Drugs of abuse have the capacity to hijack the cellular and neurocircuit mechanisms mediating reward learning, forming non-adaptable, compulsive behaviors geared toward obtaining illicit substances. Here, we discuss current findings demonstrating how drugs of abuse alter intrinsic and synaptic LHb neuronal function. Additionally, we discuss evidence for how drug-induced LHb alterations may affect the ability to predict reward, potentially facilitating an addiction-like state. Altogether, we combine  The ability to accurately predict rewarding or aversive outcomes throughout life is a critical adaptive behavior that promotes survival and allows avoidance of threatening or unpleasant confrontations. This adaptive ability is attributed to an evolutionarily conserved hedonic neurocircuit which consists of an interwoven network linking forebrain, midbrain and hindbrain regions, that together systematically regulate the release of monoamines  and reward outcomes , a brain region that sends inhibitory input to dopamine neurons in the ventral tegmental area (VTA). During negative RPEs, LHb neurons are activated and send excitatory signals to RMTg inhibitory neurons which project to and inhibit dopamine neuron firing  to a tail pinch have decreases in firing rates during cocaine microiontophoresis application  are decreased shortly after cocaine administration (0–10 min post injection), but this transient inhibition progresses to increased firing activity (15–35 min post injection) in specific neuronal populations  cocaine self-administration causes increases in LHb neuron excitability as measured using AR-mediated inhibition is decreased at entopeduncular nucleus (EPN)-to-LHb neuronal synapses (measured in brain slices)  amplitude are observed along with increases in the ratio of currents mediated by AMPA- and NMDA-type glutamate receptors (AMPAR/NMDAR) onto LHb neurons that specifically project to the RMTg  increases spontaneous action potential firing and membrane excitability in LHb neurons measured using These results suggest that the increased LHb activity may serve as a neural mechanism to facilitate drug-induced negative affect. Therefore, inhibiting LHb neuronal output could potentially prevent drug-induced anhedonia. To this end, low dose (0.25 g/kg) ethanol-induced conditioned place aversion is reversed to conditioned place preference (CPP) following lidocaine-induced LHb inhibition , likely invoking negative RPE signaling in the LHb and subsequent LHb-induced dopamine neuron inhibition Figure . TherefoGiven that positive RPE is associated with the phasic firing of dopamine neurons, and that negative RPE is associated with LHb signaling, one would expect that the acquisition or maintenance phase of drug self-administration (a positive RPE paradigm) might be independent of LHb control. In agreement with this, it has been shown that LHb lesions do not alter heroin or cocaine self-administration administration during the acquisition or maintenance phases, as LHb lesioned animals seek and obtain similar amounts of drug compared to non-lesioned animals (Wang et al., The LHb regulates dopamine neuron firing during negative RPE signaling and provides instructive signals for reward-seeking behaviors (Matsumoto and Hikosaka, In addition to regulating negative RPE, the LHb is critically involved in learning and memory processes that are associated with avoidance behaviors (Stamatakis and Stuber, In conclusion, we reviewed evidence supporting the importance of the LHb in regulating reward learning and updating of reward-related information. In preclinical experiments, lesioning the LHb or inhibiting LHb function elicits similar impairments in reward prediction when compared to human patients suffering from drug abuse. However, more work is needed in animal models of drug abuse to understand whether and how drugs of abuse facilitate reward-related learning impairments mediated by LHb function.NG, PN and YD developed the focus of this review. NG and PN wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Orchids are known for both their floral diversity and ecological strategies. The versatility and specialization in orchid floral morphology, structure, and physiological properties have fascinated botanists for centuries. In floral studies, MADS-box genes contributing to the now famous ABCDE model of floral organ identity control have dominated conceptual thinking. The sophisticated orchid floral organization offers an opportunity to discover new variant genes and different levels of complexity to the ABCDE model. Recently, several remarkable research studies done on orchid MADS-box genes have revealed the important roles on orchid floral development. Knowledge about MADS-box genes' encoding ABCDE functions in orchids will give insights into the highly evolved floral morphogenetic networks of orchids.


Emerging research indicates that exercise combined with cognitive training may improve cognitive function in older adults. Typically these programs have incorporated sequential training, where exercise and cognitive training are undertaken separately. However, simultaneous or dual-task training, where cognitive and/or motor training are performed simultaneously with exercise, may offer greater benefits. This review summary provides an overview of the effects of combined simultaneous vs. sequential training on cognitive function in older adults. Based on the available evidence, there are inconsistent findings with regard to the cognitive benefits of sequential training in comparison to cognitive or exercise training alone. In contrast, simultaneous training interventions, particularly multimodal exercise programs in combination with secondary tasks regulated by sensory cues, have significantly improved cognition in both healthy older and clinical populations. However, further research is needed to determine the optimal characteristics of a successful simultaneous training program for optimizing cognitive function in older people. Age-associated cognitive decline, which can progress to mild cognitive impairment and dementia, are growing public health concerns with no known cure. Regular exercise has been shown to provide some cognitive benefits in healthy and cognitively impaired older adults , and/or whether the cognitive training was conducted prior to or after exercise training. For instance, a 16-week RCT in older adults observed no cognitive benefits when exercise training was delivered after the cognitive training  and memory training, are associated with cognitive improvements in healthy older adults , P < 0.01), but there were no differences between the combined intervention and cognitive training alone. Secondary analysis also revealed that the effect size for sequential interventions was less than those for simultaneous interventions , but did not include exergaming or more recently published studies. Another review of 13 studies also reported that simultaneous dual-task training interventions including low-intensity activity  performed with a secondary cognitive or motor tasks, can benefit both physical function  and the cognitive abilities of older adults in dual-task situations  on cognitive function have been observed following a 12-week exergaming (Nintendo Wii) trial in one study involving 32 independent living older adults aged 65–78 years , exergaming typically includes cognitive challenges embedded within realistic physical activities, whilst providing virtual feedback. One of the first RCTs of exergaming for older adults revealed a promising differential cognitive benefit of exergaming  or motor tasks requiring divided attention , have improved multiple cognitive abilities in older adults  of simultaneous exercise and cognitive-motor training that promotes cognitive improvement in older adults. Based on the available data, interventions incorporating functional stepping exercises  of exposure, with a training frequency between 1 and 3 times per week Table , but notThe neurophysiological mechanisms underlying the cognitive improvements observed through combined cognitive and exercise training are yet to be identified; however cognitive and exercise training may stimulate similar neurobiological processes which produce a synergistic response. Exercise and cognitive training both increase cerebral blood flow  remain to be determined, studies incorporating moderate-intensity multimodal training in combination with secondary tasks involving a functional response to sensory cues have improved executive abilities and memory, which may prolong functional independence in older adults. However, further research is needed to determine if these improvements can be maintained, and even prevent or delay the onset of cognitive impairment and dementia. Finally, an understanding of the neurobiological mechanisms underpinning any cognitive improvements available from combined exercise-cognitive training in older adults also requires further investigation.JT and RMD wrote the manuscript and RLD, CM, and LM reviewed the draft versions. All authors have read and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BY and handling Editor declared their shared affiliation.


Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has increasingly been performed for the diagnosis and staging of thoracic malignancies. Findings of a necrotic lymph node raise concern for infectious process and malignancy. A hypoechoic area on ultrasound/EBUS within a lymph node without blood flow is suggestive of pathologies like infections or malignancy. Inspection of the fluid could suggest a diagnosis; clear aspirates usually suggest bronchogenic or mediastinal cysts and purulent material suggests abscesses or necrotic lymph nodes. Growing tumor cells require a blood supply; if the vascular stroma is insufficient due to rapidly growing malignant tumors this could lead to large central areas of ischemic necrosis. Necrotic aspiration of lymph nodes is not always of infectious etiology. Aspiration of fluid in EBUS-TBNA is a rare occurrence, and malignancy should be considered when purulent fluid material is obtained. We present an elderly woman who underwent bronchoscopy with EBUS-TBNA for evaluation of upper lung nodule and mediastinal lymphadenopathy. Pus-like material was obtained on needle aspiration and endobronchial biopsy and mediastinal core biopsy revealed squamous cell carcinoma. Ultrasound imaging has become part of the armamentarium of the pulmonologist; EBUS-TBNA plays an important role in the evaluation and diagnosis of several diseases especially malignancy .EBUS-TBNA is well accepted and increasingly being used as a safe minimally invasive procedure for the diagnosis and staging of lung cancers; it carries an overall sensitivity of 89% and a negative predictive value of 91% . It is aA 71-year-old woman from Dominican Republic was admitted for dyspnea, fever, and nonproductive cough of one-day duration. Her medical history was significant for diabetes mellitus, systolic heart failure, gastric B-cell lymphoma treated with chemotherapy, and surgically treated basal cell carcinoma of forehead. She was a heavy smoker with 40 packs/year. She denied alcohol or illicit drug use. Family history was noncontributory. There were no sick contacts, recent traveling, or occupational exposures and no history of exposure to tuberculosis.Initial examination showed an elderly woman on respiratory distress. Chest auscultation revealed bibasilar crackles and diffuse expiratory wheezing. There were no palpable lymphadenopathy, organomegaly, or skin lesions. The rest of exam was unremarkable. Significant laboratory findings included elevated Pro-BNP; there was no leukocytosis and renal and liver function was normal. A right sided thoracentesis was performed with pleural fluid analysis revealing transudative effusion with pleural/serum LDH ratio of 0.12 and pleural/serum protein ratio of 0.19.Patient was treated for exacerbation of heart failure with diuretics and antibiotics were given for presumptive community acquired pneumonia with clinical improvement.Chest-roentgenogram (CXR) on admission showed bilateral pleural effusion and infiltrates which rapidly improved suggesting a diagnosis of heart failure rather than pneumonic process . A chestPatient underwent flexible fiberoptic bronchoscopy (FFB) that revealed a small endobronchial lesion at the right upper lobe before the takeoff of anterior segmental bronchus. Endobronchial biopsy (EB) of the EBL as well as transbronchial biopsy (TBBx) of right upper nodule and EBUS-TBNA of the right paratracheal and subcarinal lymph nodes was performed. A 19′′ gauge needle was used for the EBUS-TBNA with a total of four needle passes per lymph node. Twenty ml of purulent appearing fluid was aspirated from the right paratracheal lymph node . AspiratAspiration of liquid material in EBUS-TBNA is uncommon. A hypoechoic area on ultrasound/EBUS within lymph nodes without blood flow is suggestive of pathologies like infections or malignancy. Inspection of the fluid is suggestive of a diagnosis; clear aspirates suggest bronchogenic or mediastinal cysts and purulent material suggests infection or rarely necrotic lymph nodes. Growing tumor cells require a blood supply; if the vascular stroma is insufficient due to rapidly growing malignant tumors this could lead to large central areas of ischemic necrosis , 5. Othe Histoplasma capsulatum leading to mediastinal abscesses and necrotic mediastinal lymphadenopathies [ Streptococcus related mediastinitis and mediastinal abscesses have also been reported in the literature [Necrotic mediastinal lymphadenopathy has been described in a wide variety of pathologies which include infectious and noninfectious etiologies. Tuberculosis is one of the most common infectious causes, especially in areas with high prevalence of tuberculosis . Other iopathies , 10. Bacterature .Noninfectious causes include histiocytic necrotizing lymphadenitis which is a benign lymphadenitis, characterized by enlarged lymph nodes with histopathological findings of proliferation of lymphocytes and histiocytes, nuclear debris, and necrotic lesions affecting mainly young women ; systemiLymphomas also may present as necrotic mediastinal lymphadenopathy. Usually metastases present more frequently as parenchymal lung nodules, but these are closely followed by mediastinal lymphadenopathy and pleural effusions .The initial differential diagnoses in our patient were infectious etiologies versus malignancy due to the strong medical history of malignancies and imaging findings. Bronchoscopic findings were conflicting, inspection revealed an endobronchial lesion, and EBUS sampling revealed cyst-like structure and aspirated material looked purulent. It is also important to note our patient had no clinical signs to suggest a rheumatologic disorder. To our knowledge, 2 cases of EBUS-TBNA of mediastinal lymph node revealing purulent material with a final diagnosis of malignancy have been reported in the English literature , 5. In bThe increased use of EBUS-TBNA to assess mediastinal diseases will likely lead to an increase in the number of patients with malignancies presenting with purulent aspirate. We suggest neoplastic conditions, especially squamous cell carcinoma, to be included in the differential diagnosis in patients where the EBUS guided needle aspiration reveals purulent material. Specimens should be analyzed to evaluate for infections like tuberculosis, fungal, and bacterial infections as well as malignancy.


Aortic mycotic aneurysms are a rare but life-threatening potential complication of infective endocarditis. Rapid deterioration of the vascular wall in highly focal areas makes these pseudoaneurysms particularly prone to rupture, resulting in uncontrolled aortic hemorrhage. While computed tomography angiography (CTA) is the imaging modality of choice for the evaluation of mycotic aneurysms, it is not routinely performed in patients with known or suspected infective endocarditis (IE). However, current valvular heart disease guidelines support the use of cardiac CTA in cases of IE and suspected perivalvular extension when there is inadequate or ambiguous visualization on echocardiography. Here, we describe a case of IE in which cardiac CTA was used for two purposes: to assess perivalvular complications and to define coronary anatomy in a patient with a suspected embolic myocardial infarction. Subsequent detection of an aortic root mycotic aneurysm not previously demonstrated on transthoracic or transesophageal echocardiography allowed for timely and uncomplicated surgical intervention, while avoiding invasive coronary angiography. Mycotic aneurysm (MA) is a rare, potential complication of infective endocarditis that carries significant mortality risk. The pathogenesis begins with bacterial infiltration into the vessel wall, which may occur directly through trauma, by local extension from an existing infection, or by seeding from a distant site via septic embolism or bacteremia. A robust inflammatory response ensues, resulting in rapid, focal wall degeneration . InfectiA 67-year-old male with a known bicuspid aortic valve was admitted with fevers and chest pain one month following a dental procedure. Upon initial presentation to an outside hospital, he was reportedly found to have an elevated troponin of 2.78 ng/mL and minor ST-segment elevations on ECG. Blood cultures drawn on admission grew alpha-hemolytic streptococci sensitive to penicillin and ceftriaxone. Both transthoracic and transesophageal echocardiograms demonstrated a subcentimeter aortic valve vegetation , moderatDue to vegetation size and the absence of heart failure symptoms, the patient was initially treated medically. A peripherally inserted central catheter was placed, and he was discharged on appropriate antibiotic therapy following negative repeat blood cultures. He subsequently returned five days later with persistent fever and new, severe left flank pain. Abdominal computed tomography demonstrated a wedge-shaped area of hypoattenuation consistent with a renal infarct . Blood cCardiac computed tomography angiography (CTA) was then performed to better visualize potential perivalvular extension and provide concomitant assessment of coronary arterial disease. CTA was performed using a prospective ECG triggered acquisition using a 64-slice scanner  during the administration of a triphasic contrast injection protocol . CTA revealed an eight-millimeter mycotic aneurysm of the aortic annulus extending into the intervalvular fibrosa and no residual aortic valve vegetation . AdditioMycotic aneurysms have widely varying clinical presentations depending on their location, the duration of infection, and patient comorbidities. The most common presenting symptoms are largely nonspecific, ranging from isolated leukocytosis or elevated erythrocyte sedimentation rate to bacteremia and fulminant sepsis . This maDue to exceedingly low incidence, little is known about the natural progression of mycotic aneurysms. Thrombosis, rapid enlargement, and even spontaneous regression are possible, though there are no known imaging findings that can accurately predict the clinical course . The repCTA is the imaging modality of choice for the diagnosis of mycotic aneurysms . By contIn this particular case, CTA identified a small but clinically relevant mycotic aneurysm that had not been visualized on either transthoracic or transesophageal echocardiography. The detailed assessment of both the coronary anatomy and the infarcted area allowed for confirmation of the embolic nature of the patient's MI and ruled out any atherosclerotic coronary disease requiring intervention during surgery.Resting or first-pass perfusion deficits can often be detected in patients with acute or chronic infarction with any modern CT scanner (64-slice or more) equipped to do coronary CTA. Cardiac MRI performed 8–10 minutes following gadolinium contrast (delayed enhancement) is a well-validated technique to detect myocardial scar (fibrosis) from any etiology based on the known retention of contrast material in areas of fibrosis. Scar (areas of hyperenhancement on delayed imaging) in a coronary distribution, as seen in this case, is typical of a myocardial infarction from a coronary etiology. Similarly, an additional noncontrast cardiac CT scan performed 8–10 minutes following the initial cardiac CTA can also be done to assess for scar (hyperenhancement on CT), similar to cardiac MRI. In this case, a delayed CT scan was not performed due to the presence of the previously performed delayed enhancement MRI and to reduce patient radiation exposure.Finally, this case highlights the advantage of cardiac CTA for coronary artery examination in lieu of high-risk catheterizations and nicely portrays its supplementary roles in both preoperative planning and the assessment of perfusion defects. It additionally demonstrates the utility of cardiac CTA for precise perivalvular assessment in infective endocarditis, particularly in cases of clinical suspicion for perivalvular extension and inadequate visualization on echocardiography.


An efficacious vaccine for HIV remains elusive. Numerous groups have isolated antibodies from HIV infected individuals that can bind and neutralise antigenically diverse HIV strains, so-called broadly neutralising antibodies (bNAbs) . HIV bNAEBioMedicine, In the current issue of The complex interplay between viral escape and Env conformation observed by Bradley et al. and others gives some pause to reductionist approaches focussing on recapitulating single bNAb specificities by immunisation. Favourable linkage interactions between different bNAb epitopes, shown here for the MPER and the CD4 binding site or V3 loop, suggests vaccines simultaneously targeted to multiple epitopes may be advantageous. While targeting the MPER by vaccination may be difficult due to described self-mimicry and frequent generation of autoantibodies , the resThe authors declare no conflicts of interest.


Brain-machine interfaces (BMI) may support motor impaired patients during activities of daily living by controlling external devices such as prostheses (assistive BMI). Moreover, BMIs are applied in conjunction with robotic orthoses for rehabilitation of lost motor function via neurofeedback training (restorative BMI). Using assistive BMI in a rehabilitation context does not automatically turn them into restorative devices. This perspective article suggests key features of restorative BMI and provides the supporting evidence: In summary, BMI may be referred to as restorative tools when demonstrating subsequently (i) operant learning and progressive evolution of specific brain states/dynamics, (ii) correlated modulations of functional networks related to the therapeutic goal, (iii) subsequent improvement in a specific task, and (iv) an explicit correlation between the modulated brain dynamics and the achieved behavioral gains. Such findings would provide the rationale for translating BMI-based interventions into clinical settings for reinforcement learning and motor rehabilitation following stroke. Such supported movements facilitate the detection of motor intention even in the absence of actual movements  and motor evoked potentials (MEP)  operant learning and progressive evolution of specific brain states/dynamics, (ii) correlated modulations of functional networks related to the therapeutic goal, (iii) subsequent improvement in a specific task, and (iv) an explicit correlation between the modulated brain dynamics and the achieved behavioral gains. Such findings would provide the rationale for translating BMI-based interventions into clinical settings for reinforcement learning and motor rehabilitation following stroke.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Some rodents produce ultrasonic vocalizations (USVs) for social communication using an aerodynamic whistle, a unique vocal production mechanism not found in other animals. The functional anatomy and evolution of this sound production mechanism remains unclear. Using laryngeal airway reconstruction, we identified anatomical specializations critical for USV production. A robust laryngeal cartilaginous framework supports a narrow supraglottal airway. An intralaryngeal airsac-like cavity termed the ventral pouch was present in three muroid rodents (suborder Myomorpha), but was absent in a heteromyid rodent (suborder Castorimorpha) that produces a limited vocal repertoire and no documented USVs. Small lesions to the ventral pouch in laboratory rats caused dramatic changes in USV production, supporting the hypothesis that an interaction between a glottal exit jet and the alar edge generates ultrasonic signals in rodents. The resulting undulating airflow around the alar edge interacts with the resonance of the ventral pouch, which may function as a Helmholtz resonator. The proposed edge-tone mechanism requires control of intrinsic laryngeal muscles and sets the foundation for acoustic variation and diversification among rodents. Our work highlights the importance of anatomical innovations in the evolution of animal sound production mechanisms. Rats et al. )


There are approximately 1 billion people living with chronic lower limb disability, many of whom are wheelchair users.Review cardiometabolic and neuromuscular risk profiles of wheelchair users, benefits of regular exercise and the causes of neuromuscular upper limb and hip injuries that hinder regular adherence.Literature published between 2013 and 2017 was adopted according to the standard practices for systematic reviews (PRISMA) through Crossref Metadata and Google Scholar searches. Individual paper quality was evaluated using a modified Downs and Black Appraisal Scale.The literature search identified 16 600 papers which were excluded if they were non-English, non-peer-reviewed or published before 2013. Finally, 25 papers were accepted, indicating that sedentary wheelchair users have poor cardiometabolic risk profiles (PCMRP) because of a lack of physical activity, limiting their quality of life, characterised by low self-esteem, social isolation and depression. Their predominant mode of physical activity is through upper limb exercises, which not only improves their cardiometabolic risk profiles but also precipitates neuromuscular upper limb overuse injuries. The primary cause of upper limb injuries was attributed to poor wheelchair propulsion related to incorrect chair setup and poor cardiorespiratory fitness.Wheelchair users have a high body mass index, body fat percentage and serum lipid, cholesterol and blood glucose concentrations. Empirical investigations illustrate exercise improves their PCMRP and cardiorespiratory fitness levels. Although literature encourages regular exercise, none discusses the need to individualise chair setup in order to eliminate wheelchair pathomechanics and upper limb neuromuscular injuries. Wheelchair users must be encouraged to consult a biokineticist or physiotherapist to review their wheelchair setup so as to eliminate possible incorrect manual wheelchair propulsion biomechanics and consequent overuse injuries. Many wheelchair users suffered injuries to the spinal cord, spinal nerves and cauda equina, and also underwent lower limb amputation  vascular and circulatory diseases precipitated through type 2 diabetes mellitus or peripheral vascular diseases, (2) trauma, (3) surgical removal of tumours and (4) congenital deformities  review the cardiometabolic risk profile and cardiorespiratory fitness status of wheelchair users, (2) determine the benefits of regular exercise, (3) determine common neuromuscular injuries adversely influencing wheelchair users adhering to regular exercise therapy and (4) identify wheelchair propulsion pathomechanics as the primary culprit of upper limb overuse and hip injuries. Previous literature encourages wheelchair users to engage in physical activity and exercise but they do not describe the initial challenges (such as muscle and neuromuscular pain and injuries) that users experience. The novelty of this commentary lies in the review of common neuromuscular injuries sustained by wheelchair users when they begin an exercise programme and which may prevent them from continuing with the programme. The identification of the cause of these upper limb overuse injuries among spinal cord injured (SCI) wheelchair users is unique to this review. This is the first commentary to discuss the abnormal force-couple relationships of the shoulder and hip muscles because of poor wheelchair setup and propulsion pathomechanics.The authors followed the standard practices for systematic reviews (PRISMA). The definitions were guided by the PRISMA checklist for participants, interventions, comparisons, outcomes and study designs (PICOS). The participants in this study were wheelchair users; the intervention was not necessarily a therapeutic intervention but is interpreted as an exposure, namely, the effect of exercise therapy on the well-being of wheelchair users. The outcomes of interest were (1) exercise therapy interventions for wheelchair users, (2) the effects of exercise therapy on wheelchair users’ health and (3) common overuse injuries of physically active wheelchair users. The exclusion criteria were (1) publications prior to 2013, (2) literature not related to the health and physical status of wheelchair users, (3) psychological therapeutic interventions, (4) non-English papers and (5) non-peer-reviewed papers.A literature search of peer-reviewed and professional journal publications was conducted in the following search engine: Crossref Metadata database, an academic meta-database which comprises the following search engines: PubMed, Medline, Science Direct, Ebscohost, CINAHL and Google Scholar . The keyThe hierarchy of evidence and quality of appraisal tool were adapted from Abdullah, McDonald and Jaberzadeh  Table 1Table 1. The quality of each paper was appraised using a modified Downs and Black Appraisal Scale, which examined the quality of randomised controlled trials and non-randomised papers  cardiometabolic risk profile, (2) benefits of regular exercise to wheelchair users and (3) common neuromuscular injuries from upper extremity exercises.Wheelchair users often lead sedentary lifestyles and consequently have poor cardiometabolic profiles   are living with chronic disability and spend a considerable amount of time in wheelchairs Kate . Most ofThe most common overuse injuries include shoulder impingement, rotator cuff tendinitis, biceps tendinitis, lateral epicondylitis, ulnar neuropathy, De Quervain’s tenosynovitis and carpal tunnel syndrome (Apple, Cody & Allen Manual wheelchair propulsion is categorised by the contact and recovery phases. Contact phase occurs when mechanical power is delivered to the wheelchair through hand contact with the rim of the wheel (Slowik et al. Sprigle  and WillSagittal plane analysis identifies an anterior pelvic tilt with increased hip flexor tightness and lumbar lordosis Sprigle  Figure . An anteIn an attempt to reduce wheelchair propulsion pathomechanics, scientists and engineers have redesigned the appearance and functionality of wheelchairs. Sports wheelchairs have undergone drastic and revolutionary design modifications in order to enhance sports performance and improve adherence to physical activity programmes. These ergonomic modifications improve the biomechanics of the user, which in turn curtails the incidence of upper limb overuse injuries (Sindall et al. It is recommended that manual wheelchair users have their wheelchairs reviewed in order to ensure that the wheelchair setup is ergonomically designed to meet their individual needs. Treatment and rehabilitation of the aforementioned overuse injuries pose a significant challenge because these individuals are primarily reliant on the upper limbs for weight-bearing activities and for mobility. It is further recommended that before starting an exercise programme, all wheelchair users should first receive clinical clearance from their medical practitioner regarding their participatory readiness. They must thereafter consult a biokineticist or a physiotherapist who will conduct a critical review of their wheelchair propulsion biomechanics in an attempt to prevent injuries. The biokineticist or physiotherapist should also prescribe an individualised therapeutic exercise programme.Wheelchair users have poor cardiometabolic risk profiles, low self-esteem and are at risk for socially withdrawn lives. Those who regularly exercise enjoy improved cardiorespiratory fitness and reduced cardiometabolic risk as well as reduced levels of depression and a consequently enhanced quality of life. Unfortunately, many wheelchair users who wish to be physically active are further restricted by upper limb overuse injuries. The primary cause of these injuries is wheelchair propulsion pathomechanics as a result of incorrect chair setup and limited cardiorespiratory fitness. It is therefore recommended that wheelchair users consult a biokineticist or physiotherapist before engaging in an exercise regime, so as to alleviate poor wheelchair propulsion biomechanics which may predispose them to overuse injuries. Medical practitioners, as well as the family and friends of wheelchair users, must encourage them to adhere to regular aerobic, muscle strength, and flexibility exercises in order to improve their quality of life.


Endotherms regulate their core body temperature by adjusting metabolic heat production and insulation. Endothermic body temperatures are therefore relatively stable compared to external temperatures. The thermal sensitivity of biochemical reaction rates is thought to have co-evolved with body temperature regulation so that optimal reaction rates occur at the regulated body temperature. However, recent data show that core body temperatures even of non-torpid endotherms fluctuate considerably. Additionally, peripheral temperatures can be considerably lower and more variable than core body temperatures. Here we discuss whether published data support the hypothesis that thermal performance curves of physiological reaction rates are plastic so that performance is maintained despite variable body temperatures within active (non-torpid) endotherms, and we explore mechanisms that confer plasticity. There is evidence that thermal performance curves in tissues that experience thermal fluctuations can be plastic, although this question remains relatively unexplored for endotherms. Mechanisms that alter thermal responses locally at the tissue level include transient potential receptor ion channels (TRPV and TRPM) and the AMP-activated protein kinase (AMPK) both of which can influence metabolism and energy expenditure. Additionally, the thermal sensitivity of processes that cause post-transcriptional RNA degradation can promote the relative expression of cold-responsive genes. Endotherms can respond to environmental fluctuations similarly to ectotherms, and thermal plasticity complements core body temperature regulation to increase whole-organism performance. Thermal plasticity is ancestral to endothermic thermoregulation, but it has not lost its selective advantage so that modern endotherms are a physiological composite of ancestral ectothermic and derived endothermic traits. The basic principles of thermodynamics dictate that the rates of physiological functions in both endotherms and ecotherms are sensitive to changes in temperature , for example, let their body temperature vary considerably with environmental temperature  and Przewalski's horse  lowered peripheral temperatures in winter, with concomitant decreases in heart rates during activity and rest , physiological reaction rates shifted with seasonal and altitudinal changes in climate. R. fuscipes from two populations living in cold high altitude climates had significantly lower body temperatures compared to those from two warm coastal populations . These data indicate that adaptation or developmental processes lower the mode of thermal performance curves in cold climates, which would be beneficial for rats experiencing lower body temperatures.In rats from warm climates, residuals of state 3 rates were lowest at 33°C and increased with temperature. In contrast, state 3 rates of cold-climate rats were highest at 33°C and decreased with increasing temperature  represent the best studied mechanism that allows cells to detect changes in their environment directly (Nilius and Voets, Cyprinus carpio; Gracey et al., Hyla japonica; Sugimoto and Jiang, Temperature can also have direct effects on post-transcriptional processes, such as mRNA degradation, splicing, and translation efficiency. For example, temperature-dependent expression patterns of cold-inducible proteins are determined by the thermal sensitivity of post-transcriptional mechanisms (Sonna et al., The cold-shock RNA-binding protein RBM3 binds mRNAs to maintain translational efficiency (Peretti et al., Peripheral cells and tissues may also mount autonomous responses to local changes in temperature by indirect thermosensory pathways, where temperature-induced imbalances in cellular metabolites trigger compensatory responses. In skeletal muscle, decreasing temperatures cause an energy deficit, resulting in an increase in the AMP:ATP ratio (Towler and Hardie, The concept that endotherms have high and stable body temperatures despite environmental temperature fluctuations (Scholander et al., The mechanisms that mediate thermal plasticity are highly conserved among animals, and their broad range of functions is likely to preclude negative selection. For example, thyroid hormone action is essential for a broad range of physiological responses in animals, and is highly conserved across taxa (Heyland and Moroz, FS and AL conceived the ideas, prepared the manuscript and figures, and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


When exposed to stress, the hypothalamic-pituitary-adrenal axis is hyperactivated, which can cause the enlargement of the pituitary gland. Hence, pituitary gland volume could be a biomarker of stress present in psychosis. However, it remains unclear if individuals with psychosis have larger pituitary gland than healthy people. Previous studies investigating this question used small samples and reported inconsistent results. In the current study, we used an automated multi-atlas segmentation method to investigate the differences between pituitary gland volumes in a large sample of individuals on the psychosis spectrum.Data collection was completed across six sites in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium with a total of 755 participants included in the study - 174 individuals with schizophrenia (SZ), 115 with schizoaffective disorder (SZA), 167 with psychotic bipolar disorder (PBD), and 299 healthy controls (HC). Structural magnetic resonance images were acquired and pituitary gland volumes were obtained using the automated MAGeT-Brain algorithm. General linear model and post-hoc independent t-tests were used to analysis the differences between subgroups of patients using clinical diagnosis and agnostic Biotype classification (Biotype 1 being the most cognitively impaired). We also explored potential effect of antipsychotic intake, symptoms severity and duration of illness. In all analyses, we used Bonferroni correction for multiple comparisons and entered confounds as covariates .Overall, the pituitary gland volumes were not significantly different between patients and HC. No significant main effect of diagnosis was observed, but SZ patients had trending larger pituitary volume compared to HC . We observed a significant main effect of Biotype (p=.003), with Biotype 1 having significantly larger pituitary gland than HC and Biotype 2 (p=.004 and p=.013). In the patients group, no significant relationship between the pituitary gland and the amount of antipsychotic intake was observed . Significant correlations with the pituitary gland volume were observed with symptoms severity , and with the duration of illness . Importantly, Biotypes did not significantly differ in terms of symptoms severity nor duration of illness.As a group, individuals with psychosis do not have abnormal pituitary gland volume, but larger pituitary gland is related to shorter duration of illness and greater symptoms severity. Therefore, larger pituitary gland volume could be a state-related biomarker of psychosis. Moreover, while we did not observe any significant subgroup differences using clinical diagnosis, our results suggest an increase in pituitary volume in biotype 1 patients compared to HC. These findings clarify previous inconsistent reports, and encourage further investigation of stress biomarkers in individual with psychosis with lower cognitive abilities. In the future, this could lead to the development of more targeted treatments for this specific subgroup of patients.


BluePen Biomarkers provides a unique comprehensive multi-omics biomarker discovery and validation platform. We can quantify, integrate and analyze genomics, proteomics, metabolomics and lipidomics biomarkers, alongside clinical data, demographics and other phenotypic data. A unique bio-inspired signal processing analytic approach is used that has the proven ability to identify biomarkers in a wide variety of diseases. The resulting biomarkers can be used for diagnosis, prognosis, mechanistic studies and predicting treatment response, in contexts from core research through clinical trials. BluePen Biomarkers provides an additional groundbreaking research goal: identifying surrogate biomarkers from different modalities. This not only provides new biological insights, but enables least invasive, least-cost tests that meet or exceed the predictive quality of current tests. The company was founded by experts from the field of biomarker discovery and validation at the University of Pennsylvania, which complements the bioinformatics expertise provided by Emerald Logic from Aliso Viejo . A major goal of the company is to address the problem of poorly predictive biomarkers that was identified by George Poste in his provocative 2011 article in Nature [BluePen Biomarker's team of management and scientific advisors comprises leading biomedical scientists who provide a coordinated approach to fully integrated biomarker solutions;Genomics, proteomics, metabolomics and lipidomics research is conducted in BluePen Biomarkers’ laboratories using state-of-the-art instrumentation;The products of multi-omics research are integrated using sophisticated bioinformatics based on combinatorial signal processing and analytic approaches developed by Emerald Logic to provide a fully integrated biomarker solution ;The fundamental conviction of the company's founders is that any intervention that has a biologic outcome will have a detectable predictive biomarker signature. The challenge is to detect that signature;The comprehensive multi-omics systems biology platform available at BluePen Biomarkers coupled with Emerald Logic's innovative signal processing approach provides a powerful solution to the biomarker needs of academia as well as pharmaceutical and biotech industries ;The substantial expertise available within the company provides a unique resource for assessing potential clinical biomarker needs;Biomarker discovery and validation can be tailored to the particular project under consideration;BluePen Biomarkers now provides a commercial multi-omics platform that can quickly yield highly predictive biomarkers.BluePen Biomarkers was established in April 2016 in Philadelphia PA through a collaboration between the University of Pennsylvania's Center for Innovation, Blueprint Bio and Emerald Logic from Aliso Viejo , which is sometimes known as whole transcriptome shotgun sequencing. RNA-Seq, which is conducted by next-generation sequencing (NGS) using an Illumina HiSeq 3000 instrument, has largely replaced microarray analysis for the quantification of mRNA transcripts in a biofluid sample at a given moment in time. This can provide biomarker signatures of particular disease states. RNA-Seq can also be used to assess alternative gene-spliced transcripts, post-transcriptional modifications, gene fusion, mutations/single-nucleotide polymorphisms, different populations of RNA, total RNA, micro-RNA and transfer-RNA;Proteomics analyses normally involve targeted quantification of the major proteins that are identified as being upregulated by the RNA-Seq data. Analyses are conducted using nanospray ionization coupled with two-dimensional ultraperformance liquid chromatography/high-resolution mass spectrometry (UPLC-HRMS/MS) coupled with parallel reaction monitoring (PRM). These studies are conducted on a Thermo Q Exactive HF Hybrid Quadrupole-Orbitrap mass spectrometer operating in a targeted mode. Validation of differentially regulated proteins is conducted using rigorous stable isotope dilution UPLC-HRMS. Stable isotope-labeled protein standards are generated using stable isotope labeling by amino acids in cell culture (SILAC) based methodology ;Metabolomics and lipidomics analyses are conducted on serum samples that have been extracted using Bligh and Dyer methodology ,7. For bwww.lipidmaps.org). This means that BluePen Biomarkers can potentially discover lipid biomarkers where no standards are available to confirm structures. In this case, total synthesis is conducted using the extensive synthetic expertise that is available within the company so that absolute structural confirmation can be conducted before embarking on extensive clinical studies;Stable isotope-labeled metabolite and lipid standards are generated using stable isotope labeling by essential nutrients in cell culture (SILEC) methodology . There aBioinformatics analyses are conducted by Emerald Logic using a proprietary analytic platform that they have developed. This will identify signals in mRNA, protein, metabolite and lipid expression between cases and controls. An optimal panel of biomarkers will then emerge with maximal clinical specificity and sensitivity for a particular indication.Whole blood is normally provided to BluePen Biomarkers for genomics analysis; whereas serum is normally supplied for proteomics, metabolomics and lipidomics analyses. However, buffy coat or peripheral blood monocytes (PBMCs) are sometimes provided for proteomics analyses and platelets are sometimes provided for metabolism studies or specific mitochondrial protein quantification . BluePenDeveloping clinically useful biomarkers in biofluids is a complex process that often results in failure . TherefoQuantitative biomarker studies generally require the most sensitive means of detection possible ,11. The An authentic stable isotope-labeled analog of a biomarker is identical to the endogenous molecule, except for its mass . The resThe search for small molecule biomarkers that are predictive of cardiovascular disease, neurodegenerative diseases and cancers has been particularly intense and frustrating . HoweverBluePen Biomarkers was established in April 2016 to provide a coordinated approach to fully integrated biomarker solutions;The products of multi-omics research are integrated using sophisticated bioinformatics based on combinatorial signal processing and analytic approaches developed by Emerald Logic to provide a fully integrated biomarker solution;BluePen Biomarkers believes that by linking biomarker discovery and validation with the sophisticated bioinformatics provided by Emerald Logic that it will be possible to rationally approach the development of biomarkers for specific diseases;RNA-Seq is used to assess the potential utility of transcript profiling for biomarker analysis and upregulation of relevant proteins is confirmed by targeted proteomics;BluePen Biomarkers uses methods based on UPLC-HRMS for proteomics, metabolomics and lipidomics methods on their Thermo Q-Exactive HF instruments;This provides the only commercial multi-omics platform currently available that can quickly yield highly predictive biomarkers;The fundamental conviction of the company's founders is that any intervention that has a biologic outcome will have a detectable predictive biomarker signature.


Negative symptoms are core features of schizophrenia and can be grouped into two domains. These are apathy including anhedonia, avolition and asocialty as well as diminished expression including blunted affect and alogia. A large body of research found that ventral striatal hypoactivation is linked to negative symptoms. In particular, it has been shown that this neural correlate is specific for apathy but not diminished expression. Here, we investigated whether this dissociation can also be found in ventral striatum volume.We included brain structural T1 MRI data of 60 patients diagnosed with schizophrenia (SZ) and 58 healthy controls (HC). Negative symptoms in these groups have been assessed using the Brief Negative Symptom Scale (BNSS). We performed voxel-based morphometry (VBM) using the statistical parametric mapping package . We performed a region of interest (ROI) analysis of ventral and dorsal striatal volume between patients with schizophrenia and healthy controls. Furthermore, we analyzed the correlation of right and left ventral striatal volume with apathy and diminished expression in patients with schizophrenia. Moreover, we analyzed potential group differences in gray matter volume in an exploratory whole-brain analysis. Finally, we performed an exploratory whole-brain linear regression to identify potential correlations between the two negative symptom dimensions and gray matter volume. Patients with schizophrenia showed no differences in ventral striatal volume compared to healthy controls. Apathy or diminished expression did not correlate with ventral or dorsal striatal gray matter volume in patients with schizophrenia. In the exploratory whole-brain analysis we found significant less gray matter volume in the right insula of schizophrenia patients compared to healthy controls . Our exploratory whole-brain linear regression revealed no significant correlation between apathy or diminished expression and gray matter volume changes in patients with schizophrenia.Although a correlation of apathy and ventral striatal volume has been shown in a previous study with fewer subjects, we could not reproduce this finding in a larger group of 60 patients with schizophrenia . However, while these negative findings do not support the association between apathy and ventral striatal volume, there may be more subtle brain structural changes linked to the pathophysiology of apathy, which cannot be detected by voxel based morphometry. The gray matter reduction in the right insula in subjects with schizophrenia replicated findings from previous studies in schizophrenia .


Medical students matriculating in the coming years will be faced with treating an expansive increase in the population of older lesbian, gay, bisexual, and transgender (LGBT) patients. While these patients face healthcare concerns similar to their non-LGBT aging peers, the older LGBT community has distinct healthcare needs and faces well-documented healthcare disparities. In order to reduce these healthcare barriers, medical school curricula must prepare and educate future physicians to treat this population while providing high quality, culturally-competent care. This article addresses some of the unique healthcare needs of the aging LGBT population with an emphasis on social concerns and healthcare disparities. It provides additional curricular recommendations to aid in the progressive augmentation of medical school curricula.Abbreviations: Liaison Committee on Medical Education (LCME); LGBT: Lesbian, gay, bisexual, transgender In the year 2000, 1 to 2.8 million lesbian, gay, bisexual, or transgender (LGBT) adults aged 65 and older were living in the United States . As suchRecently, the Association of American Medical Colleges (AAMC) published a 300+ page resource for medical educators outlining the implementation of curricular and institutional climate changes to improve the healthcare of LGBT and gender nonconforming patients . The pusOlder LGBT adults experience significant health disparities related to aging . In a poAging LGBT individuals experience a wide array of physical and psychological healthcare concerns synonymous with their heterosexual, binary, or gender-conforming peers . HoweverWith these ‘chosen families’ comes significant differences in caregiving and social support networks in the older LGBT community. While studies of the general US population indicate that between 25–44% of caregivers are male, within the LGBT community there is an even percent of male and female LGBT caregivers . Thus suConsiderations regarding ‘chosen families’ and unique caregiving responsibilities impact decisions related to retirement and end-of-life care. Completion of a living will or durable power of attorney is approximately 29% for both LGBT adults and non-LGBT adults . HoweverIn accordance with LCME accreditation Standard 7.6 emphasizing culturally competent care and development of solutions for healthcare disparities , studentIn addition to addressing concerns related to health disparities, medical students must be advised about the unique support systems and potential stressors in order to provide improved, culturally competent care to their future patients. This can be accomplished by increasing exposure of students to older LGBT adults by utilizing a panel of local community members. This panel could be modeled from The Gay and Grey Program (GGP)’s trainings given by older LGBT adult volunteers to students and professionals in Portland, Oregon . OverallIn addition, complex end-of-life care decisions and the legal experiences of LGBT patients with ‘chosen families’ could be addressed in medical school ethics courses by utilizing a Problem Based Learning (PBL) approach. Unlike traditional passive learning with professor-designed didactic lectures, PBL involves active learning with dynamic interactions between learners and teachers . StudentIn order to educate a new generation of physicians equipped to provide culturally competent care, specific gaps in knowledge must be assessed. There are well-documented gaps in the cultural competency of LGBT older adult patients among health and social service providers . Gaps inSocietal problems of perceived discrimination, coupled with a lack of adequate training for future physicians, may contribute to unmet healthcare needs of the older LGBT patient population. Increased cultural competency related to physician-patient relationships must be addressed through progressive augmentation of medical school curriculum. As current and future healthcare providers, we must see that the needs of older LGBT adults are adequately addressed in medical education in order to ensure well-rounded, culturally competent care.


Gilles de la Tourette syndrome (GTS) is a sensorimotor disorder where the sensitivity to external and internal stimuli might be increased and unwanted responses to such stimuli cannot be sufficiently suppressed.Transcranial magnetic stimulation (TMS) studies indicate that, at rest, axonal excitability of cortico-spinal neurons and intra-cortical inter-neurons was consistently normal in GTS. However, synaptic excitability in cortico-spinal neurons and the SICI circuit may be lower than normal. In addition, an electrophysiological marker of sensory motor integration, SAI, was reduced in the baseline state consistent with reduced efficiency of synaptic inhibition. Given the possible influence of sensory inputs in triggering the release of tics reduced SAI may be a direct physiological reflection of increased access of sensory input to motor output in GTS. Experiments examining control of voluntary movements revealed that in GTS motor cortex excitability increases less than in controls when preparing a movement even though intra-cortical inhibition (i.e. SICI) normalises.In GTS the gain of many motor circuits may be reduced and hence less sensitive to small changes in input from other areas. These cortical changes may constitute an adaptive response to abnormal basal ganglia-motor cortex inputs.


Implementation of interprofessional clinical guidelines for the prevention ofneuropathic diabetic foot ulceration has demonstrated positive effects regardingulceration and amputation rates. Current foot care recommendations are primarilybased on research regarding the prevention of ulcer recurrence and focused onreducing the magnitude of plantar stress (pressure overload). Yet, foot ulcerationremains to be a prevalent and debilitating consequence of Diabetes Mellitus. Thereis limited evidence targeting the prevention of first-time ulceration, and thereis a need to consider additional factors of plantar stress to supplement currentguidelines.The first purpose of this article is to discuss the biomechanical theoryunderpinning diabetic foot ulcerations and illustrate how plantar tissueunderloading may precede overloading and breakdown. The second purpose of thiscommentary is to discuss how advances in biomechanical foot modeling can informclinical practice in the prevention of first-time ulceration.Research demonstrates that progressive weight-bearing activity programs to addressthe frequency of plantar stress and avoid underloading do not increase ulcerationrisk. Multi-segment foot modeling studies indicate that dynamic foot function ofthe midfoot and forefoot is compromised in people with diabetes. Emerging researchdemonstrates that implementation of foot-specific exercises may positivelyinfluence dynamic foot function and improve plantar stress in people withdiabetes.Continued work is needed to determine how to best design and integrate activityrecommendations and foot-specific exercise programs into the currentinterprofessional paradigm for the prevention of first-time ulceration in peoplewith Diabetes Mellitus. Exercise is often overlooked in current ulcer prevention guidelines.Abnormal plantar loading and foot function may contribute to ulceration.Progressive weight-bearing programs can be considered for ulcer prevention.Foot-specific exercises may improve foot function and ulcer prevention.Continued study may endorse inclusion of exercise into current guidelines.,Approximately one out of eleven adults, equating to 415 million people worldwide, havediagnosed or undiagnosed Diabetes Mellitus (DM)--,Among the numerous multi-system health consequences of DM, foot ulceration is an all toocommon problem. Lifetime prevalence estimations of foot ulceration in people with DM areas high as 25%, with a yearly incidence rate of 2-4%,recurrence,first-time ulceration. Yet, the evidenceto guide preventative efforts of first-time ulceration is strikingly limitedClinical guidelines have been developed to direct treatment and prevention strategiesfor foot ulceration, and are regularly updated based on current evidence---Biomechanical research has been an integral component underlying our understanding oftissue breakdown and in the development of ulcer prevention guidelines. For example, theuse of specialized footwear and/or insoles to relieve zones of high plantar pressure isfounded on the biomechanical theory that plantar tissue overload creates tissuebreakdown. While off-loading footwear is vital to ulcer healing and important to theprevention of ulcer recurrence, it is less clear how and when to apply the tissueoverloading principle to the prevention of first-time ulceration. Recent evidencesuggests that too much off-loading, as measured by decreased weight-bearing activityfrequency, may be counterproductive in ulcer prevention effortsThe purposes of this article are to present the contemporary biomechanical theoryunderpinning diabetic foot ulcerations and to discuss how advances in research andbiomechanical foot modeling can inform and influence clinical practice in the preventionof first-time ulceration.-,-overloading via momentary high stress or the accumulation ofundetected and repeated low to moderate stress on an area of the plantar neuropathicfootrepetition ofmechanical loading is as important as the magnitude of loading and howrepeated exposure to episodes of stress lowers the threshold of tissueinjury,-Neuropathic foot ulceration begins with insufficient blood glucose control, and it is acombination of intrinsic and extrinsic elements that beset the foot of an individualwith DM. Peripheral neuropathy coupled with the external stress of weight bearing hasbeen recognized historically as the primary pathway to neuropathic ulcerationunderloading may precede mechanical overloading of plantartissue. People with DM and peripheral neuropathy (DMPN) have reduced or variableweight-bearing activity prior to ulceration,,Therefore, external mechanical stress is a composite value that includes direction ofload application, time , and magnitude (force/area),,-Current ulcer prevention guidelines advocate for an interprofessional approach thatincludes physicians, nurses, physical therapists, orthotists, caregivers, and patients.A comprehensive strategy, including regular glucose monitoring, patient education, dailyfoot inspection, regular foot screenings and care, and footwear modification, isrecommendedmagnitude of plantarloading (pressure) are commonly combined with reduced weight-bearing activity todecrease the repetition of loading. Evidence suggests footwearintervention should aim for a pressure relief target value of 30% to reduce andredistribute plantar pressure and thus mitigate the potential for tissue breakdownand the assessment of the pressure-relievingeffects of the prescribed custom footwear/insoles. Further, footwear intervention iscontingent on patient adherence, as adherence below 80% negatively affects the footwearefficacy,,Contemporary recommendations for footwear intervention primarily ascribe to theoverloading theory of ulceration and remain an important aspect of ulcer prevention.Footwear interventions aimed at reducing the re-ulceration rates. While thepositive effects of footwear intervention are clear, differences in study designs andfootwear/insole strategies (over-the-counter vs. custom) have created different resultsacross studies. Nevertheless, a recent randomized clinical trial (RCT) that followedbest practice guidelines demonstrated that people with DMPN had less ulcer recurrencewhen wearing custom footwear with monitored pressure relief (<200 kPA or 25%reduction at targeted forefoot/midfoot sites) versus a custom footwear only groupIn a systematic review, van Netten et al.,,Recommendations for prevention of first-time ulceration also rely on the overloadingparadigm previously described. Rizzo et al.While the need for more research regarding footwear intervention and foot screeningpractices remains important, additional factors that may also prevent first-time tissuebreakdown should be considered. These factors include the frequency of weight-bearingactivity and the quality of dynamic foot function. Weight-bearing activity frequency isan important consideration as it pertains to plantar tissue tolerance to stress. Ratherthan reducing weight-bearing activity prior to tissue damage in the at-risk patient,maintenance or progression of weight-bearing activity  may helpavoid tissue underloading. An understanding of dynamic foot function and how the footmay be internally stressed during each step of every day in a patient with DMPN isequally important. Abnormal stress secondary to altered dynamic foot function fromneuropathic tissue changes may expedite deformity and plantar tissue damage. Withcontinued research focused on weight-bearing activity and dynamic foot function,interventions to modify these factors may advance and warrant inclusion in clinicalguidelines.increase the risk for futureulceration,,While exercise (including weight-bearing activity) is recommended to improve glycemiccontrol, current guidelines are vague regarding how clinicians should dose andpromote exercise in people with DM who are at risk for ulceration. Further, activityincrease in people with DM is complicated by co-morbid medical conditions. Yet,equally important is the idea that plantar tissue may already be deconditioned priorto first-time ulceration. Research demonstrates that too much off-loading duringpreventative care may potentially ,Efforts to increase weight-bearing activity and promote plantar tissue resilience andglycemic control in people with DMPN are promising regarding tissue breakdown. TwoRCTs demonstrate that ulcer rates do not increase following an intervention toincrease weight-bearing activity,reduce ulceration risk has yet to be delineated. Apossible barrier to the development of such a protocol is the lack of an establishedbiomarker  toguide the assessment of plantar tissue integrity. The inability to definitivelyassess tissue integrity and adjust activity dosage in a patient-specific mannerlikely precludes inclusion of weight-bearing activity regimens in currentpreventative guidelines. For this reason, it is relevant to consider not only howoften the foot is stressed during weight-bearing activity, but alsohow it is stressed.At present, conscientious patient instruction should include a program of regulardaily weight-bearing activity in an attempt to improve glycemic control andpotentially maintain plantar tissue integrity-In-vivo assessment of dynamic foot function fosters hypotheses generation about howinternal structures are performing and consequently stressed during weight-bearingactivity. Additionally, dynamic foot function represents the behavior of the footduring the time period when the primary extrinsic stimulus of ulceration occurs. Dynamic foot function can be assessed using single- or multi-segmentmodeling approaches . Single--Single-segment modeling investigations of foot biomechanics in people with DMPN haveproduced mixed results regarding factors potentially linked to tissue breakdown.There have been variable findings regarding passive ankle joint mobility, anklemotion during walking, and forefoot plantar pressure,,,-,,st metatarsal and lateral forefoot sagittal plane ROM, duringwalking to elevated forefoot plantar pressures in people with DMPN. Changes in DMPNmulti-segment kinematics are also present during higher-level tasks. Hastings etal.Studies employing multi-segment foot modeling approaches have identified changes inkinematics during walking in people with DM and DMPN and in people with DMPN with ahistory of ulceration,,The use of multi-segment models in diabetic foot research demonstrates how morespecific modeling approaches can better link regions of foot dysfunction to regionsof diabetic foot pathology ; however, relationships between foot kinematics and plantarpressures are commonly generated from data collected during separate walking trials.Giacomozzi et al.,both ankle andmidfoot power may better reflect the degree of internal stresses, particularly at themidfoot, during functional tasks in people with DMPN. DiLiberto et al.and midfoot as factors of abnormal dynamic foot function inpeople with DMPN. Specifically, the reduced active mechanism support at the archraises questions regarding abnormal internal stresses on passive structures at bothregions of the foot. The cumulative effect of this kinetic pattern may contribute tothe development and/or progression of midfoot deformityApplication of single- and multi-segment modeling approaches has also advanced ourunderstanding of kinetic performance  in people with DMPN. Studiesusing single-segment foot models demonstrate a reduction in peak ankle plantarflexionpower during walking in people with DMPN, as compared to healthy controls,Changes in DMPN dynamic foot function have been attributed to neuropathic tissuechanges such as decreased tissue extensibility  and muscle atrophy/fatty infiltration. Recent research specifically supportsthe relationship between neuropathic muscle changes, multi-segment foot kinematics,and deformity in people with DMPN. Hastings et al.There is increasing focus on how to design intervention strategies to improve dynamicfoot function in people with DM who are at risk for ulceration,-Some studies have demonstrated promising biomechanical results by incorporatingfoot-specific exercises in people with DMPNPreservation of plantar tissue integrity and foot function for the prevention offirst-time neuropathic foot ulceration is a challenging endeavor for people with DMPNand their care providers. The effectiveness of preventative interventions is predicatedon blood glucose control, the advancement of the neuropathic process, and plantar tissueintegrity. It is imperative for clinicians to address the interplay between themagnitude (pressure), frequency (weight-bearing activity), and quality (dynamic footfunction) of foot stress. One of the most difficult challenges is to determine how tostrike an effective balance between too much (overloading) and too little (underloading)stress. When deciding between parameters of loading, the clinician is advised that thethreshold for tissue damage is contingent on both the current state of the foot tissueand how it will be stressed in the future.While there is room for improvement regarding foot-screening procedures to best evaluatetissue integrity and predict injury, recent research offers insight that may augmentcurrent clinical guidelines. In addition to the interprofessional approach and foot carepractices described previously, advising patients on interventions to address thefrequency and quality of stress should be considered. A progressive and well-monitoredweight-bearing activity regimen that includes walking, balance, and leg strengtheningcan positively influence patient health and function. Activity regimens not only promoteglycemic control, potentially slowing the effects of neuropathy, but also possiblydecrease the potential of plantar tissue underloading. Further, multi-segment modelinginvestigations suggest that addressing dynamic foot function is an additional supplementfor the prevention of first-time ulceration. Specifically, assessment of forefoot andmidfoot mobility, as well as assessment of intrinsic and extrinsic muscle strengthshould be part of routine foot screening examinations. Examination findings should guideclinical decisions for implementation of progressive exercise programs to improvedynamic foot function or direct patients to other appropriate interventions/careproviders . Continued work is needed to determine how to best design andintegrate activity recommendations and foot-specific exercise programs into the currentinterprofessional paradigm for the prevention of first-time ulceration in people withDiabetes Mellitus.


Postpartum haemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide. Experimental and clinical studies indicate that prolonged oxytocin exposure in the first or second stage of labour may be associated with impaired uterine contractility and an increased risk of atonic PPH. Therefore, particularly labouring women requiring cesarean delivery constitute a subset of patients that may exhibit an unpredictable response to oxytocin. We mapped the evidence for comparative studies investigating the hypothesis whether the risk for PPH is increased in women requiring cesarean section after induction or augmentation of labour.clinicaltrials.gov and the WHO registry platform. We identified a total of 36 controlled trials investigating the exogenous use of oxytocin in cesarean section. Data were extracted for study key characteristics and the current literature literature was described narratively.We performed a systematic literature search for clinical trials in Medline, Embase, Web of Science, and the Cochrane Library (May 2016). Additionally we searched for ongoing or unpublished trials in Our evidence map shows that the majority of studies investigating the outcome PPH focused on prophylactic oxytocin use compared to other uterotonic agents in the third stage of labour. Only 2 dose-response studies investigated the required oxytocin dose to prevent uterine atony after cesarean delivery for labour arrest. These studies support the hypotheses that labouring women exposed to exogenous oxytocin require a higher oxytocin dose after delivery than non-labouring women to prevent uterine atony after cesarean section. However, the study findings are flawed by limitations of the study design as well as the outcome selection. No clinical trial was identified that directly compared exogenous oxytocin versus no oxytocin application before intrapartum cesarean delivery.Despite some evidence from dose-response studies that the use of oxytocin may increase the risk for PPH in intrapartum cesarean delivery, current research has not investigated the prepartal application of oxytocin in well controlled clinical trials. It was striking that most studies on exogenous oxytocin are focused on PPH prophylaxis in the third stage of labour without differing between the indications of cesarean section and hence the prepartal oxytocin status.The online version of this article (10.1186/s12884-017-1584-1) contains supplementary material, which is available to authorized users. Postpartum haemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide –4. ApproThe most widely used uterotonic drug for augmenting labour or to maintain uterine contractility during labour is oxytocin , 16. OxyConsidering that PPH rates are higher in cesarean section compared to spontaneous labour , particuWe adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) protocol for identifying, screening and eligibility of studies to conduct the present research work ). Furthermore, significantly more women in the labouring group compared to the non-labouring group required additional uterotonic agents . (ii) The other dose-response study from Balki et al. estimated the minimum effective intravenous dose of oxytocin required for adequate uterine contraction after cesarean delivery for labour arrest, however, without using an active control group [From 36 studies identified, 8 studies (1705 patients) included solely women requiring intrapartum cesarean delivery, mainly because of labour arrest –33. Howeturients . Thirty-ol group –32. WhetOur mapping also revealed that the majority of studies investigating PPH rates for different treatment groups are focused on prophylactic uterogenics and included women with different types of cesarean delivery (intrapartum and prelabour cesarean section). However, the PPH rates given in these studies were not stratified according to the indications for cesarean section. In addition, the prepartal oxytocin status was not considered as confounding factor by conducting subgroup analyses –63.ClinicalTrials.gov Identifier: NCT01869556 and NCT02794779). The estimated completion date for both studies is by the end of 2017. In addition, we identified HOLDS, a multicentre, double-blind randomised controlled trial to compare standard and high dose regimens of oxytocin for women with confirmed delay in the first stage of labour (http://www.isrctn.com/ISRCTN99841044). This trial randomises 1500 women and measure differences in rates and complications associated with cesarean section. If this study provides a subgroup analysis of PPH rates in those women requiring cesarean sections, important insights addressing the present research question will be given.The search for ongoing and unpublished studies identified 2 RCTs which may provide subgroup data estimating the blood loss and risk for PPH after cesarean section for labour arrest  Checklist. (DOC 60 kb)Additional file 2:Search Strategy in Medline (OvidSP). (DOCX 14 kb)