment strategies: (i) pharmacological inhibition of LRRK2 activity and (ii) silencing of the LRRK2 gene by the use of ASOs. Both options aim to reduce LRRK2 activity in the CNS whereby ASOs may bypass potential peripheral adverse effects of kinase inhibitors due to its intrathecal application  in blood. A trial with DNL151, a second LRRK2 inhibitor, is still actively recruiting healthy volunteers   the enhancement of PRKN or PINK1 expression, (ii) the prevention of Parkin or PINK1 inactivation, and (iii) the control of the downstream Parkin/PINK1 signaling pathway (Gaki and Papavassiliou PRKN or PINK1 mutation carriers) as listed in Table PRKN/PINK1 mutation carriers, heterozygous PRKN/PINK1 mutation carriers, and two IPD groups defined by the statistical extrema as determined by a mitochondrial PRS . Both studies have multimodal neuroimaging in common that will be applied as a surrogate marker for examining beneficial effects of in-vivo brain energy metabolism, i.e., by determining the change of energy equivalents using 31Phosphorus Magnetic Resonance Spectroscopy Imaging (31P-MRSI).Mitochondrial dysfunction is one of the main concepts in PD pathogenesis. Mitochondria play a fundamental role for a plethora of cellular processes relevant for the supply of energy, the overall cellular homeostasis, and neuronal survival. The first evidence for a role in PD derived from environmental studies illustrating the effect of neurotoxic agents in inhibiting the mitochondria's electron transport chain (ETC) . The disease-modifying management of PD is herewith more challenging due to the absence of validated and dynamic mechanism-based biomarkers.SNCA  and high energy phosphates such as ATP levels (31P-MRSI) (Bonvento et al. Biomarkers in clinical PD trials are mainly required to demonstrate target engagement and to quantify disease progression. Stratification of PD patients based on their primarily involved disease mechanisms is one substantial prerequisite for targeted therapies (Redenšek et al. The genetic discoveries in PD have aided the deepened understanding of clinical manifestations, underlying pathogenesis, and the potential for targeted therapies (Brüggemann and Klein


A 28-year-old primigravida with 22.3 weeks of gestation came for dedicated level II ultrasonography for anomaly scan to the antenatal clinic of AVBRH, Sawangi (India). The previous antenatal check-up was not done. The patient neither had a history of maternal systemic diseases like diabetes or hypertension nor history of any trauma or drug intake during pregnancy. There was no family history of congenital anomalies. On obstetric examination, the uterus was of about 20 weeks in size. On ultrasonography, single live intrauterine foetus with an average gestational age of 21 weeks 5 days corresponding to effective foetal weight of 396 grams showing right foot abnormality with persistent adduction and inward rotation suggestive of clubfoot with mild pylectasis of left kidney was noted. However, there was no obvious abnormality of left foot. There was amniotic band in right lower quadrant of gravid uterus.


KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies  and other associated malformations . Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the  Wiedemann–Steiner syndrome  is a rare severe autosomal dominant disorder, characterized by intellectual disability (ID), developmental delay, hypertrichosis cubiti and distinctive facial features ,5,6,7,8.The introduction of next-generation sequencing (NGS) and the implementation of human phenotype ontology (HPO) have revolutionized diagnostics for rare diseases . ReverseKMT2A (lysine methyltransferase 2A) gene (MIM# 159555), located on chr11q23, previously known as MLL (mixed lineage leukemia). Germline and somatic KMT2A variants are, respectively, associated with WDSTS and multiple neoplastic diseases, along with gene structural rearrangements that are common in acute leukemia  and and22] ap-value < 0.01.In order to identify the regions that are differentially methylated between the subjects with WDSTS and controls, we used the DMRcate package  and seleKMT2A pathogenic variants may disturb the normal process of H3K4me3 deposition coupled at gene promoters. The methylome analysis did highlight a substantial change in the global methylation pattern in WDSTS samples, and resulted in 87% hypomethylated and 13% hypermethylated probes. Our studies reported that the expression of several homeobox containing genes (including HOX or HOX-related genes) is consistently altered in the blood of WDSTS patients. If also present in other tissues, dysregulation of normal methylation of homeobox gene expression may explain part of the ID, facies and associated malformations observed in WDSTS patients. These provide novel insights into the molecular etiology of WDSTS and likely explain the broad phenotypic spectrum of the disease.In conclusion, the identified WDSTS DNA methylation episignature is added to the list of Mendelian NDDs with known DNA methylation episignatures that can be used for screening and diagnosis of NDD patients.


Biomarkers ideal for geroscience trials could be those simultaneously identified using targeted and discovery assays and which strongly associate with complementary disease (multimorbidity) and longevity  outcomes. To identify a tractable set of biomarkers for use in geroscience trials, we used the Cardiovascular Health Study (CHS), whose participant makeup closely aligns with the Targeting Aging with MEtformin (TAME) trial. In ~4800 CHS participants, quantitative assays of nine a priori-identified biomarkers were used to construct a biomarker index which strongly associated with the TAME primary outcome of mortality and multimorbidity over 6 and 10 years of follow-up. In ~3000 CHS participants, 1300 proteins were measured with unbiased aptamer proteomics and associated with survival to age 90 over 25 years of follow-up. Proteins in the biomarker index were identified as some of the strongest associated with survival to 90. This convergent evidence suggests these biomarkers may be well-suited for geroscience trials.


An important quality marker for end-of-life services is congruence with patient’s preferred place of care, but this congruence in place of care is less likely for those facing structural inequalities . As homelessness among older adults in the United States grows , the urgency in understanding place of care in palliative care with unhoused patients grows. This presentation illustrates results from an organizational case study  of a novel homeless palliative care team and focuses on a qualitative content analysis of charts of patients over 50 receiving care both before and during the COVID-19 pandemic (n=27). Findings highlight (1) the interplay between environmental factors, psychosocial resources and constraints, and medical acuity in determining where care can take place, (2) facilitators for care in marginal settings such as emergency shelters and encampments, and (3) where opportunities for more equitable age-friendly healthcare system interventions exist.


BRCA2) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; BRCA2 PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in BRCA2 compared with non-BRCA2 mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC.Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 ( PSA decline of greater than 50% was observed in 50% of patients with BRCA1/2 and 3% of those with non-BRCA biallelic DDR gene alterations. Similar to olaparib, rucaparib was approved by the FDA for use amongst mCRPC patients with germline and/or somatic BRCA1/2 mutations undergoing prior progression on AR signaling inhibitor or taxane. Europe still awaits approval . Multiple phase I and phase II trials are evaluating immune checkpoint inhibitors in combination with treatments such as abiraterone and cabozantinib [NCT04477512], radiation therapy , and an experimental IL-8 directed monoclonal antibody [NCT03689699]. In addition, perioperative ipilimumab in combination with castration prior to radical prostatectomy has demonstrated feasibility with longer follow-up ongoing .DNA sequencing efforts have changed the molecular classification of prostate tumors and are leading to precision medicine strategies as well as defined prognosis and clinical features of molecular subsets of PC. Nevertheless, prospective studies demonstrating clinical value of biomarkers for prognostication or prediction of response are warranted. Somatic and germline DNA testing for patients with advanced PC should be considered in view of the therapeutic consequences for the patient and the possibility of pursuing targeted screening in this population. Metastatic tumor biopsies are recommended to obtain information regarding mCRPC tumor features. Germline samples are easily collected and analyzed, but still half of the patients with somatic DDR defects would not be identified. Liquid biopsies may be used to monitor for the detection of secondary mutations that may restore the function of a gene previously altered.PARP inhibitors represent one of the recent biggest therapeutic developments for PC patients. Combination of PARP inhibitor with AR-targeting agents is worthy due to the cross-regulation of both pathways and the central role of hormonal therapy in PC. Immunotherapy has shown still limited efficacy in these patients. However, immunotherapy combinations will probably overcome intrinsic resistance of PC to immunotherapy. Ongoing studies that assess the role of immunotherapy in PC are NCT04104893, NCT04019964 and NCT03570619.


OBJECTIVES/GOALS: The aim was to examine whether nicotine patch was more effective in encouraging abstinence from cigarettes smoking compared to placebo. METHODS/STUDY POPULATION: Randomized controlled trials involving the general teenage age group smokers who were current smokers-“smoked less than 100 cigarettes over their lifetime and smoked at the time of the interview. Databases were searched for relevant studies reported in English that employed a randomized design published since 2000. Two authors extracted data and assessed quality. The primary outcomes and prioritization were continuous abstinence at 3, 6 and 12-month follow-up or more for the number of patients who responded to treatment, defined as a reduction/abstinence. Heterogeneity between studies did not preclude combined analyses of the data. RESULTS/ANTICIPATED RESULTS: 4 of 266 publications were included. Four studies reported positive effects on smoking cessation at end of treatment: (1) nicotine patches improved continuous abstinence at 6 weeks – 9 weeks months; (2) nicotine patch improved continuous abstinence at 3 to 6 months; (3) nicotine patches improved continuous abstinence 6 and 12 months; (4) nicotine patches improved continuous abstinence at 6 months – 12 and 24 months (5). All studies showed, continuous abstinence at follow up differed in percentage between groups both at 6 weeks through 24 months, with NRT (Nicotine patch) intervention groups achieving higher rates in most of the studies compared to placebo intervention group. Conclusions: NRT intervention methods seem to increase smoking abstinence in those treated for smoking cessation. Further and larger sample size studies are required to make stronger the base of evidence. DISCUSSION/SIGNIFICANCE OF IMPACT: Four randomized controlled trials investigating the effectiveness of smoking cessation interventions, for teenagers who smoke cigarettes were identified for inclusion in this review. Four of the studies reported significant effects on smoking cessation, providing evidence of effectiveness of NRT (nicotine patch), behavioral support and combinations of the two, although not all trials intervention treatments found an effect. The four studies reported important intervention effects at both the short and long follow-ups required: 6 weeks up to the 24 months, thereby, providing stronger evidence to support the effectiveness of NRT intervention on smoking cessation. All studies showed some evidence of improved smoking abstinence outcomes. The four studies had in common that the smoking cessation interventions provided a combination of intent to treat prevention, and of all the clinical trials none of them suggested a negative effect of smoking cessation treatment on substance use outcomes using NRT. However, the studies used reliable methods and reported their cases properly, but the small number of studies reviewed for the systematic review makes the conclusion about the effectiveness of these interventions uncertain. The papers visibly stated how the trials protected against bias, as indicated by the Yes (low risk). No (high risk) and U as “unclear risk.” All four studies conducted a random sequence generation of participants enrolled into the study sample.


This special issue is devoted to the celebration of the century anniversary of Xiamen University (XMU) (6 April 2021) and the establishment of the LSA Editorial Office in Xiamen (3 July 2021), a collection to highlight the recent exciting research works performed in XMU or by XMU alumni, from all aspects of optics and photonics, including basic, applied and engineering research and applications. The guest editors are three XMU alumni who are active researchers in these areas: Professor Minghui Hong from National University of Singapore, Professor Zhongqun Tian and Professor Junyong Kang from XMU.1; (2) Development of mode-locked fibre lasers towards visible-wavelength2; (3) A new route for stress recording based on the Force-induced charge carrier storage effect in mechanoluminescence materials3; (4) Identification of unconventional host–guest complexation at nanostructured interface by surface-enhanced Raman spectroscopy4; (5) Quantification of electron accumulation at grain boundaries in perovskite polycrystalline films by correlative infrared-spectroscopic nanoimaging and Kelvin probe force microscopy5; (6) Improvement of detection in graphene/silicon heterojunction photodetectors through engineered tunnelling layer with enhanced impact ionization6; (7) Innovative approaches to determine the embedded electronic states at nanoscale interface via surface-sensitive photoemission spectroscopy7; (8) Development of AlGaN materials and optoelectronic devices that lead to the significant revolutions of solar-blind UV detection technology8; (9) Development of novel concepts and techniques in AlGaN-based LEDs for effectively controlling and tailoring the crucial properties of nitride quantum structures9; (10) Design of light-responsive and corrosion-resistant gas valve with non-thermal effective liquid-gating positional flow control10; (11) Design of nano/micro structures and macro-optical systems to enhance the detection sensitivity of surface-enhanced Raman and infrared spectroscopies11; (12) Demonstration of transmitting high-dimensional orbital angular momentum state at the single-photon level utilizing non-zero quantum discord12; (13) Development of hybrid laser processing technologies and their applications in the precision engineering of transparent hard materials13; (14) Demonstration of X-ray-charged bright persistent luminescence for multidimensional optical information storage by inkjet-printing NaYF4:Ln3+@NaYF4 nanoparticles14.XMU is a renowned university continuously featuring creativity and dedication. It was the first university established by an overseas Chinese (Mr. Tan Kah Kee) and has been selected for the “Double First-class Initiative” Scheme, as one of the leading pioneers in achieving China’s ambition of building world-class universities. XMU is also the first prestigious Chinese university to set up an overseas branch campus , which has been honoured as the “shinning pearl” of “Belt and Road Initiative”. Rooted in XMU, the motto “Pursue Excellence, Strive for Perfection”, has been widely extended to all over the world through more than 400,000 of XMU graduates. During the century-long growth, XMU has achieved significant progress in the field of optics and photonics and become pioneers in several aspects: Development of laser holography that greatly promoted the anti-counterfeiting technology in China; study of entangled photon pairs that lead to quantum communications and optical micromanipulations, as well as the creation of facial recognition techniques based on the light beams; Development of surface-enhanced Raman spectroscopy (SERS) that not only conquers the material and surface limits of SERS, but also realizes the fast detection of trace hazards in the field of food safety; Improvement of efficiency for light-emitting diodes (LEDs) via creative pathways, including deep ultraviolet LEDs and high colour rendering warm-white LEDs. Research scholars across different disciplines in XMU are working on optoelectronic materials and devices, with interests in the designs and syntheses of luminescent materials, quantum dots, electrochromic materials as well as their applications in solid-state lighting, emissive displays, sensing, smart windows and photovoltaic cells. Experiments based on synchrotron-radiation light source as well as other advanced techniques are combined with computations/simulations to deeper understand the composition-structure-property coupling mechanism of functional materials, providing guidelines for developing high-performance materials and optoelectronic devices. This collection features some recent representative achievements in optical and optoelectronic sciences and technologies, contributed by XMU scholars and alumni. The innovative reports include: (1) Enhancement of deep ultraviolet emission by regulating the orbital state couplingEnlightened by Light, Xiamen University, this 100-year-old university will become more elegant with greater academic excellence, especially in optics and photonics research.


The authors have demonstrated an exciting evolution of neoadjuvant chemotherapy (NAC) trends after radical cystectomy (RC) in the USA in the present study . During


We aim to investigate the effectiveness of repetitive Transcranial Magnetic Stimulation (rTMS) in reducing consumption and craving among patients with Substance Use Disorder (SUD) and comorbid depressive disorder.Dorsolateral prefrontal cortex (DLPFC) is greatly involved in SUD evolution (1). Research has turned to targeting this brain area with rTMS; a non-invasive brain stimulation technique that modulates cortical excitability by sending pulsatile electromagnetic fields through the skull and into the brain (2). rTMS is an FDA approved and safe treatment option for treatment-resistant depression (TRD) (3).Fifty-four patients were admitted over six-month period of time (June 2019- December 2019) to the inpatient unit of Erada center for treatment and rehabilitation of SUD in Dubai. All patients who fulfilled ICD-10 diagnoses of Depressive disorder and SUD were screened for further assessment.Positive drug screen was confirmed through urine analysis. Hospital Anxiety and Depression Scale (HADS) and Brief Substance Craving Scale (BSCS) were applied to all participants. Patients were contracted for 5-times weekly High frequency (10 Hz) rTMS for 4 weeks . Those who managed to complete their contracted TMS sessions were matched for age and sex with similar number of patients who received standard treatment as usual (TAU). Stimulation was as per FDA clearance for rTMS application in TRD.Eight patients were excluded (previous head trauma). A total of 46 patients had TMS mapping; nine of whom completed 20 sessions.Opioids was the most commonly used drug in almost 52% of patients (n = 14), followed by amphetamines in almost 30% (n = 8) and Cannabis in 18.5% (n = 5).Among those who completed 20 rTMS sessions; HADS scores on anxiety and depression fell by 85% and 78% respectively. BSCS score fell by 98%. Relapse rate (defined by positive drug screen) at 3 months was 33%.For those who completed 10 sessions; there was only 50% reduction on BSCS scores and 66% relapse rate. There were no data available on their HADS scores (only collected at baseline and at completion of 20 sessions).Those who only had TAU; there were no reduction in their BSCS (average score of 7 at both baseline and after 2 weeks).Our findings suggest that rTMS may be an effective and safe treatment for both depressive disorder and craving for SUD which is supported by other studies .Our study is probably the first of its kind within Middle East population with addiction problems.


CDHR1 alleles, and compare the associated phenotypes with previous reports.To describe the clinical and electrophysiological features of adult-onset macular dystrophy, due to novel combinations of CDHR1 were reviewed. Data analysed included best corrected visual acuity (BCVA), fundus images: autofluorescence (AF) and optical coherence tomography (OCT); full field electroretinography (ERG) and pattern ERG (PERG).The clinical records of patients with macular dystrophy and biallelic variants in CDHR1: p.(Gly188Ser), p.(Met1?), or p.; one patient was compound heterozygous for two previously unreported variants: c.297+1G>T in trans with p.(Pro735Thr). The range of BCVA at the last clinic review was (6/5–6/60). Autofluorescence showed macular flecks of increased AF in mild cases and patches of reduced AF in severe cases. The OCT showed attenuation of the ellipsoid zone (EZ) in mild cases and loss of the EZ and the outer nuclear layer in severe cases; one patient had subfoveal hyporeflective region between the EZ and the retinal pigment epithelium. The full field ERG was normal or borderline subnormal in all cases, and the PERG was subnormal in mild cases or undetectable in severe cases.Seven patients from six pedigrees were ascertained. One patient was homozygous for a known synonymous variant p.(Pro261=), four were compound heterozygous for the p.(Pro261=) variant and a novel allele of This report corroborates previous observations that genotypes distinct from those causing pan-retinal dystrophy can cause a milder phenotype, predominantly affecting the macula, and expands the spectrum of these genotypes. The findings in this cohort suggest a potential macular susceptibility to mild perturbations of the photoreceptor cadherin. CDHR1—OMIM 609502) is a transmembrane protein, expressed at the base of the rod and cone outer segments, and maintains outer segment structure , has been associated with adult-onset macular dystrophy.The present study corroborates the association between the p.[Pro261=] variant and macular dystrophy and presents novel alleles associated with the macular dystrophy phenotype.Our study adds CDHR1 to the list of candidate genes to screen in patients with likely autosomal recessive macular dystrophy.Figure S1_legendFigure S1


Although potential anticancer activities of benzimidazole-based anthelmintic drugs have been approved by preclinical and clinical studies, modes of binding interactions have not been reported so far. Therefore, in this study, we aimed to propose binding interactions of some benzimidazole-based anthelmintics with one of the most important cancer targets (Tubulin protein). Studied drugs were selected based on their structural similarity with the cocrystallized ligand (Nocodazole) with tubulin protein. Quantum mechanics calculations were also employed for characterization of electronic configuration of studied drugs at the atomic and molecular level. Order of binding affinities of tested benzimidazole drugs toward colchicine binding site on tubulin protein is as follows: Flubendazole > Oxfendazole > Nocodazole > Mebendazole > Albendazole > Oxibendazole > Fenbendazole > Ciclobendazole > Thiabendazole > Bendazole. By analyzing binding mode and hydrogen bond length between the nine studied benzimidazole drugs and colchicine binding site, Flubendazole was found to bind more efficiently with tubulin protein than other benzimidazole derivatives. The quantum mechanics studies showed that the electron density of HOMO of Flubendazole and Mebendazole together with their MEP map are quite similar to that of Nocodazole which is also consistent with the calculated binding affinities. Our study has ramifications for considering the repurposing of Flubendazole as a promising anticancer candidate. Microtubules play a key role in the invasion and metastatic spread of tumor cells, depending on its crucial roles in mitosis, signaling, trafficking, proliferation, and migration of eukaryotic cells . Drugs tThe success rate for new anticancer drugs from Phase I trial to commercial use by FDA approval is estimated to be around 6.7% from 2003 to 2011, taking about 8.3 years as an average . The ovede novo drug compounds and constitutes nowadays 30% of the newly marked drugs in the United States  . DespiteIn vitro and in vivo studies revealed the potential of some members of benzimidazole anthelmintic drugs to suppress tumor progress through inhibition of multiple biological targets such as tubulin polymerization and angiogenesis (Benzimidazole anthelmintic drugs having over 40 years of safe use as over the counter medications . They arogenesis .Nocodazole (NZO) is a benzimidazole-based experimental drug targeting both protein kinases and microtubules. It is used as a lead compound for the discovery of novel CBSIs . In thishttps://pubchem.ncbi.nlm.nih.gov/). The nine tested compounds underwent energy minimization after examining the structure and the formal charges on atoms using a 2D depiction model. The partial charges were also automatically calculated. Structure of the co-crystallized NZO obtained from two subunits of the target tubulin protein (B and D subunits) and the nine tested benzimidazole drugs were imported together in the same database and saved in the form of MDB file to be docked in two separate processes for each subunit pocket, B and D, respectively.Docking studies using the Molecular Operating Environment (MOE) software package  were perhttp://www.rcsb.org/). All steps for the preparation of the target protein for docking calculations were done. The addition of hydrogen atoms with their standard 3D geometry to the system, automatic correction to check for any errors in the connections and types of atoms, and fixation of the potential of the receptor were also performed. The selection of the same active site of co-crystallized inhibitor in the protein structure was done by using Site Finder where dummy atoms were created at the same binding site of the pocket.The X-ray structure for tubulin protein (PDB: 5CA1) complexed with the native NZO was obtained from the Protein Data Bank  were used to approximately describe the polarity of colchicine binding pocket. All simulations were performed using GAUSSIAN 09 Revision C.01  based Becke’s three-parameters Lee-Yang-Parr hybrid functional (B3LYP)  was emplion C.01  on Swinb2O616). Hydrophobic interactions were also observed between Leu253 and the benzene and imidazole moieties. The 2D graphic views of binding interactions between studied benzimidazole ligands and NZO with the target protein are deposited in Crystallographic data of co-crystallized NZO complexed with tubulin protein (PDB: 5CA1) revealed the existence of two binding sites for NZO inside the protein, subunits B and D, respectively. It was obvious that subunit D is larger than subunit B in size. By analyzing the binding modes (3D graphic views) of NZO inside the two subunits , it was By studying the binding site in both B and D subunits, it was concluded that the crucial amino acids for binding interactions between CBSIs and the two subunits are Glu198 and Val236, besides Asn165 for B subunit and Cys239 for D subunit. The refined NZO was also docked among other studied benzimidazole drugs into subunits B and D to validate the molecular dynamic model used in conducting the current study. For the B subunit, the docked NZO showed almost a fingerprint binding mode as the original co-crystallized one. Interestingly, loss of binding interactions between the oxygen atom of its carbonyl group and Cys239 was also noticed. Furthermore, as expected, the binding interaction between N (3)-benzimidazole and Glu198 was lost in two subunits (B and D) as a result of using the neutral form of refined NZO in contrary to the protonated form of native NZO. The other nine benzimidazole drugs were refined and docked into NZO binding pocket subunits (B and D), respectively. Results revealed that all of the tested drugs, except for Thiabendazole (8) and Bendazole (9) members, showed very similar binding modes to the native NZO due to the great structural similarity. Regarding B subunit, Flubendazole (5) showed a nearly similar fingerprint binding mode compared to the native and docked forms of NZO. Concerning D subunit, surprisingly, Albendazole (2), Ciclobendazole (3), Flubendazole (5), and Oxfendazole (7) showed the binding interaction with Cys239 similar to the native NZO which was lost in the docked NZO itself. Especially Ciclobendazole (3) and Oxfendazole (7) showed a fingerprint binding interaction with Cys239 with the same direct and indirect pathways. It was concluded that Flubendazole (5) showed the highest similarity in binding modes compared to the native NZO in both B and D subunits of protein pocket. Furthermore, Thiabendazole (8) and Bendazole (9) lost some of the binding interactions compared to the native NZO due to the differences in the structure of side chains of their benzimidazole moieties but maintained the binding interactions with both Val236 and Asn165. By reviewing molecular dynamics scoring and other parameters listed in 2O616) calculated at 3.14 Å which is comparable to the same bond formed at 2.70 Å by the native NZO.Another confirmatory tool for validating the binding interactions between the tested ligands and the target protein is through measuring the lengths of H-bonds involved. By representing the 3D filling positions of our tested compounds inside the deep protein pockets of two subunits B and D compared to the co-crystallized inhibitor, we observed a very close similarity between all in each subunit confirming the same binding mode and structural similarity between them as shown in Moreover, the large size of the two pockets of subunits B and D, especially D subunit, gives us an idea about the possible drug modifications especially at the side chain of thiophene ring of NZO to obtain larger compounds that can occupy the binding pockets more efficiently maintaining the same essential binding interactions with the crucial amino acids and at the same time forming extra binding ones for better inhibition.It is well known that outermost electrons are those involved in the binding interaction between a ligand and target protein, we therefore, computed the electron density of the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), and the molecular electrostatic potential (MEP) map. Figures of the electron density distribution of HOMO, LUMO, and MEP are depicted in The electron density of HOMO in NZO was found to be localized mainly on benzimidazole moiety, while the electron density of LUMO was solely localized on the thiophene side chain. The electron density of HOMO and LUMO of all other studied drugs are delocalized except for Mebendazole (1), Fenbendazole (4), and Flubendazole (5) in the case of HOMO and Oxibendazole (6) in case of LUMO. The electron density of HOMO of Mebendazole (1) and Flubendazole (5) is quite similar to that of NZO which is consistent with the calculated binding affinities [Flubendazole (5) > Oxfendazole (7) > NZO (docked) > Mebendazole (1)]. Despite of this consistency, the binding affinity does not solely depend on the energies and the electronic density distribution of HOMO and LUMO, but also on other determinants such as hydrogen bonding, electrostatic interactions, hydrophobic and Van der Waals forces and presence of clusters of water. We also noted that the electrons of HOMO are localized mainly on the benzene moiety and the aromatic side chain of Fenbendazole 4) in a different pattern to that observed with NZO.The MEP maps of all studied compounds revealed that one of benzimidazole nitrogen acts as an electron donating site capable of forming H-bond with amino acids in colchicine binding sites. Whereas the other benzimidazolyl nitrogen is electrophilic moiety acting as H-donor group. Interestingly, the MEP map of Mebendazole (1), Albendazole (2) and Flubendazole (5) are quite similar which is also consistent with the calculated binding affinities, where Flubendazole (5) > Oxfendazole (7) > NZO (docked) > Mebendazole (1) > Albendazole (2) > Oxibendazole (6) > Fenbendazole (4) > Ciclobendazole (3) > Thiabendazole (8) > Bendazole (9). Lack of 5 (6) substitution on the benzimidazole pharmacophoric group leads to a significant change in the MEP of Thiabendazole and Bendazole. Weaker binding affinities of these two drugs can be ascribed to the change in electronic configuration due to the absence of 5 (6) substitution.Among the nine tested members of benzimidazole anthelmintic drugs, Flubendazole (5) exhibits the most similar binding interactions, scoring, electron density distribution, and electrostatic map to that reported for NZO in tubulin protein (PDB: 5CA1). This suggests that Flubendazole (5) would be the most active member exerting antitumor activity mainly at CBS. At the same time, more structural modifications are required for FDA approved benzimidazole anthelmintic drugs and the original NZO inhibitor to obtain larger compounds with better fitting and binding modes inside the two large pockets of subunits B and D respectively.


This Correction follows an Expression of Concern relating to this article previously published by Portland Press.Fragaria ananassa methanolic extract in a rat model of cadmium chloride-induced neurotoxicity” (Biosci Rep (2018) 38(6), DOI: 10.1042/BSR20180861) would like to correct The authors of the original article “Protective effects of The authors have stated that the overlapping images had been selected from the same group in error, and further confirm that this error does not affect the conclusions of their study. The correct version of


An increasing number of people are affected by various neurodegenerative diseases each year, impacting the quality of life of millions of people worldwide. However, considerable knowledge gaps in the mechanistic understanding of these diseases present a challenge to address this threat to human life successfully. Recent endeavors in basic research, clinical trials, and other research areas have provided vital insights to discover novel biomarkers for improved diagnosis and better treatment options for patients suffering from such diseases. Articles published as part of the Special Issue “Biomarkers in Neurodegenerative Diseases” highlight the recent advances in this field and emerging strategies to counter such diseases in the future.Three research articles published in the Special Issue focused on molecular mechanisms involving Alzheimer’s disease (AD). First, Paik et al. used human SH-SY5Y neuroblastoma cells to show the neuroprotective role of Somatostatin-14 (SST). The possible mechanism involves the ability of SST to regulate the intracellular calcium levels and Collapsin Response Mediator Protein 2 (CRMP2) phosphorylation . NaturalKessler and others show a correlation between dysregulation of Monopolar Spindle 1 Kinase (MPS1) and tumor aggressiveness in glioblastoma multiforme (GBM) patients . The resOne key aspect of neurologic disorders includes complications arising from traumatic brain injuries (TBIs). In this regard, Alam et al. investigated the role of quinpirole in dopamine D2 receptor (D2R) activation using a mouse model simulating TBI . This stFulgenzi et al. provide an excellent update in the investigation of chelation therapy involving EDTA as a potential treatment for neurologic disorders. They studied more than 300 patients from a broad age group to monitor their toxic metal burdens before and after receiving EDTA as part of the therapy . InformaOne of the critical challenges for better treatment outcomes is correctly identifying the causes behind indicators of different neurologic conditions. Chien and coworkers used an artificial neural network to distinguish between dopamine transporter single-photon emission computed tomography (DAT-SPECT) images obtained from patients with Parkinson’s disease or parkinsonism resulting from other illnesses with high (more than 80%) accuracy .Apart from these original research papers, the Special Issue also contains an excellent collection of review articles highlighting recent progress, challenges, and future directions in the field. For example, the review articles published by Jacopo Meldolesi and Bălașa et al. are excellent resources summarizing the significant advances made in fluid and imaging biomarkers for the early detection of neurodegenerative disorders in recent times ,9. The aI hope that these excellent research works and review articles published as part of the Special Issue will provide an invaluable reference for further research to counter the menaces posed by neurologic disorders in the future.


The presence of 2 ventricular signals caused by structures near the His bundle region is rare. Some associative and dissociative maneuvers for dissociating a certain electrical signal from others of known origin are used to ascertain the source of an unknown potential. Figure 1 was obtained. The arrow points to a signal after the ventricular potential on the His-bundle (HB) catheter that was consistently seen in sinus rhythm . What could be the origin of this second unexpected potential?A 64-year-old man with recurrent episodes of wide QRS tachycardia with the absence of overt structural heart disease underwent an electrophysiological evaluation. An echocardiogram showed mildly depressed left ventricular function. During an electrophysiological study, the electrogram in 2 A wide range of diagnoses are possible, including (1) intermittent accessory pathway (AP) conduction with an antegrade 2-for-1 phenomenon, (2) intermittent fused premature ventricular complexes (PVCs) arising from the diseased tissue near the HB region, (3) intermittent right bundle ectopy, (4) intermittent nodoventricular (NV) conduction, (5) intermittent atriofascicular (Mahaim fiber) conduction, (6) fragmented ventricular potential, or (7) basal septal or periaortic ventricular late potentials and local abnormal ventricular activities (LAVAs).3 Mahaim fibers or the NV pathway may also produce a second HB deflection after the ventricular potential on the HB catheter because of the retrograde conduction of the right bundle.2 Other antegrade-conducting unusual AP connections from the right atrial appendage to the right ventricular outflow tract may also cause complex signals on the HB catheter. A 2-for-1 phenomenon can occur when the atrial impulse simultaneously travels down the AP (activating the annular ventricular myocardium) and the atrioventricular node (AVN) and the HB . Afterward, the ventricular activation wavefront may travel back toward the base .1The presence of 2 ventricular signals caused by structures near the HB region is rare.5 The atrial extra-stimulus testing might give us some important clues. The timing of the extra potential is expected to correlate with either the degree of pre-excitation or the amount of fusion (if a PVC or fascicular beat occurs). If the candidate signal is ventricular or otherwise associated with pre-excitation , then causing a delay to signal activation would cause less pre-excitation.2 In the current case, there was a delay from the atrial signal to both the HB and the candidate potential without a change in the degree of pre-excitation an atrial extra-stimulus beat  that showed more decrement in conduction down the AVN. A relatively fixed relationship was seen with V to this potential (single arrows), with a further delay with S2 (double arrow) in activating the tissue responsible for the extra (unexplained) potential. However, it would be difficult to explain the phenomenon via the effects of atrial pacing with a Mahaim fiber.2 For this to occur, a very similar decrement in conduction down the Mahaim fiber and the AVN is needed. The delay to the extra potential despite AH prolongation excluded all AP-related diagnostic possibilities in the current case, including NV pathways.8 Electroanatomic mapping revealed periaortic fibrosis that was consistent with this unusual potential , and then 4 different ventricular tachycardia (VT) morphologies were induced .Some associative and dissociative maneuvers for dissociating a certain electrical signal from others of known origin are used to ascertain the source of an unknown potential.11 These VTs from small regions of the periaortic scar can mimic idiopathic VT but are suggested by multiple VT morphologies .12 Several methods have been studied to invoke dynamic substrate changes in critical regions to target ablation, including decrement-evoked potential mapping,5 which involves a drivetrain and an S2 pacing protocol identifying sites of decremental LAVAs. This small periaortic site was then targeted for radiofrequency ablation . During ablation, the amplitude of this potential decreased, and all VT morphologies were no longer seen. Electrophysiologists must have a thorough understanding of how unexplained potentials can be analyzed using pacing maneuvers and by observing changes of association and dissociation that occur between these unknown signals and other known potentials .1 These techniques are useful in identifying the culprit sites and targets for ablation for several arrhythmias.2Periaortic fibrosis is increasingly recognized as a distinct clinical substrate for scar-related VT in the presence and absence of overt structural heart disease.


From th studies .Medline (Pubmed) search using the following: “vascularization maxillary sinus cadavers”, completed with the revision of the bibliographical references of the selected articles in order to identify further relevant studies. Inclusion criteria: (1) Published between 2008 and 2015. (2) Cadaver Studies. (3) Studies that evaluate the position of the anatomical position of the anastomosis between arterial branches of the posterior superior alveolar artery and the infraorbitary artery. Exclusion Criteria: (1) Non cadaveric studies. (2) Foetal and paediatric studies.Eight articles were selected.The vascular anastomosis is frequently found in the lateral wall of the maxillary sinus. Its position and depth are variable, as well as its trajectory and morphology. Pre-surgical determination of its precise anatomical variations is of the utmost importance to avoid vascular damage and complications during external sinus lifts osteotomies.


The temporomandibular disorders (TMD) are one of the main concerns regarding orofacial pathologies and there are an ascending number of cases. They are characterised as a group of pathological conditions that may affect the temporomandibular joint (TMJ), the masticatory musculature and/or other adjacent anatomical structures, leading to pain and dysfunction . The mulA 24-year-old female patient with a history of temporomandibular disorder and bruxism she presented an non-assisted mouth opening (UMO) of 28 mm and an assisted mouth opening with pain in the masseter and TMJ bilaterally of 29 mm, after the clinical assessment with the DC/TMD protocol we arrived at a diagnosis of disc displacement without reduction (DDwR) with limited opening, degenerative joint disease in the left TMJ, arthralgia (II), myofascial pain (III) in the masseter with pain referred to other anatomical regions. All the assumptions of the Helsinki Declaration have been fulfilled and an informed consent for clinical case of Clinica Dentária Egas Moniz approved by the ethic commission of Instituto Universitário Egas Moniz. The treatment plan consisted of cognitive behavioural therapy (CBT), prescription of muscle relaxants, occlusal splint especially for reduction of overload due to bruxism, infiltration with 1 ml of hyaluronic acid of high molecular weight in the TMJ bilaterally followed by articular mobilisation techniques and neuromuscular and myofascial techniques. The patient was instructed to continue with the physiotherapy.The follow up was made 2 months after with 8 sessions of physiotherapy and 1 more hyaluronic acid infiltration bilaterally as protocoled session, we could observe an absence of temporomandibular joint pain, UMO of 42 mm, decreased crepitation, decreased intensity of myofascial pain (I) and (DDwR) without limited opening.The multidisciplinary dentist-physiotherapist team combines inputs from different professions with the aim of promoting the best patient care and represents an added value for the management of the signs/symptoms of patients with temporomandibular dysfunction.


Health and social care providers are ill-equipped to address the complex needs of individuals growing older with IDD and their families when dementia is suspected or diagnosed. Addressing the growing need for professionals to acquire practical diagnostic, treatment, and management methods requires an interorganizational and interprofessional approach. A consortium of aging and IDD organizations developed a successful Project ECHO  model to create a virtual community of practice connecting a hub team and participating spoke sites. This paper reviews reasons for the model’s success, including: (1) curriculum providing practical solutions to complex problems, (2) integration of interprofessional team approach, (3) “all teach, all learn” model promoting sharing among participants, and (4) the inclusion of case studies engaging participants in developing solutions and strategies to improve the quality of life of clients and families. Implications of this model and recommendations for future professional educational programs are presented.


For people living with HIV, there are multiple barriers to engagement with care. This study qualitatively examines the role of use of alcohol and other drugs (AOD) on the health and management of Human Immunodeficiency Virus (HIV) disease among older African Americans (≥50 years). It draws on interviews conducted with twenty-seven older African Americans living with HIV in the Louisville, Kentucky area. Interviews were transcribed verbatim and then analyzed using constructivist grounded theory analytic techniques. Participants’ understandings of their AOD use fell on a continuum of problematic use to use for self-care. Regardless of where participants fell on this continuum, they faced a) environmental impacts of AOD use and b) current or historic discrimination from the health care system. The analysis focused on gaining a deeper understanding of the intersection of AOD use and engagement in the HIV care continuum. This revealed six major phases, which occurred at various stages of the continuum: (1) Linking AOD use as the cause of HIV diagnosis (2) Having AOD use facilitate denial of HIV, (3) Experiencing problematic use, (4) “Testing the Waters,” (5) Relying on AIDS Service Organizations (ASO) and medical providers and (6) Maintaining health and/or using AOD for self-care. We discuss the ways that stigma along the lines of race, gender, and age intersect with co-occurring conditions such as substance use disorders in complex and multifaceted ways. Recommendations include assessing a patients’ AOD use in relationship to the HIV care continuum to assess patients’ experiences and barriers within systems of care.


Following publication of the original article , the autThe incorrect author name is:Chayma (given name) Saheli (family name)The correct author name is:Sahli (given name) Chaima (family name)The author group has been updated above and the original article  has been


Dear Editor,Our immune gene model is of great help to predict the prognosis of colon cancer patients. The model genes could be used as prognostic markers and potential new targets for colon cancer patients.Colon cancer is a common tumor with high incidence worldwide.Different genes were analyzed by colon cancer data from TCGA database, and immune‐related genes were extracted. The immune differential genes were combined with the clinical data, and the model was constructed and evaluated. The model genes were enriched and analyzed. Single‐cell expression data of model genes were extracted, grouped according to the amount of each gene expression, and the percentage of infiltration of each cell phenotype in different groups was observed. The model genes were compared with immune checkpoints and immune cells. Analyzing the relationship between the key genes of the model and clinical information and using HPA database to verify model genes.Three hundred ninety‐six immune differential genes were screened, and the corresponding heatmap and volcanic maps were plotted  Correlation analysis between the expression of model gene CD19 and patient age. (B) Correlation analysis between model gene expression and tumor anatomical location. (C) Correlation analysis between model gene expression and occurrence of mismatch repair. (D ) Correlation analysis between the expression of model gene UCN and the occurrence of lymphatic invasion. (E) Correlation analysis between the expression of model gene and the occurrence of microsatellite instability. (F) Correlation analysis between model gene expression and tumor TNM staging. (G) Correlation analysis between model gene expression and lymphatic metastasis. (H) Correlation analysis between model gene expression and distant metastasis. (I) Correlation analysis between model gene expression and clinical stage of patients. (J) Correlation analysis between CD3E gene expression and tumor recurrence after treatment. (K) Correlation analysis between UCN gene expression and initial treatment effect. (L) The expression of prognostic‐related immune differential genes in colon cancer tumor tissues and normal tissuesClick here for additional data file.


The application of femtosecond lasers in ophthalmology has enabled precise and reproducible tissue cutting, which is expected to improve the outcomes of surgical treatment, particularly in anterior segment surgeries such as cornea, cataract, and refractive surgery.As we have introduced in the call for papers for this Special Issue, the articles published cover topics focused on the application of femtosecond lasers in anterior segment surgery, including the development of the technologies behind femtosecond lasers and their application in ophthalmic surgery, the efficacy and safety of anterior segment surgery using femtosecond lasers, and imaging techniques associated with the application of femtosecond lasers.Femtosecond lasers have been increasingly used in cornea and refractive surgery. The laser can be used to create customized trephination edges for deep anterior lamellar keratoplasty and penetrating keratoplasty and for allowing ultrathin cut for Descemet stripping automated anterior lamellar keratoplasty. It can also be helpful for improving the consistency and reproducibility of refractive surgery, including laser-assisted in situ keratomileusis (LASIK), small incision lenticule extraction (SMILE), intrastromal corneal ring segment implantation, and astigmatic keratotomy.Femtosecond laser cataract surgery (FLACS), in which a femtosecond laser is employed for corneal incision, anterior capsulotomy, lens fragmentation, and liquefaction, is also expected to improve the reproducibility and safety of cataract surgery. In this Special Issue, the authors contributed 10 original papers and one review article regarding the use of femtosecond lasers in anterior segment surgery.The authors have reported the results of their research on various topics related to femtosecond lasers in anterior segment surgery: (1) extrusion of femtosecond laser-implanted intrastromal corneal ring segments in keratoconic eyes: prevalence, risk factors, and clinical outcomes; (2) clinical observation of silicon hydrogel contact lens fitted immediately after SMILE; (3) preliminary results of a novel standardized technique of femtosecond laser-assisted deep anterior lamellar keratoplasty for keratoconus; (4) long-term evaluation of capsulotomy shape and posterior capsule opacification after low-energy bimanual femtosecond laser-assisted cataract surgery; (5) anatomical and visual outcomes after LASIK performed in myopic eyes with the WaveLight® refractive suite ; (6) correlation analysis of refractive and visual quality after wavefront-optimized laser in situ keratomileusis for 50% and 100% angle kappa compensation; (7) comparison of femtosecond laser-assisted cataract surgery and conventional phacoemulsification in shallow anterior chambers and glaucoma; (8) characteristics of facial asymmetry in congenital superior oblique palsy according to trochlear nerve absence; (9) a modified femtosecond laser technique for anterior capsule contraction syndrome; and (10) evaluation of astigmatic correction using a vector analysis after combined femtosecond laser-assisted phacoemulsification and intrastromal arcuate keratotomy. This Special Issue also includes one review article on the application of femtosecond lasers in anterior segment surgery.We believe these papers will provide readers with valuable information on the application of femtosecond lasers in anterior segment surgery and new ideas for research on related topics.


The COVID-19 pandemic has renewed interest in endemic human coronaviruses (HCoV), which are responsible for an estimated 5-10% of acute respiratory infections (ARI) in temperate climate zones A total of 4,375 specimens from children and adults, who had presented with acute respiratory symptoms to a sentinel physician between October 2019 and September 2020, were examined by qPCR see . EndemicBB wrote the manuscript with support from DYO and RD; BB is responsible for data acquisiton; BB and DYO analysed the data; RD is responsible for the virological section of the sentinel system; TW and RD supervised the project.The authors declare that no competing interests exist.


Typhoid fever, also known as typhoid, is a life-threatening bacterial infection that remains a global health concern. The infection is associated with a significant morbidity and mortality rate, resulting in an urgent need for specific and rapid detection tests to aid prevention and management of the disease. The present review aims to assess the specificity and sensitivity of the available literature on the immunodiagnostics of typhoid fever. A literature search was conducted using three databases  and manual searches through the references of identified full texts to retrieve relevant literature published between 1 January 2011 and 31 December 2020. Of the 577 studies identified in our search, 12 were included in further analysis. Lipopolysaccharides (LPS) and hemolysin E (HlyE) were the most frequently studied antigens. The specimens examined in these studies included serum and saliva. Using blood culture as the gold standard, anti-LPS IgA gave the highest sensitivity of 96% (95% CI: 93–99) and specificity of 96% (95% CI: 93–99) for distinguishing between typhoid cases and healthy controls, whereas the combination of anti-LPS and anti-flagellin total IgGAM gave the highest sensitivity of 93% (95% CI: 86–99) and specificity of 95% (95% CI: 89–100) for distinguishing typhoid cases and other febrile infections. A comparably high sensitivity of 92% (95% CI: 86–98) and specificity of 89% (95% CI: 78–100) were shown in testing based on detection of the combination of anti-LPS (IgA and IgM) and anti-HlyE IgG as well as a slightly lower sensitivity of 91% (95% CI: 74–100) in the case of anti-50kDa IgA. Anti-50kDa IgM had the lowest sensitivity of 36% (95% CI: 6–65) against both healthy and febrile controls. The development of a rapid diagnostic test targeting antibodies against lipopolysaccharides combined with flagellin appeared to be a suitable approach for the rapid detection test of typhoid fever. Saliva is added benefit for rapid typhoid diagnosis since it is less invasive. As a result, further studies could be done to develop additional approaches for adopting such samples. Salmonella enterica serovar Typhi (S. Typhi). The life-threatening disease has been a public health problem in developing and underdeveloped countries for generations. A systematic analysis by typhoid and paratyphoid collaborators estimated that 10.9 million cases of typhoid fever occurred globally in 2017, resulting in 116.8 thousand deaths  AND [“antigen” OR “antibody”] AND [“diagnosis” OR diagnostic”] AND [“specificity” OR “sensitivity”]. An additional search was conducted by manually screening the references of the retrieved literature.The literature search was conducted in January 2021 according to the modified preferred reporting items for systematic reviews and meta-analyses guidelines . The seaArticles were excluded if (i) the studies were published before 1 January 2011, or after 31 December 2020; (ii) the studies were published in languages other than English or Malay; (iii) the studies did not mention the types of antigens used. We limit the studies to post 2011 (10 years) as the older literatures are not relevance to represent current diagnostic performance of the newly developed assays. Only studies that analyzed samples of at least two groups consisting of healthy controls and typhoid patients confirmed by positive blood culture were included in this systematic review. The retrieved literature was downloaded into Mendeley reference manager and duplicates were identified and removed. The references were distributed to four authors, who independently reviewed the titles and abstracts. A satisfactory agreement for the screening process was assessed between the reviewers. All four reviewers performed full-text screening and summarized the findings. Data from the selected sources were collated and summarized using a standard charting table consisting of six domains: (i) detection assays; (ii) biomarker; (iii) biological specimens; (iv) sample size; (v) specificity and sensitivity; (vi) year of publication.The number of true positives (TF), true negatives (TN), false positives (FP) and false negatives (FN) was independently retrieved from each article by three investigators and entered into an Excel datasheet. Discordant findings were assessed through discussion and when in doubt, the authors sought verification. Using blood culture as the reference standard, we calculated the sensitivity and specificity for each of the studied biomarker. Sensitivity was calculated by dividing the number of true positive outcomes with the sum of true positive and false negative outcomes. Specificity was calculated by dividing the number of true negative outcomes with the sum of true negative and false positive outcomes. Performance comparison of the immunodiagnostic assays was presented using forest plots based on control groups.The risk of bias for all included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool . The QUAThe present systematic review provides an overview of the performance of immunodiagnostic tests for typhoid fever and found that tests based on anti-LPS in combination with anti-flagellin offered the best diagnostic performance for the diagnosis of typhoid fever and that anti-HlyE could be an alternative option with a performance comparable to that of anti-LPS. Our results highlight the limitations of the ongoing immunodiagnostic development and provide baseline information for future studies to select appropriate biomarkers in the development of RDTs for typhoid fever. Based on the good performance of anti-LPS and anti-HlyE, these two antigens appear to be suitable options for the development of future POCTs for typhoid fever. The currently low number of studies using saliva samples for detection suggests that more studies could explore the development of alternative approaches implementing such samples, which have the advantages of less invasive sample collection, which would help to boost accessibility and facilitate efficient testing in a community, especially during a disease outbreak and in areas where access to laboratory-based testing is not available.


This study aimed to assess the impact that the COVID-19 pandemic has had on the Hertfordshire Community Perinatal Team (CPT) group interventions and the innovations made.The CPT is a multidisciplinary mental health service that runs three groups: Circle of Security (CoS), Emotional Coping Skills (ECS) and a peer support group - Wellbeing and Lifestyle. The service has received an increase in referrals during the COVID-19 pandemic.Methods: Team member and client semi structured interviews were conducted with answers transcribed in real time and analysed. Patient clinical records were accessed via PARIS and analysed in order to identify patient demographics within each group and whether these had changed during the pandemic. Clinical outcome measures and client feedback were evaluated to see whether the change in groups is impacting their clinical effectiveness.Results: Innovations made by the CPT include: groups becoming virtual, launching of the new Circle of Security Group which helps women tackle the ‘Ghosts in the Nursery’ and strengthen maternal bonds, restructuring existing groups, breakout room forums and incorporating communication platform apps such as Whatsapp. The Wellbeing and Lifestyle Group increased in size and reach (7 women from 7 areas in 2019 vs 12 women from 12 areas in 2021) with an increased retention rate (71% in 2019 vs 100% in 2021) and a decreased attrition rate (29% in 2019 to 0% in 2021). The Emotional Coping Skills group experienced similar changes (10 areas represented in 2019 vs 15 different areas in 2021) with an increased retention rate (58% in 2019 vs 100% in 2021) and decreased attrition rate (42% in 2019 vs 0% in 2021).The Hertfordshire Community Perinatal Team has responded to the pandemic by innovating existing groups and creating new forums; many of which will continue on even after the pandemic ceases. The groups have acted as a lifeline for women breaking up the monotony and isolation of lockdown life and providing an invaluable space for women to be heard.


Despite two decades of palliative care services, there remains numerous barriers to patient and caregiver use of palliative care. For many years, policymakers believed lack of funding for palliative care was the primary obstacle to accessing palliative care services. In 2017, we undertook a randomized controlled trial to test the effectiveness of a home-based palliative care (HBPC) program within accountable care organizations and in partnership with an insurance company that covered the cost of HBPC. After 20 months, we had recruited just 28 patients. This symposium will: (1) describe outcomes from various approaches undertaken to engage primary care physicians and recruit patients and their caregivers into this trial; (2) present barriers to HBPC referral identified from a qualitative study of primary care physicians; (3) present findings from a qualitative study of patient- and caregiver-identified barriers to HBPC; (4) describe physician and patient barriers to research participation; and (5) discuss implications of these findings for researchers and healthcare providers. Information presented in this symposium will inform researchers and policy makers about challenges and facilitators to recruiting patients, caregivers, and physicians to participate in research studies as well as inform healthcare practitioners of potential obstacles to increasing patient access to HBPC.


Insomnia and obstructive sleep apnea (OSA) are two prevalent sleep disorders which share nocturnal sleep disturbances, impairments to daytime activity and quality of life, and high healthcare and social costs. The treatment of both disorders is often limited by the relatively low acceptance or long-term adherence to cognitive and behavioral therapy for insomnia (CBTi) or continuous positive airway pressure (CPAP) therapy, respectively.Unsurprisingly, the review published by Sweetman et al.  on comor(1)Refine the diagnosis and measurement of COMISA to assess both the independent and the shared symptoms of insomnia and OSA disorder.(2)Investigate the potential bi-directional relationships in COMISA in order to identify the predictors of the greatest response to insomnia or OSA treatments.(3)Examine the efficacy of the combined treatments for COMISA, administering both cognitive and behavioral therapy for insomnia (CBTi) and continuous positive airway pressure (CPAP) therapy.(4)Explore the mechanism(s) underlying the relationship between obstructive sleep apnea and insomnia.(5)Define the role of circadian rhythms in COMISA.(6)Clarify the moderating role of sex, race, age, and regional differences.(7)Assess the clinical evolution of insomnia during OSA treatments.Based upon recent randomized controlled trials, some issues that should be considered in the future research agenda include :(1)RefinCo-morbid insomnia and sleep apnea (COMISA) represent a clear model of bi-directional relationships between two different disorders. The review by Sweetman et al.  is able


When a trainee is unable to advance the tip of the tracheal tube through the vocal cords and the patient's pulse oximeter signals declining oxygen saturation (SpOThis oxygenation technique has proved consistently successful provided (1) the ETT tip is immediately supraglottic (retro-epiglottic) and (2) glottic closure (laryngospasm) has been prevented by prior administration of a muscle relaxant drug.In the late 1990s, members of our department began employing NLPAWS to ventilate adult patients (following anesthetic induction or cardiac arrest) via an orally inserted tracheal tube when PPV could not be administered because of a large leak at the facemask-skin interface. Such occurrences most often resulted from (1) the patient having a full beard or sunken cheeks, (2) the anesthetist having small hands or a lack of experience, or (3) use of a missized facemask .1 In approximately 20% of these cases, however, PPV failed because of airway obstruction (not air leak). A solution to this problem was found to be using a laryngoscope to guide the ETT tip to the same immediately supraglottic position that had always been a part of NLPAWS use during nasotracheal intubation.2 Two advantages of this technique of rescue ventilation compared to similar use of a laryngeal mask airway (LMA) are (1) faster access to an ETT and (2) suitability of almost any ETT size.At first, we used NLPAWS to permit ventilation through an oral ETT inserted a distance approximating the length of an appropriately sized oral airway.2 and PEEP 20 cm H2O) to reverse a rapid decline in blood oxygenation (SpO2 88% → 42%) and elevate it to 58% during the time required for a replacement ETT to be brought to the patient's negative-pressure intensive care unit room.Very recently, members of our department have learned to use NLPAWS to enable PPV (1) in the presence of a leaking LMA (5 cases); (2) via a nasal airway fitted with an ETT adaptor during upper GI endoscopy ; and (3) via a correctly inserted ETT (4 cases). In 3 cases in the last category, the problem was simply that that the air syringe reserved for inflating the ETT cuff had been misplaced. In the fourth case, however, NLPAWS use may have been lifesaving. ETT cuff rupture occurred (probably from contact with a prominent incisor) during intubation of a patient with severe COVID-19 pneumonia. NLPAWS enabled sufficient Ambu ventilation (100% OWe are not aware of any instance of gastric aspiration occurring during NLPAWS use by a member of our department. Risk of this complication may be similar to risks associated with PPV performed using a facemask plus oral airway.


Inflammation is originated by tissue injury and triggers several biochemical reactions that sensitize the nervous system for pain perception. Chronic inflammation induces adaptive changes that can cause altered pain signal processes. Indeed, inflammatory mediators provokes structural and functional changes in the peripheral or central sensory circuits, resulting in pain like behaviors, such as hyperalgesia, allodynia, and spontaneous pain. Accumulating evidence suggests that central sensitization is driven by neuroinflammatory processes mediated by activation/proliferation of resident microglia and glial cells with the consequent release of inflammatory mediators; furthermore, several recent studies are relating the role of non-neuronal cells of the peripheral nervous system with the modulation of neuroinflammation involved in the development and maintenance of chronic pain.Boccella et al.).Currently treatments for chronic pain are quite unsatisfying. Therefore, there is a need for research aimed at discovering novel biological targets for new pharmacological approaches. Recently the authors collectively participated in the study of neuropathic pain and the role of HCAR2 expressed by Schwann cells in a sciatic nerve ligation model.  in arthritis by using different mouse models mimicking pathophysiology of rheumatoid arthritis in humans and integrative methodology  with special emphasis on pain. They provide the first evidence that HK-1 mediates several arthritic inflammatory mechanisms and pain by direct activation of primary sensory neurons not via its classical NK1 receptor.➢ Li et al., summarize the current knowledge of the role of microglia during sepsis by showing the contribute of these cells in long-term sensorial and cognitive deficits. The Authors appropriately illustrate the activation of microglia in the Central nervous system by describing specific neurotransmissions and molecular pathways which may promote the cognitive damage and chronic pain during sepsis.➢ Pacini et al. test the effects of the natural antioxidant thioctic acid which is clinically used as racemic mixture. The Authors report preclinical and clinical evidences suggesting positive properties of thioctic acid in the treatment of low back pain with a more relevant efficacy of (+)-thioctic acid as compared to (+/−)-thioctic acid on pain, on time of onset of therapeutic effects.➢ De Caro et al., show the anti-inflammatory and analgesic properties of Perampanel, the selective non-competitive AMPA receptor antagonist in acute (tail flick and hot plate tests) and chronic pain (Chronic constriction injury). They also suggest the involvement of the cannabinergic system  in Perampanel actions.➢ Scuteri et al., provide a systematic review and meta-analysis assessing the efficacy of essential oils in pain. They describe the literature search conducted on databases relevant for medical scientific literature, i.e., PubMed/MEDLINE, Scopus, and Web of Science following the PRISMA  criteria. Among a total number of 30 studies included, three investigated neuropathic pain conditions.➢ Borges et al., review recent clinical and preclinical studies investigating the epidermal growth factor receptor (EGFR) signaling pathway in chronic pain states. EGFR inhibitors are known for their use as cancer therapeutics however recent evidence suggested their clinical use for treating chronic pain. Here, the Authors provide an overview of EGFR signaling, highlighting possible mechanisms by which EGFR and its ligands may influence pain hypersensitivity and modulate inflammatory mediators of pain.➢ Brik et al., investigate the behavioral and biochemical changes after intra-articular injection of sodium monoiodoacetate (MIA). This model mimics the degenerative changes observed in osteoarthritic patients. The Authors have characterized grading changes after injection of 1, 2 or 3 mg of MIA over a 28-day period. They report significant dose- and time-dependent changes in both gene expression and protein secretion levels of inflammatory factors.➢ Mazzitelli et al., provide a direct evidence for the modulation of pain-like behaviors and spinal neuronal activity by basolateral amygdala-central nucleus (BLA–CeA) signaling and central nucleus-corticotropin releasing factor (CeA–CRF) neurons on under normal conditions and in an arthritis pain model.➢ Ma et al., reveal the (fat-mass and obesity-associated protein) FTO-triggered epigenetic mechanism of matrix metallopeptidase 24 (MMP24) upregulation in the spinal cord after spinal nerve ligation (SNL). They show that blocking the SNL-induced increase of MMP24 in the spinal cord mitigate pain hypersensitivity both in the development and maintenance phase without altering the basal/acute responses or locomotor functions. The Authors suggest that MMP24 may be an endogenous initiator of neuropathic pain and could be a potential target for this disorder’s prevention and treatment.➢ Bruno et al., indicate that β-adrenergic receptors (β-ARs), mainly β2-and β3-ARs, contribute to tumor proliferation and progression and cancer-associated pain in a mouse model of cancer pain generated by the para-tibial injection of K7M2 osteosarcoma cells. This study highlights the ability of β-ARs antagonists in modulating both tumor growth and the neuroinflammation, showing a new therapeutic targets for cancer therapy and associated pain.➢ In this Research Topic, different signaling implicated in neuroinflammation and chronic pain and possible therapeutic approaches have been described:


Natural disasters and COVID-19 likely add complexity to caregiving efforts, yet little is known about these effects. We will discuss our findings exploring additional needs and challenges experienced by caregivers during hurricanes, floods, and COVID focused on US Gulf Coast states. We interviewed caregivers of both Veterans (n=13) and non-Veterans (n=11). The presentation will include an overview of 1) types of resources needed or used related to storms and to COVID, including social support and access to information for both emergency planning and recovery; 2) caregiver experience before, during, and after the disaster including psychological effects on caregivers and addressing special health needs; 3) comparisons of challenges during storms versus COVID including emotional impact and access to health and specialty care; and 4) additional resources used by caregivers of Veterans. We will also address how these data are informing national caregiver support programs.


Public health measures implemented to mitigate the spread of COVID-19 have transformed the physical and social environments in which we live. The effects of these policies on persons living with dementia (PLWD) and their care partners (CPs) are not fully understood. This study explores the experiences, attitudes, and perceptions of caregiving dyads during the COVID-19 pandemic. Cross-sectional survey data were drawn from a larger longitudinal study examining the relationship between PLWD aged 65+ and their CPs being conducted in a metropolitan city significantly affected by COVID-19. Interviews with were conducted remotely via videoconferencing and telephone. Data on sources and types of care provided for the PLWD, relationship quality and conflict, and caregiver stress were collected and analyzed using descriptive statistics and tests of independence. Preliminary results from PLWD (n=8) and CPs (n=13) confirmed a reduction in social interaction with family members and friends. CPs reported they (n=5) or other family members (n=2) changed their schedules to provide care for the PLWD. CPs reported increased conflict with the PLWD regarding care provision, going out or welcoming visitors, and home management. In contrast, PLWD reported a lack of conflict among household members (n=6) and the perception of good changes (n=2) and increased quality time with CPs. Preliminary findings provide empirical evidence of the effects of pandemic public health policies on dyads enrolled in this study and reveal differences in perceived relational conflict between PLWD and their CPs. Further research is needed to better understand the experiences of dyads and develop supportive interventions.


Service users of secure forensic units can be prone to weight gain due to various reasons including medications, physical illnesses, sedentary habits and mental health difficulties. They in turn are at greater risk of obesity related health problems like Diabetes, Hypercholesterolaemia, Ischaemic Heart Disease, Depression among others.Our project was aligned with government's plan to improve prevention and screening for the obesity and metabolic syndrome among the patients of medium secure facilities by 2020.Our primary objective was to gather and analyse the data on current metabolic parameters such as weight, body mass index (BMI), blood pressure (BP) and biochemistry markers of the service users on a 18 bedded Male medium secure long term rehabilitation ward.Our secondary objective was to suggest healthy weight interventions that would help patients to loose weight and to explore the effects of these interventions on biochemistry markers and vital signs parameters.We collected cross sectional data in given period of time (mid-March 2020). Seventeen service users were included in the final sample. Following initial data collection, we suggested various healthy weight interventions for the patients and repeated data collection after four months (July 2020).Interventions offered:Healthy eating group1:1 sessions with doctors and pharmacistsGym referralsDietician referralsRelaxation groupBaselineFourteen patients on the ward (n = 14) were found to be either overweight or obese. Two patients (n = 2) had high BP, twelve patients (n = 12) had deranged lipid profile, six (n = 6) had high blood glucose (existing Diabetes).Following interventionFourteen patients (n = 14) remained either overweight or obese. Nine patients (n = 9) lost weight following the intervention. Eight patients (n = 8) gained weight over 4 months. In both of the patients (n = 2) with raised BP the readings came back to normal after the intervention. One (n = 1) patient with normal BP at the baseline had high blood pressure following intervention.Our service evaluation projects revealed that majority of the patients on the ward had deranged metabolic parameters such as increased BMI, abnormal blood tests and high BP.Following our intervention more than a half of the patients lost weight whilst other half gained weight during the period of observation, which we suspect is associated with significant physical activity restrictions during the coronavirus pandemic. In both patients with high BP at the baseline it has improved following the intervention.We would continue implementing healthy weight interventions on the ward and across the unit.


The effects of the COVID-19 pandemic on both those experiencing homelessness  and those with life-limiting illnesses  is of great public health concern. This presentation details the findings from an organizational case study  aimed at investigating COVID-related changes to the service environments in which unhoused palliative care patients receive care. Through ethnographic field observation  and interviews with a homeless palliative care team and their community partners , findings included 1) decreased staff capacity due to de-congregated care; 2) efforts to extend care in community settings due to relocation barriers; 3) conflict between reducing viral risk and honoring unique population needs; and 4) provider perceptions of COVID-19 as an “equalizer.” Findings illustrate the impact of emergency response within housing and healthcare systems on unhoused patients’ care and offer potential pathways to quality end-of-life care for homeless populations.


Previous research has established the role of lifelong learning in promoting psychological wellbeing and active aging. Population aging necessitates an understanding of the unique opportunities and challenges around formal and informal learning in later life. This paper will share findings from a mixed methods study with the MIT AgeLab 85+ Lifestyle Leaders, a panel comprised of octogenarians and nonagenarians from across the United States. Drawing on an online survey and virtual focus groups with 29 Lifestyle Leaders from January 2021, findings suggest the Lifestyle Leaders most often learned new things from talking with others (46%) and reading print (54%) or online (54%) sources. The majority were familiar with attending in-person lectures or classes (89.7%) and were now using videoconferencing to do these (78.6%). A majority (56.7%) had or are currently participating in a lifelong learning program. Most consider themselves lifelong learners and described this around remaining curious and engaged with life, choices around what one learns, and greater enjoyment of learning. In the survey, a plurality of Lifestyle Leaders indicated the top two challenges affecting their ability to learn were sensory burdens  (35%) and their energy level (32.4%); focus group data revealed that recall also is a barrier. Focus group data further highlighted generational experiences around early life learning and career paths, specifically how gender roles, diagnoses of learning disabilities, and evolving digital technology have affected these and changed over the course of their lifetimes.


Herein we reportthe first alkynylation of quinolones with terminalalkynes under mild reaction conditions. The reaction is catalyzedby Cu(I) salts in the presence of a Lewis acid, which is essentialfor the reactivity of the system. The enantioselective version ofthis transformation has also been explored, and the methodology hasbeen applied in the synthesis of the enantioenriched tetrahydroquinolinealkaloid cuspareine. A) derivativessuch as ciprofloxacin B are well known as broad-spectrumbacteriocidal agents6 -catalyzed alkylations usingorganomagnesium and organoaluminum reagents -catalyzed alkynylation ofquinolones has not been accomplished so far.31On the contrary, the use of readily available and structurallydiverse terminal alkynes as pronucleophiles, along with the mild reactionconditions, offers an attractive strategy for the synthesis of structurallydiverse quinolone derivatives. Several examples of this approach,including Cu(I)-catalyzed alkynylations of (thio)chromonesHerein we report the first example of the direct Cu(I)-catalyzedalkynylation of 4-quinolones with terminal alkynes as pronucleophiles1c. This 1a and phenylacetylene 2a in the presence ofbase DIPEA and catalytic amounts of Cu(I) salt. On the basis of ourgroup’s experience with Lewis-acid-promoted Cu(I)-catalyzedconjugate additions,35 we evaluated the effect of severalLewis acids to enhance the electrophilicity of the quinolone substrate 1a. Excellent conversion to the desired addition product 3a was observed in the presence of a stoichiometric amountof tert-butyldimethylsilyl triflate (TBDMSOTf) afterstirring overnight (Supporting Information) confirmed the conditions in entry 1 as the mostoptimal. Next, we evaluated the effect of the protecting group ofthe quinolone substrate on the reaction outcome.At the start of this work, the optimization studies were carriedout for the alkynylation reaction between Cbz-protected quinolone 3a were obtained when trimethylsilylhalides were used instead (entries 9 and 10). The use of strongersilicon-based Lewis acids such as trimethylsilyl (TMS) and triethylsilyl(TES) triflates resulted in moderate reaction rates (entries 11 and12), whereas the boron-based Lewis acid BF3·Et2O did not improve the reaction outcome either (entry 13).The superiority of TBDMSOTf over other explored silyl triflates canbe rationalized by the higher stability of a possible TBDMS-enolateintermediate formed during the reaction.No conversion was observed whenunprotected or benzyl-protectedquinolones were used (entries 3 and 4). Moreover, replacing the Cbzprotecting group on the quinolone substrate by a Boc group resultedin a significant drop in the conversion (entry 5). Further studiesconfirmed that the presence of a copper salt and a stoichiometricamount of a Lewis acid are mandatory to promote the reaction to completion.No conversion of quinolone was observed in the absence of copper saltor using only a catalytic amount of a Lewis acid (entries 6–8).With silyl-based Lewis acids other than TBDMSOTf, a lower substrateconversion was obtained (entries 9–13). Only traces of theaddition product Having the optimizedconditions in hand (entry 1), we moved tostudy the scope of the reaction. For this purpose, various alkynesand quinolones were tested 2.3ab–3aj). An excellent yield was also obtained withheteroaromatic alkyne 3ak. Similar results were obtainedwhen using cyclopropyl-, isobutyl-, and ester-substituted alkynes. Surprisingly, the linearterminal alkyne 1-pentyne was unreactive under the optimized reactionconditions (3ao). The limited reactivity of alkyl alkynesand the lack of reactivity of linear alkynes are consistent with theliterature observations in other Cu-catalyzed reactions.37 Various quinolones can be usedwith this catalytic system. Excellent yields were obtained for quinolonesboth with activating and with deactivating groups present in the quinolonering (3eg–3ig) and for those withdisubstituted substrates (3jg and 3kg).The reaction was successfully extendedto several aromatic terminalalkynes bearing electron-donating and electron-withdrawing groupsand four-, three-, and two-substituted aromatic rings -cuspareine (5)without racemization, allowing the determination of the absolute configurationof the stereogenic carbon by comparing the optical rotation of cuspareinewith literature data.17The hydrogenation of In summary, an efficientmethodology for the alkynylation of quinoloneswith readily available terminal alkynes has been accomplished. Thismethodology tolerates the presence of several functional groups inboth the quinolone and alkyne reagents and complements the previouslydeveloped arylation and alkylation reactions of quinolones. We havealso demonstrated the feasibility of an enantioselective version andapplied the current methodology to the synthesis of the enantioenrichedHancock alkaloid (+)-cuspareine. Further studies are under way, aimingto improve the enantioselective variant and shed light on the underlyingmechanism.


This study provides one of the first population-based studies investigating associations between social isolation, especially its two sub-dimensions (family isolation and friendship isolation), and sleep quality among older adults in China. We address three major research questions: 1) Does the risk of poor sleep quality vary by social isolation status? 2) Are the associations between social isolation and sleep quality mediated by mental disorders (depressive symptoms and loneliness) and physical impairments (pain and comorbidity)? and 3) Does the isolation from family members and friends differ in explaining sleep quality? We analyzed data from the 2014 wave of the China Longitudinal Aging Social Survey (CLASS), in which 7,597 respondents (aged 60-98) had complete information on measures of sleep quality (self-rated sleep difficulty), social isolation , and other analytical variables. Logistic regression models were estimated to predict the risk of sleep difficulty and Karlson-Holm-Breen (KHB) decomposition method was employed to test potential mediating effects. Results showed that social isolation, both family and friendship isolation, was significantly associated with higher risks of having sleep difficulty. The adverse effect of family isolation was found to be stronger than that of friendship isolation. Although both mental disorders and physical impairments mediated significant shares of associations between social isolation and sleep quality, physical impairments explained a lesser extent of them than mental disorders. These findings will be helpful for health policymakers and practitioners to design effective intervention strategies to help older adults with sleep problems.


Salmonella typhimurium (HKST) on intestine against IR was investigated. Through mouse intestinal organoids and whole body irradiation of mice, we found that the pretreatment with HKST significantly preserved the structure of small intestine upon IR exposure and promoted the proliferation of intestinal cells post-IR. Further study revealed that the radioprotective effects of HKST were involved in DNA damage response (DDR) signaling. Moreover, the stimulation of DDR signaling by HKST upon radiation damage was mediated by Wnt signaling, in which the inhibition of Wnt signaling diminished the radioprotective effects of HKST. To sum up, our study suggested HKST as a potential radioprotectant used for prevention of IR-induced GI toxicity.Gastrointestinal (GI) toxicity caused by ionizing radiation (IR) is a dose limiting factor in radiotherapy and a great threat for individual nuclear-related military missions. However, there are currently no available strategies to effectively prevent the damage on the intestine induced by IR. In the present study, the protective activity of Heat Killed  Patients received radiotherapy and victims from nuclear accidents unavoidably suffer from the damage induced by ionizing radiation (IR) . Acute rEscherichia coli O111: B4 LPS, the coagonist of TLR4 and TLR2, exerts stronger immune stimulation effects than that from TLR2 or TLR4 agonist used alone or in combination Gastrointestinal (GI) toxicity caused by ionizing radiation (IR) appears to be a limited factor in radiotherapy and a great threat for those exposed to high dose radiation. However, there are currently no available strategies to effectively prevent or mitigate the damage on intestine induced by IR. Our study demonstrated that Heat Killed


My Sister’s Keeper is an online education and support group created by women of color in response to disproportionate stresses related to COVID-19 experienced by women of color. The current study aims to examine the Stage 2 evidence that an online support group formed by members of the community may help mediate inequity-related stressors and increase receptiveness to health-related recommendations. To begin to develop this evidence, a thematic analysis of 8 in-depth individual interviews was performed. Resulting themes included: 1) feeling empowered; 2) solidarity in sisterhood ; 3) being focused (on women of color) yet being inclusive; 4) currency of knowledge ; and 5) preferring virtual accessibility to stay connected. Preliminary data suggest that social support offered through an online platform dedicated to women of color can promote health during the pandemic and possibly beyond.


The current study examines how cohort differences across two age-matched groups of midlife and older women from the Health and Retirement Study are associated with well-being and self-perceptions of aging (SPA). Women aged 51–60 (n=2318) and 61–70 (n=1650) were selected from the 2008 and 2018 waves. No significant cohort differences were identified for life satisfaction  or positive SPA . The 2008 cohort of midlife women reported significantly higher negative SPA compared to 2018 (p<.05). Linear regression analyses find that cohort and SPA are significantly associated with life satisfaction in both age groups, and that the association of negative SPA differs by cohort for the midlife women (p<.01). Implications are discussed within the life course developmental framework.