Liver lesions are difficult to diagnose and to differentiate primary from metastatic carcinoma, while Biopsy has its limitations. Cell block technology is easily accessible with high diagnostic accuracy. Our aim is 1) To find the role of cell block technology as an alternative to biopsy in identifying liver lesions; 2) To find the efficacy of cell block along with immunohistochemistry (IHC) and ancillary studies in differentiating primary from metastatic lesions; 3) To identify the site of origin of metastatic lesions. This is a descriptive study undertaken in two tertiary care hospitals over a period of three years.Retrospective review of adequate samples from fine needle aspirations from liver lesions under radiological coverage, converted into cell block was done. IHC was applied as needed. Usefulness of cell block preparation was evaluated, and the final diagnosis correlated with the biopsy results.Analysis of 323 cases found sensitivity of 98.75% and positive predictive value of 99% for all lesions. Sensitivity for metastatic carcinomas was slightly more than hepatocellular carcinoma. However, accuracy of cell block results for individual metastatic lesions and site of origin was less. IHC and morphological pattern worked as an important adjunct in the final diagnosis. On the other hand, contribution of viral markers as a supplement in the final work up was ambiguous. High precision of validity results of cell block technology in comparison with biopsy highlights its pivotal role in conjunction with supportive tests for diagnosing and differentiating liver lesions as well as identifying primary sites in liver metastasis.  Carcinoma of liver has a prevalence of 2-8% worldwide . MetastaDiagnostic sensitivity of FNAC of liver varies from 67-100% and specificity 93-100% , 5. ThisThe Aim of this study was to evaluate the scope and accuracy of cell block following FNAC with or without immunohistochemistry along with ancillary studies for diagnosing various liver lesions . Also, we aimed at evaluating the role of cell block for differentiating primary hepatic malignancy from metastatic lesions of the liver along with the use of cell block as an adjunct to FNA in sub typing the various metastatic carcinomas and identifying the source or the origin of the malignancy.This is a retrospective descriptive study carried out at both KPC medical college, Kolkata and Medical College, Patna over a period of 3 years. As it was a retrospective study no ethical issue or patient consent was needed. A detailed previous history of any other preexisting liver disease and record of serological viral marker, where available, were collected from the surgery department. FNAC was carried out either blindly or with USG/CT guidance in the radiology department. Direct air-dried smear were stained with MGG. Some smears were immediately fixed in 95% alcohol and stained with Pap. The remaining material in the syringe was allowed to clot to form cell block, where aspiration was adequate for cell block formation .Results were analyzed by two independent senior pathologists and a final conclusion of the diagnosis was derived after discussions with a third senior faculty. All the procedures were performed following the standard operating procedures with routine and con-sistent checks to identify and address various types of errors and omissions, ensuring data integrity, correct-ness and completeness of all the available records. The quality control checks included accurate patient identification, proper fixation time, adequate processing measures, appropriate embedding techniques, precision in microtome sectioning, unacceptable artifacts and regular inspection of controls used in IHC and special stains to determine the correctness in our method.Statistical analysis was done using Chi-square to compare various parameters. The P-value was calcula-ted using the sampling distribution of the test statistics under the null hypothesis and our sample data as in a two-sided test. In our analysis, an alpha of 0.05 was used as the cut off for significance. When the P-value was less than 0.05, we rejected the null hypothesis that there is no difference between the means; thus, we concluded that a significant difference exists. So, in our study, P-value below 0.05 was taken as significant and over 0.05 as not significant. Fischer’s exact test was also done to compare various parameters in the patients.Out of 416 cases who underwent guided FNAC from liver, 15 cases were considered inconclusive for reporting due to very scanty cellularity or blood only aspirate. Among the adequate aspirations which were 401 in number, the aspirate was enough to make cell block in 349 cases. Others were reported on FNAC as benign or malignant and were not included in our study.Age range varied from 42 to 84 years, with a mean age of 65.5 years. Hepatocellular carcinoma was in the range of 48-84 years with a mean of 67.2 years while metastatic age range was 42-81 years with a mean of 58.4 years. Highest amount of inadequate and inconclusive smears was when the lesion size was <1 cm. Male to Female ratio was 6:4. In 251 out of 349 cases, immunohistochemical study could be done on cell block preparation. Among the rest 98 cases, 54 did not require IHC due to clear morphology on H&E staining for a final diagnosis. Of these cases, 23 were non-compliant for IHC study, mostly due to economic reasons and decided to go for direct incision biopsy as it is the gold standard. Of the patients, 18 opted for further investigation and treatment in an oncology center, while 3 were lost in follow up after H&E reporting on cell block. So, the total biopsy results were obtained for 323 cases which remained our study sample . On cell block, with or without immunohistoche-mistry, 43 cases (13.31%) were positive for hepato-cellular carcinoma, 254 cases (78.63%) were positive for metastatic lesions, 7 cases (2.1%) were suspicious of malignancy and 19 cases (5.8%) were designated as benign lesions .Individual comparison of cell block results with that of biopsy, which is the final diagnostic tool, showed a few discrepancies in interpretation of individual lesions. In biopsy, 52 cases (16.09%) were primary hepato-cellular carcinoma, 253 cases (78.32%) were metastatic lesions while 15 cases (4.64%) were actually benign and 3 cases (0.9%) were regenerative nodules . A detaiThere was occasional variance between both the results of cell block and biopsy in almost all lesions, however the disparity was obvious in undifferentiated carcinoma with eight false positive cases. Hepatocellular carcinoma was diagnosed when polygonal cells with eosinophilic cytoplasm, large vesicular nucleus with prominent nucleoli were seen in the smears. When smears showed malignant cells arranged in loose clusters or sheets of pleomorphic cells with moderate to abundant cytoplasm, they were diagnosed as metastatic adenocarcinoma. Adenocarcinoma metastasis from GIT, ovary, and pancreas with metastatic adenocarcinoma from gall bladder was differentiated with IHC and other ancillary studies like radiological imaging, history along with clinical examination of the patient. Similarly, for undifferentiated metastatic carcinoma, the site of origin of primary focus was determined by considering all the above parameters. Round cell tumor had tight clusters of monomorphic cells with nuclear molding and scanty cytoplasm. Sarcoma metastasis showed oval to spindle cells with indistinct cytoplasm. Regenerative nodules had hyperplastic hepatocytes with no distinctive cyto-architectural features and were mistaken as suspicious for malignancy on cytology. Hematological diagnosis was also missed in cell block technique. Due to aspiration from necrotic area, a few cases of metastatic adenocarcinoma were missed. Immunohistochemistry was utilized to arrive at the final diagnosis, as and when essential. Morphology was observed from the smears obtained with MGG, PAP and H&E routinely from the cell block preparation. Special stain was PAS (to look for mucin) and reticulin (to look for trabecular strand) was also performed on cell block preparation. In morphology, P=0.0001) (b) hepatocytic appearance  (P=0.0000) C) Intracellular bile (P=0.005);1) Cytological features used were a) trabecular pattern (2) Gland formation-well-formed cluster of glands mostly seen in moderately to well differentiated adenocarcinoma.3) Special stain- a) Reticulin stain was used to see the trabecular strands thickness which was usually present in hepatocellular carcinoma and some benign lesions whereas it was absent in metastatic carcinoma.b) PAS to look for mucin was present in some varieties of moderately differentiated to well differentiated metastatic carcinoma (mucin secreting adenocarcinoma) whereas it was universally absent in hepatocellular carcinoma and benign lesions.Immunohistochemistry was done with CK7 & CK20, Hep Par-1 and p CEA staining. All cases of hepato-cellular carcinoma were positive to Hep Par-1 and negative for CK7 and CK20. pCEA was equivocal. All cases of moderately to well differentiates adenocarci-nomas were strongly positive for CK7 and weakly positive for CK20 and pCEA. Hep Par-1 was uniformly negative. Poorly differentiated metastatic carcinoma was positive for CK7 and negative for Hep Par-1. CK20 and pCEA were equivocal and were not helpful. Benign lesions of the liver were Hep Par-1 positive except for the abscess (2 cases). α feto protein was highly positive for hepatocellular carcinoma but poorly differentiated lesions also showed focal positivity in certain cases. Neuroendocrine markers were positive for round cell tumors with chromogranin displaying stronger positivity than synaptophysin. A few equivocal results were also discerned in metastatic lesions. SMA was positive in sarcomatous lesions which along with morphology helped in diagnosis. All the other markers were negative.Serological studies of viral markers were documented from the patient’s history recorded in the surgical department and were available for 16 cases of metastatic carcinoma and 39 cases of HCC. Serum viral markers including HbsAg  and anti HCV antibody checked. Viral assay for both Hepatitis B (titer of Hep B DNA) and Hepatitis C (titer of Hep C RNA) were done. While either hepatitis B or Hepatitis C were present, in cases of hepatocellular carcinoma (39/323) consistently more often than in both poorly differentiated and moderately to well differentiated metastatic adenocarcinoma, it is not helpful to differentiate between benign liver disease and hepatocellular carcinoma. The number (16/323) of viral markers done in the metastatic group was very less, however an increased percentage was found to be positive in those tested as it was done only in cases showing liver damage (obtained by history and elevated liver enzymes) .A detailed statistical analysis showed sensitivity of all the lesions diagnosed through cell block method to be 98.75% with positive predictive value of 99% and P-value highly significant at <0.00001. Diagnosing metastatic carcinoma was also very accurate with positive predictive value of 99.2%. Primary lesion like hepatocellular carcinoma with 100% positive predictive value, 91.5% sensitivity and significant P-value had very precise results on cell block. However, differentiating the various types of metastatic lesions on cell block was less on target with accuracy ranging from 66.66% to 100% for various carcinomas . FNAC from liver has proven to be a better diagnostic tool than core needle biopsy or open biopsy in terms of cost, procedure and early diagnosis . Liver a et al. and Willems et al.  bigger than 5 cm had better successful aspiration and greater accuracy than tumor <1 cm. Similar results depending on tumor size is detected by Voits et al. , 11. For similar to Tao et al.  whose st et al. , 14. Int et al. . et al. ( et al. ( et al. and Fan et al. ( et al. and Edoo et al. (Immunohistochemistry helps in classification and prognostication of hepatocellular tumors which is shown in the study by Cheuk-lam Lo et al. . Careful( et al. . CK7 andn et al. , 19. Theo et al. , 21 foun et al. and Nguyen et al.  ( et al. ( et al. and Murugavel et al. ( et al. ( et al. ( et al. (pCEA is a useful contributor to the diagnosis of small liver tumor still amenable by surgery. Wang et al.  , 23 show( et al.  stated tl et al. , 26 corr( et al.  and Veen( et al.  found ch( et al.  showed t et al. ( et al. (et al., Di Bisceglie et al. and Yuen et al. ( et al. ( Noh et al.  found ou( et al.  believedn et al. -35 also ( et al.  found ou et al. (et al. and Iyer et al. ( et al. (Mathew et al.  discover et al. , 35. Ourr et al. , 38 thour et al. . Our stur et al. . In a fe( et al.  found poCell block converts a suspicious report into a definitive diagnosis. We have to ask ourselves, “Do we really need to do core biopsy?” Because in resource limited areas cell block is a poor man’s core needle biopsy and can be used as an adjunct to histopathology.In cell block, architecture of tumor is maintained at places whereas core biopsy can have crush artifact. Even in higher centers, in certain cases, cell block is better than core biopsy, which is formalin fixed, as studies show that formalin can hinder in DNA extraction, especially in molecular studies. However, in pediatric age group, FNAC with cell block can be used in certain cases though core biopsy remains the gold standard in most pediatric tumors. Some believe that biopsy tract seedling using unsheathed needle is probably more common than fine needle aspiration spilling, though there is no proven data. A satisfactory FNAC sample with cell block is a very useful diagnostic tool for evaluation of various liver lesions with high degree of diagnostic accuracy. Also, it reduces the timing, the economic burden and morbidity of the patient.In cases where diagnosis by FNAC is equivocal, it is recommended to perform FNA with cell block preparation and IHC studies as a part of routine laboratory practice to improve diagnostic precision. Because of its high sensitivity, Cell Block technique is a useful adjunct to routine FNA smear because multiple sections can be cut from a cell block and IHC and special stains can be applied. Viral markers, if available, can be correlated to arrive at the final diagnosis. The combination of cell block with all these adjunct techniques is of immense help in identifying primary carcinoma and differentiating it from metastatic deposits in the liver without any invasive procedure. The source of the primary site in metastatic deposits can be detected which can guide the treatment protocol and even helps in predicting the prognosis.


Cardiovascular Diabetology, Sinha et al. :66) reported that prediabetes (defined as a fasting plasma glucose concentration of 100–125 mg/dL) was associated with a higher lifetime risk of heart failure in middle-aged White adults and Black women, with the association attenuating in older Black women. This study provides important evidence that the risk of heart failure is increased in people with a fasting plasma glucose concentration as low as 100 mg/dL, supporting the definition of prediabetes according to the American Diabetes Association guideline. The study also strongly supports the notion that prediabetes should be regarded not only as a high-risk state for the development of diabetes but also as a risk factor for cardiovascular morbidity.In a recently published paper in  Prediabetes, also termed “intermediate hyperglycemia,” is an intermediate metabolic state between type 2 diabetes mellitus (T2DM) and normoglycemia and includes patients with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) , 2. IFG Cardiovascular Diabetology, Sinha et al. [In a recently published paper in a et al.  analyzeda et al. . This sta et al. , Cai et a et al.  publishea et al. . The resa et al. . TogetheNotably, individuals with prediabetes are more likely to progress to T2DM. Therefore, the risk of heart failure may be confounded by progression to T2DM. Unfortunately, these studies did not adjust for such confounders. In future studies, a series of blood glucose measurements is needed in individuals with prediabetes to determine the blood glucose trajectory and the association of diabetic complications, including heart failure. Furthermore, it is known that lifestyle interventions in people with prediabetes can reduce the risk of cardiovascular events and all-cause mortality . It is a


Periprosthetic joint infection (PJI) is the most devastating complication of joint replacement that seriously affects the quality of life and causes a heavy burden to the families and society. Due to shorter hospital stays, lower costs, improved joint function and less morbidity, a process of debridement, antibiotics and implant retention (DAIR) is recommended as the preferred treatment for acute periprosthetic joint infection. However, the factors that impact the success rate of DAIR remain controversial. This article evaluates the influential factors of DAIR and provides insights for orthopaedics surgeons to make optimal decisions to improve the success rate of DAIR.Staphylococcus aureus (MRSA) infections may be associated with lower DAIR success rate. To the contrary, early surgery, radical debridement, exchange of removable components, washing with iodine and vacuum sealing drainage (VSD) may improve the success rate of DAIR. A sinus tract may not be absolutely contraindicated, but surgeons should treat it with caution. As there is no consensus on many issues, more high-quality research is required.The poor general condition of patients, high preoperative C-reactive protein (CRP) level, repeated joint surgeries, and Methicillin-resistant  PJI is the most serious complication that contributes to more than a quarter of revision surgeries after joint arthroplasty , 2. As pThe treatment of PJI aims to eradicate infection, relieve pain and improve function. The therapeutic regimens include simple antibiotic treatment, DAIR, one-stage revision or two-stage revision, arthrodesis and amputation , 6. Due DAIR is currently considered the preferred treatment for acute PJI due to its low trauma, satisfactory cost-effectiveness and less impairment on joint function , 9, 10. et al [DAIR is only suitable for those PJI patients with good conditions of bone and soft tissue in whom no sinus tract exists between the joint prosthesis and the skin . Qasim eet al  showed tWith the development of a surgical technique for DAIR and the application of postoperative antibiotics, some studies showed that the existence of a sinus tract was no longer an absolute contraindication for DAIR. A retrospective study reported 14 PJI cases of a sinus tract treated with radical debridement, removal of dead tissue, shaving of pseudo-membrane, and intraoperative irrigation with a large volume of physiological saline, hydrogen peroxide and iodine. A satisfactory outcome was achieved in all patients as there was no recurrence of infection after 1–5 years follow-up [et al [et al [et al [Preoperative CRP level is also an influential factor contributing to a failed outcome of DAIR . Vilchezet al  believedl [et al  believedl [et al  reportedet al [ et al [Previous joint surgery also affects the prognosis of DAIR. Abrman et al  reported [ et al  showed aIn addition to the above factors, age, immunity and nutritional conditions, the American Society of Anesthesiologists (ASA) score, and complications such as hypertension and diabetes also affect the success rate of DAIR .There is no consensus on age. Although most scholars suggest increased age as a risk factor for failure, recently a high-quality meta-analysis  reportedStaphylococcus infection has been reported [Staphylococcus infection [et al [Staphylococcus infection. Wouthuyzen et al [Staphylococcus should be reconsidered. A recent study found that the success rate in patients treated with DAIR for Staphylococcus infection was 76.2% [Although a 100% success rate of DAIR for reported , most stnfection , 24–26. n [et al  reporteden et al  showed tStreptococcus is relatively high [et al [Streptococcus infection was 84%. However, in 2017, a large multicenter retrospective study showed that the success rate of DAIR for Streptococcus infection was only 57.9% [The success rate of DAIR for treating periprosthetic infection caused by ely high , 28. Lamh [et al  reportedly 57.9% .Periprosthetic infections caused by gram-negative bacteria have been infrequently reported. A large multicenter retrospective observational study  reportedStaphylococcus, Acinetobacter, Propionibacterium species, and Corynebacterium species which were more common in seronegative infections. This study suggested that low virulence infections may contribute to a relatively high success rate. However, the sample size was small and further data are needed.McArthur et al  reportedet al [et al [Fehring et al  showed al [et al  suggesteet al [et al [Sendi et al  reportedl [et al  reportedl [et al  reportedThe presence of biofilm on the surface of an implant is the most important reason for the transformation of an early infection of an artificial joint into a chronic infection . Three wet al [et al [Liu et al  reportedl [et al  showed tl [et al  suggestel [et al , 40. We Thorough debridement is essential to the success of DAIR. All infected tissues, synovial membrane, necrotic tissues, scar tissue and foreign materials must be completely removed. The success rate of DAIR in PJI patients is very low if debridement is not performed .et al [et al [The prosthesis is retained when DAIR is performed to treat PJI, but removable components must be exchanged whenever possible , 35, 42.et al [et al [High volume povidone-iodine and low-pressure irrigation should be used intraoperatively with a lavage volume at least 9 L. Li et al  reportedl [et al VSD helps to continuously drain necrotic tissue and exudate, eliminate edema, stimulate growth of the granulation tissue, improve local blood supply and enhance local immunity. Since its development, the VSD technique has been applied to the treatment of PJI with increasing frequency.et al [The negative pressure value of VSD also had a significant influence on the effect of drainage. When high negative pressure drainage was performed, the total drainage and infection control rate were significantly better compared to low negative pressure drainage . In 2014et al  reportedWe suggest VSD be used for selected patients because of limitations such as requirement for frequent exchange of materials which increases hospitalization expenses and hospital stays. et al [et al [et al [et al [et al [vs. 71%). Moreover, Jacobs et al [A voluminous literature discussed the relationship between single or multiple debridement and the success rate of DAIR. Some scholars reported that multiple debridement was related to the increased failure rate of DAIR , 47–50. l [et al  also repl [et al  reportedl [et al  reportedbs et al  found thWhen PJI patients were treated by DAIR without postoperative antibiotics, the failure rate after 3 years follow-up was as high as 86% .For PJI patients with positive bacterial culture and drug sensitivity test results, antibiotics sensitive to pathogenic bacteria should be used after DAIR. The selected antibiotics also should be biofilm- penetrative to kill the pathogenic bacteria remaining in the biofilm after DAIR.et al [et al [et al [For PJI patients with negative bacteria culture or no drug sensitivity results, empirical antibiotic therapy usually is required. Selected antibiotics must have an adequately broad antibacterial spectrum to cover common pathogenic microorganisms. Sousa et al  suggestel [et al  reportedl [et al  in 2013 As to the duration of antibiotic treatment after DAIR, the Infectious Diseases Society of America (IDSA) advises initial intravenous therapy for 2–6 weeks followed by oral antibiotics for 3 months after hip surgery or 6 months after knee surgery. Several studies showed no differences in infection control rate when comparing shorter duration with longer duration postoperative antibiotics. Other studies indicate that prolonged parenteral antibiotic therapy increases the economic burden and the risk of drug resistance , 56.DAIR is the preferred treatment for acute PJI with lower trauma and cost compared to revision surgery. A poor general condition of the patient, high preoperative CRP level, repeated joint surgery, MRSA infections may be associated with reduced DAIR success rate. Early surgery, radical debridement, the exchange of removable components, washing with iodine and VSD may improve the success rate of DAIR. A sinus tract may not absolutely contraindicate DAIR, but surgeons should treat it with caution. Orthopedic surgeons should take precautions to achieve a better outcome in PJI patients. As studies about DAIR are mostly retrospective and involve small samples, there is still no consensus on many aspects of DAIR effectiveness. More high-quality researches are required to improve the success rate of DAIR for PJI.


Appl. Mech.86, 011002 (doi:10.1115/1.4041352)) is used to infer power-law creep parameters, the creep exponent and the associated pre-exponential factor, from noise-free as well as noise-contaminated indentation data. A database for the Bayesian-type analysis is created using finite-element calculations for a coarse set of parameter values with interpolation used to create the refined database used for parameter identification. Uniaxial creep and stress relaxation responses using the identified creep parameters provide a very good approximation to those of the ‘experimental’ materials with stress exponents of 1.15 and 3.59. The sensitivity to noise increases with increasing stress exponent. The uniaxial creep response is more sensitive to the accuracy of the predictions than the uniaxial stress relaxation response. Good agreement with the indentation response does not guarantee good agreement with the uniaxial response. If the noise level is sufficiently small, the model of Bower et al.  provides a good fit to the ‘experimental’ data for all values of creep stress exponent considered, while the model of Ginder et al.  provides a good fit for a creep stress exponent of 1.15.Load and hold conical indentation responses calculated for materials having creep stress exponents of 1.15, 3.59 and 6.60 are regarded as input ‘experimental’ responses. A Bayesian-type statistical approach (Zhang  Instrumented indentation is attractive for identifying creep properties as it is non-destructive, requires a relatively small specimen, and has been used for the identification of mechanical properties of a broad range of materials. However, indentation involves a complex deformation field, and extracting material properties from experimentally measured indentation quantities can be complex and non-unique.et al. )et al.  and from [et al. .et al. [Here, the Bayesian statistics-based approach of Zhang et al.  is used  (i)Can very different power-law creep parameters give nearly the same responses in load and hold indentation creep? There are sets of rate-independent plastic material parameters that have indistinguishable force versus depth responses in conical indentation but very different uniaxial responses –17. (ii)Does using the residual surface profile in addition to or instead of the indentation depth versus time data improve the quality of the prediction? (iii)How sensitive is the predicted creep response to noise in the ‘experimental’ indentation data? (iv)et al. [et al. [How do the power-law creep properties obtained using the analytical steady-state creep results of Bower et al.  and Gind [et al.  compare The questions addressed include:. 2Indentation into an isotropic elastic power-law creep solid by a conical indenter is modelled as sketched in Calculations are carried out for an indenter angle on depth . The indm=htanγ .The calculations are carried out using a quasi-static Lagrangian implementation in the commercial finite-element program ABAQUS  standard (a)The magnitude of the indentation force in the As described in the ABAQUS  manual, The coefficient of friction is taken to be equation  are termWith  (b)The elastic-creep constitutive relation of ABAQUS  standardThe creep part of the rate of deformation tensor, . 3The equations of the Bayesian-type statistical approach used to infer the creep parameters given in .The ‘experimental’ indentation data consist of: (i) a vector characterizing the residual surface profile, Finite-element solutions for a normalized residual surface profile, denoted by Treating the indentation depth versus time data and the surface profile data as being independent, the posterior probability The constants et al. [The likelihood functions, which measure the difference between the ‘experimental’ data and the predicted responses in the database, are 3.4p amorphous selenium (Se) at For Se, the values of ken from , and the is from . For CsHble 1 of . The val 1(a) of . For Sn,ken from  and the  2(b) of . The vale 45 GPa  and the ken from .. 5 (a)The imposed loading history models a constant load and hold indentation creep test, with the magnitude of the applied force on the indenter, equation , prescriet al. [For power-law creep with elastic strains neglected, equation , Bower eet al.  derived rea) see , and β iFor equation  with resFor an elastic solid, the relation between indentation depth  Sneddon :5.5helaet al. [As exploited by Su et al. , the inde length . Attentie length .The values of et al. [In their experiments Su et al.  found thequation  were car (b)The reference finite-element mesh for the configuration in n ABAQUS  standarde ABAQUS  indentate ABAQUS .Convergence was investigated using a refined mesh with  (c)a shows the computed normalized indentation depth, et al. [Figure 2n et al.  and showb shows c shows a b. Note that the value of a–c, and are not used for identifying the power-law creep parameters.Figure 2In the early stages of indentation, the plot of indentation depth trast to , the find shows the normalized surface profiles near the indenter after unloading for the three materials. The residual surface profile of Figure 2a–c, respectively. For each of the three materials, the state of deformation shown is at the maximum indentation depth equation . The sizThe extent, in terms of aterials . The cred–f shows the contours of the corresponding mean normal stress Figure 3 (d)The creep exponent equation  define tFor each of the three ‘experimental’ materials in quations , and of quations , the ‘exIn all three databases, the creep exponent As in ,26,27, dThe accuracy of the interpolation was checked by carrying out a few finite-element calculations using interpolated values of material parameters. The agreement between calculated and interpolated responses was best for larger values of the creep stress exponent . 6Values of the creep material parameters For uniaxial creep loading the prescribed stress For an imposed For uniaxial stress relaxation loading, the displacement rate is prescribed so that For an imposed quations  and (6.4A significant difference between the indentation depth versus time response in equation  and the  (a)For the three ‘experimental’ materials in equation .Once the initial database is constructed, the computations for the interpolation and for the statistical analysis are very light and are quickly carried out on a personal computer . (i)For each database, the posterior probability distribution is calculated from: (i) indentation depth versus time data (HT); (ii) residual surface profile data (S); and (iii) both indentation depth versus time data and residual surface profile data (HTS). The values of For Se, the predicted values of The predicted parameter values The predicted parameter values of a. The corresponding stress relaxation responses using equation With the noise-free ‘experimental’ responses denoted by e Matlab  functionThe standard deviation As in , calculaThe material parameters and associated posterior probability obtained based on indentation depth versus time data (HT), residual surface profile data (S) and on both indentation depth versus time data and residual surface profile data (HTS) are given in The predicted uniaxial creep and stress relaxation responses for Se obtained from one-element finite-element calculations (giving homogeneous stress and strain fields) using the creep properties in For The creep parameters and associated posterior probability values obtained for g. 10 of , with inb. On the other hand, the creep response in figure 14a shows a large difference between the uniaxial creep response of the ‘experimental’ material and the prediction based on the The comparison of ‘experimental’ and noise-contaminated HTS data predicted indentation responses for Sn in a, the creep responses predicted based on both the The noise-contaminated uniaxial creep and stress relaxation predictions for Sn in figure 16For all three materials, values of The results here show an increasing sensitivity to noise with increasing creep stress exponent  (b)c are taken to be et al. [et al. [The aim of the analytical power-law creep models is to provide explicit expressions for relating measured indentation responses to the constitutive parameters equation . The firequation , the sloet al. [et al. [Using expressions derived by Bower et al.  and idenequation  with the (et al. :6.7αBFN angle γ . The valand 2 of .et al. [The closed-form algebraic expression for r et al.  based onFor the noise-contaminated predictions of the analytical models, noise is added to the power-law regime indentation depth versus time data using the Matlab  functionequation  and the equation . Note thquations  and (6.8The values of equation  is givenFor Se (For equation  while thequation  differ fFor Sn (equation  are bothequation  also proequation  being obThe accuracy of the predictions becomes more sensitive to noise for larger values of the stress exponent equation  and equaequation , respect. 7et al. [et al. [et al. [ 1. —For Se ( —For Sn (The Bayesian-type statistical approach provides the values of power-law creep parameters that provide a good fit to the indentation responses of all the materials considered when based on noise-free data and for sufficiently small noise amplitudes. The sensitivity to noise increases with increasing creep stress exponent  2.Can very different power-law creep parameters give nearly the same responses in load and hold indentation creep? In the circumstances analysed, different values of the power law creep parameters did give reasonably good fits to the ‘experimental’ indentation data, particularly for noisy data, but no cases were found where very different values of both power-law creep parameters gave nearly the same indentation response. 3.Does using the residual surface profile in addition to or instead of the indentation depth versus time data improve the quality of the prediction? Using both indentation depth versus time data and residual surface profile data generally leads to an improved prediction of the uniaxial creep and stress relaxation responses. For Se ( 4.How sensitive is the predicted creep response to noise in the ‘experimental’ indentation data? The uniaxial creep response is more sensitive to the accuracy of the predicted values of the power-law creep parameters, and therefore to noise, than is the uniaxial stress relaxation response. 5.et al. [et al. [et al. [et al. [et al. [How do the power-law creep properties obtained using the analytical steady-state creep results of Bower et al.  and Gind [et al.  compare  [et al.  are in vThe Bayesian-type statistical approach of Zhang et al.  has beenr et al.  and Gind [et al. .1. The


To investigate clinical outcomes and unmet needs in individuals at Clinical High Risk for Psychosis presenting with Brief and Limited Intermittent Psychotic Symptoms (BLIPS).Prospective naturalistic long-term (up to 9 years) cohort study in individuals meeting BLIPS criteria at the Outreach And Support In South-London (OASIS) up to April 2016. Baseline sociodemographic and clinical characteristics, specific BLIPS features, preventive treatments received and clinical outcomes (psychotic and non-psychotic) were measured. Analyses included Kaplan Meier survival estimates and Cox regression methods.One hundred and two BLIPS individuals were followed up to 9 years. Across BLIPS cases, 35% had an abrupt onset; 32% were associated with acute stress, 45% with lifetime trauma and 20% with concurrent illicit substance use. The vast majority (80%) of BLIPS individuals, despite being systematically offered cognitive behavioural therapy for psychosis, did not fully engage with it and did not receive the minimum effective dose. Only 3% of BLIPS individuals received the appropriate dose of cognitive behavioural therapy. At 4-year follow-up, 52% of the BLIPS individuals developed a psychotic disorder, 34% were admitted to hospital and 16% received a compulsory admission. At 3-year follow-up, 52% of them received an antipsychotic treatment; at 4-year follow-up, 26% of them received an antidepressant treatment. The presence of seriously disorganising and dangerous features was a strong poor prognostic factor.BLIPS individuals display severe clinical outcomes beyond their very high risk of developing psychosis and show poor compliance with preventive cognitive behavioural therapy. BLIPS individuals have severe needs for treatment that are not met by current preventive strategies. The BL, et al. d). For e et al., ), it ext, et al. a). Despi et al., a. A simiThis study aims at unravelling the broader clinical outcomes in individuals experiencing a BLIPS and highlighting their potential unmet needs. Firstly, we will describe the uptake of NICE-recommended treatment as well as other types of treatments in this population. Secondly, we will describe the risk of developing poor clinical outcomes such as the risk for the first admission to mental health hospital, of receiving a first compulsory treatment, of developing a psychotic disorder and of receiving a first antipsychotic or antidepressant treatment. Thirdly, we will describe the association between candidate prognostic predictors and clinical outcomes.et al., et al., et al., et al., We included all CHR-P subjects referred for suspicion of psychosis risk to the Outreach and Support in South London (OASIS) service, South London and Maudsley (SLaM) NHS Foundation Trust  cohort study in CHR-P subjects who met BLIPS criteria. The clinical assessment and follow-ups were done as part of the standard clinical routine of OASIS.et al., et al., et al., et al., et al., et al., The details of the psychopathological CHR-P assessment conducted at OASIS have been described previously , type of BLIPS , the presence of seriously disorganising and dangerous features  was investigated plotting Kaplan Meier .Sociodemographic and clinical characteristics of the sample, as well as treatments uptake over follow-up, were described with mean and s.d. = 5.81), 79% of them were single and 34% unemployed. The proportion of white (43%) and black (46%) ethnicities was similar  and reflected by a HONOS score of 10 (s.d. = 6.36). Most BLIPS subjects (60%) did not meet additional CHR-P subgroups. About one-third (30%) of them displayed seriously disorganising or dangerous features. The BLIPS episodes lasted on average 7 days . In about one-third of the BLIPS (35%), the onset was abrupt (within 48 h). Acute stress was present in about one-third of BLPS (32%), while significant life events were noted in half of the cases (49%). A minority of the BLIPS episodes (20%) were induced by illicit substances, but the proportion of lifetime use of illicit substances was higher (55%). About 38% of individuals with BLIPS presented a positive familial history for psychotic or non-psychotic mental disorders. Lifetime trauma was recorded in about 45% of BLIPS, while the proportion of comorbid emotionally unstable personality disorder was 24%.As shown in The vast majority of BLIPS individuals (80%), despite being systematically offered CBT for psychosis, did not fully engage with it and did not receive the minimum effective dose . Only thThe cumulative risk of a first episode of psychosis was 0.194 (95% CI 0.126–0.290) at 1 year , 0.299 (95% CI 0.211–0.415) at 2 years , 0.428 (95% CI 0.314–0.562) at 3 years , 0.483 (95% CI 0.359–0.624) at 4 years , 0.519 (95% CI 0.368–0.667) at 5 years  a.Fig. 1The cumulative risk of a first hospitalisation b was 0.1The cumulative risk of a first MHA c was 0.0The cumulative risk of a first antidepressant d was 0.1The cumulative risk of a first antipsychotic e was 0.3The only prognostic factor which was significantly associated with the risk of psychosis onset, risk of first hospitalisation and risk of first MHA section was the presence of seriously disorganising and dangerous features . This fan = 102) with the longest follow-up (up to 9 years). They were mostly young males of black and white ethnicities with low baseline functioning. The onset of the BLIP was abrupt and associated with acute stress in one-third of the cases, and only in a minority of the cases with illicit substance use. The vast majority (80%) of BLIPS individuals, despite being systematically offered CBT for psychosis, did not engage with it and did not receive the minimum effective dose. Only 3% of BLIPS received the appropriate dose of CBT. At 4-year follow-up, 52% of the BLIPS developed a psychotic disorder, 34% were admitted to hospital and 16% received a compulsory admission. At 3-year follow-up, 52% of them received an antipsychotic treatment and 26% an antidepressant treatment. The presence of seriously disorganising and dangerous features was confirmed to be a significant prognostic factor. These findings indicate that BLIPS individuals have severe unmet needs for treatment that are not currently targeted by preventive interventions.To our best knowledge, this is the largest cohort of BLIPS individuals . The combination of real-world ecological outcomes and psychometric interviews (e.g. CAARMS-based definition of psychosis onset) in a longitudinal design is rare in the CHR-P literature (Webb et al., et al., et al., et al., et al., et al., Firstly, this study described the uptake of preventive treatments that are recommended by current clinical guidelines. As noted above, CBT is the first-line treatment recommended not only by the NICE NICE,  but alsoet al., et al., et al., et al., et al., et al., et al., Secondly, this study described the risk of developing poor clinical outcomes. The very high risk of developing psychosis of BLIPS individuals is not a novel finding (Fusar-Poli et al., Thirdly, this study described the association between candidate prognostic predictors and clinical outcomes in BLIPS. Our group has previously demonstrated that the presence of seriously disorganising or dangerous features was a robust prognostic factor when controlling for several confounders including age, HONOS, SOFAS, CAARMS P1-P4 total score, gender, borough, ethnicity, marital status, employment status, BLIPS subgroup and recurrence of BLIPS (Fusar-Poli a priori predictors that were selected based on a priori clinical knowledge, in line with methodological recommendations (Fusar-Poli et al., There are also some limitations to this study. Although this is the largest cohort study in BLIPS individuals ever conducted, it was still representing a relatively small sample size. As such, the current study may have been underpowered to estimate the impact of substance-induced BLIPS on the first hospitalisation, first MHA section and first prescription of antidepressant. Because of these inherent limitations, we did not seek to develop a prognostic model and to validate it but rather provided descriptive analyses on the potential association of prognostic factors and clinical outcomes. To further contain the risk of fishing expeditions and type I false positives, we restricted the Cox regression analyses to a subset of BLIPS individuals display severe clinical outcomes beyond their very high risk of developing psychosis. There is poor uptake of preventive CBT in BLIPS individuals. These individuals have severe needs for treatment that are not met by current preventive strategies.


The authors dissect three possible enzyme mechanisms of TIM that have arisen in the decades since the first X-ray crystal structure of this enzyme was published in 1975.Insights are offered on the study by Kelpšas  Knowles & Albery  Fig. 1 was diffbery 1977 also rem al. 2021, reporteet al., 1975et al., 1981et al.  of two complexes of the Leishmania mexicana triosephosphate isomerase. These complexes comprise reaction intermediate mimics, which shed light on the proton shuttling steps of the enzyme mechanism. Triosephosphate isomerase is yet another example of the case of an enzyme mechanism where controversy develops between competing models of proton movements and neutron crystallography is invoked.By 2010 there were ‘at least 111 crystal structures of triosephosphate isomerase in the PDB’ reviewed by Wierenga  al. 2010, a co-auet al. (2021Leishmania mexicana amino acid sequence numbering): ‘there are (i) the so-called classical mechanism, where His95 donates a proton to the enediolate oxygen and then abstracts a proton from the other hydroxyl group of the enediol, (ii) the criss-cross mechanism where the protonated Glu167 first reprotonates the charged enediolate oxygen, followed by another proton abstraction from the other hydroxyl group of the resulting enediol. In this criss-cross mechanism the role of His95 is solely to stabilize the negative charge through strong hydrogen bonds. (iii) Another possibility, called the shuffle mechanism, is where the classical mechanism is performed in only one step, with two protons being transferred concurrently. This would avoid the formation of an intermediate where His95 would have a negative charge.’. The authors have three conclusions: ‘(i) the general base is (shown to be) definitely Glu167, (ii) there is no indication of any low-barrier hydrogen bonds and (iii) that the three suggested mechanisms are all energetically possible’. This latter point relied on the cross validation of the experimental results and QM calculations.Kelpšas  al. 2021 combinedet al. (2021et al., 2019The paper of Kelpšas  al. 2021 rather met al. (2021In this whole story of commitment to this enzyme, its structure and its mechanism of action, there was also the detailed X-ray crystallographic study at atomic resolution by Alahuhta & Wierenga 2010, also of al. 2021. This inet al. (2021Overall, Kelpšas  al. 2021 confirms


The degree of anisotropy (DA) on radiographs is related to bone structure, we present a new index to assess DA.In a region of interest from calcaneus radiographs, we applied a Fast Fourier Transform (FFT). All the FFT spectra involve the horizontal and vertical components corresponding respectively to longitudinal and transversal trabeculae. By visual inspection, we measured the spreading angles: Dispersion Longitudinal Index (DLI) and Dispersion Transverse Index (DTI) and calculated DA = 180/(DLI+DTI). To test the reliability of DA assessment, we synthesized images simulating radiological projections of periodic structures with elements more or less disoriented.Firstly, we tested synthetic images which comprised a large variety of structures from highly anisotropic structure to the almost isotropic, DA was ranging from 1.3 to 3.8 respectively. The analysis of the FFT spectra was performed by two observers, the Coefficients of Variation were 1.5% and 3.1 % for intra-and inter-observer reproducibility, respectively. In 22 post-menopausal women with osteoporotic fracture cases and 44 age-matched controls, DA values were respectively 1.87 ± 0.15 versus 1.72 ± 0.18 (p = 0.001). From the ROC analysis, the Area Under Curve (AUC) were respectively 0.65, 0.62, 0.64, 0.77 for lumbar spine, femoral neck, total femoral BMD and DA.The highest DA values in fracture cases suggest that the structure is more anisotropic in osteoporosis due to preferential deletion of trabeculae in some directions. Sugita et al.  observedet al.  and perm [et al.  concludeThe determination of collagen and crystal orientation in connective tissues at molecular scale has been studied, for instance by diffraction -6. Amorpet al. [et al. [et al. [et al. [in vitro sample and 14 simulation models derived from this sample. The authors reported a very good correlation (r = 0.99) between anisotropy values assessed on the 3D trabecular structure and the 2D projection images. Luo et al. [Different methods are available to characterize the structural anisotropy on bone radiographs. In 1970, Singh  [et al.  develope [et al.  introduc [et al.  or proje [et al. , and an  [et al. . A MIL t [et al.  by fitti [et al. . The MIL [et al. ,16 or Ma [et al. . Therefo [et al.  to compao et al.  insistedet al. [et al. [et al. [et al. demonstrated the contribution of normalized Bone Mineral Density (BMD), structural features and patient age to bone mechanical properties. In 1993, Oxnard reported slight visible microarchitectural changes from the Fourier transform on bone radiographic images but no parameter calculation was performed [et al. considered the properties of Fast Fourier Transform (FFT) to evaluate trabecular bone structure: the directional pattern of frequencies with high-magnitude can identify the orientation of trabeculae. He defined three indices including spectral trabecular index, longitudinal and transversal trabecular indices [et al. concluded that this quantification detects structural changes occurring with age and may be useful in osteoporosis studies [et al. [et al. concluded that this texture analysis might lead to a better prediction of the osteoporotic fracture risk [Few methods evaluating the trabecular structure have been developed on radiographs. Caldwell et al.  develope [et al.  develope [et al. . Jiang e [et al.  developeerformed . The samerformed . Wigdero indices . These i studies . Caligiu [et al.  also useure risk . Recentlure risk .et al. have shown significant differences [Our research group has previously experienced fractal analysis on bone radiographs -29. The ferences  but the The osteoporotic fracture risk prediction is important especially in postmenopausal women. BMD is currently measured in clinical practice and textural parameters can be assessed on trabecular bone radiographs ,24,25,31We describe here a new quantitative method based on the FFT to obtain anisotropy indices on bone radiographs of the calcaneus and a validation on synthetic images. The intra and inter-observer reproducibility and a pilot clinical study comparing osteoporotic fracture cases to control cases are presented.Postmenopausal women were recruited from a cross-sectional unicenter case control study. The protocol screened 400 women: 349 were enrolled. The inclusion and exclusion criteria have been previously described in details . For thi® 4500 device) at lumbar spine and femoral neck. The mean lumbar spine BMD was respectively 0.814 ± 0.09 g.cm-2 and 0.895 ± 0.16 g.cm-2 (p < 0.05) for fracture cases and control cases. The mean femoral neck BMD was respectively 0.650 ± 0.09 g.cm-2 and 0.686 ± 0.12 g.cm-2 (ns) for the fracture cases and control cases.The BMD was measured by dual energy x-ray absorptiometry . The ROI of 256 × 256 pixels  with 256 gray-levels. Calcaneus is known to be a heterogeneous site of trabecular bone . For thiThe low frequency noise of an image corresponds to the gray-value variations over large distances, due to the radiological artifacts and to the fat tissues projections on the radiograph. In order to remove the low frequency noise and to take into account only trabecular components of the image, we used a convolution filter previously described by Geraets . A kernexOy) plane and can be expressed as a two-dimensional function f. The Fourier transform is expressed by a function F with the two variables μ and υ corresponding to spatial frequencies in (μ Oυ) plane. The 2D Fourier transform spectrum of an image is expressed by the following formula:The Fourier transform represents a signal in spatial frequency space. An image can be considered as a repartition of bright intensities in a  spectrum are spread over an angle corresponding to the deviation of the structure in the original image. By analogy, we hypothesized that the periodic structure is represented by trabeculae projection, and the degree of disorientation by anisotropy.The magnitude of the transform corresponds to:Re = real part of the FFT and Im = the imaginary part of FFT.where The FFT was calculated on the gray level filtered images of the trabecular bone using the Visilog 5.1 software (Noesis). Then the magnitudes of the frequency images were divided to the total magnitude of the transform to normalize the contrast in the images according to the following formula:Trabecular bone was assimilated to an oriented structure with two main directions, the ROI including longitudinal and transversal trabeculae Figure . All theAn index relative to the trabecular fabric or degree of anisotropy was derived from the measured parameters DLI and DTI. The Degree of Anisotropy (DA) was defined as:For a perfectly isotropic structure, the FFT spectrum has a disc shape and DA is equal to unity. More isotropic trabecular bone structures will have DA values closer to unity.Figures To test the reliability of DA assessment, we tested this method on projected volume with known disorientations. We synthesized 6 series of 8 images composed of beam like structures more or less aligned following two directions in order to obtain structures close to trabecular bone of calcaneus. For the less anisotropic structure, horizontal and vertical disorientations varied from 0 to 80° Figure , and forThe two measured parameters DLI and DTI and the derived parameter DA were determined to calculate the intra and inter-observer reproducibility. To determine the intra-observer reproducibility, a single observer performed two sets of measurements on the FFT spectra of 20 subjects with a one day interval between each set. To determine the inter-observer reproducibility, two sets of measurements were performed on the FFT spectra of 20 subjects by two observers. The observers were blinded for each sets of measurements.n subjects with the root mean square RMS average according to the following formula [The intra-observer and inter-observer reproducibilities were calculated for  formula :SDj is the standard deviation for the subject j and  is the average of the measurements for the subject j.where t-test for comparisons of the means after checking Gaussian distribution. The area under ROC curves was calculated for BMD measurements and DA.Results in these two groups were compared using Student's The results of synthetic images are represented on Table Table Table  corresponding to the 95% confidence interval of the measurements [In control cases DA was closer to 1 due to a large spreading of frequencies in the FFT spectra while DA was higher in osteoporotic cases in relation to a narrower frequency spreading. Comparing the DA values from Table urements .Differences in DA determined by spectral analysis (p < 0.01) and lumbar spine BMD p < 0.05) were significant  in control cases than in osteoporosis cases with vertebral fractures. The larger range of orientations in controls corresponds to a lesser anisotropic structure than in osteoporosis. DTI was the best discriminant parameter between fracture patients and control cases but also the less reproducible. There are only few transversal trabeculae comparatively to longitudinal ones and they disappear first with osteoporosis due to a less contribution in bone strength. The difference between fracture cases and controls was close to errors attributed to the intra or inter-observer reproducibility. The intra-observer reproducibility is close to the 1 to 2% of reproducibility found in usual bone densitometry method as dual x-ray absorptiometry . The pooet al. [et al. was performed with the MIL method on 3D magnetic resonance images at the radius. The MIL method is widely used to determine the trabecular 3D structure anisotropy but some authors [The higher anisotropy found in osteoporosis cases is in accordance with the findings of Newitt et al.  who repo authors ,40 discuThis concept of transversal and longitudinal systems of trabeculae must be cautiously interpreted in our study. Indeed the ROI on the calcaneus radiographic images is tilted around 45 degrees Figure . The traet al. [The anisotropy of trabecular bone is different according to the skeletal sites: in a study comparing the properties of calcaneus, distal femur, proximal femur and vertebrae on human specimens, Majumdar et al.  found thet al. [et al. [et al. [et al. [Our results corroborate the studies of Geraets et al.  on hip a [et al.  on wrist [et al.  on verte [et al.  on femoret al. showed in a study of the distal radius that the Line Fraction Deviation values decreased along the transversal direction with age whereas the orientation along the axial direction remains stable during the entire life [et al. [et al. in vertebrae [et al. [et al. characterized iliac trabecular bone by micro-QCT and showed that trabeculae thinning led to a more isotropic structure in the first postmenopausal years whereas the structure became more anisotropic in the later years [The lower values of the Line Fraction Deviation index found in osteoporotic subjects were consistent with the early loss of the secondary compressive trabecular group of the hip . Moreoveire life . Wigdero [et al.  found usertebrae  showed tertebrae . Ciarell [et al.  also fouer years . They hyet al. [2 in each calcaneus. They found a spatial heterogeneity in the posterior region of 40 %. In our study the ROI was 2.7 × 2.7 cm2 and represented a much larger area; it was accurately defined by anatomic marks, this point avoiding large variation in fractal analysis [It has been well established that the calcaneus structure is heterogeneous ,46. Lin et al.  have stuanalysis . FurtherThis study has shown that the DA can be determined on plain radiographs using spectral analysis. The reproducibility of the DA values may be improved by automating the method. The distinction between fracture cases and control cases is very promising, but further studies are necessary to know if the DA evaluation could improve the osteoporotic fracture risk determination when combined with BMD and other textural parameters such as fractal analysis.The author(s) declare that they have no competing interests.BBI participated in the design of the study, carried out the measurements and the manuscript preparation, G L carried out measurements of reproducibility and synthetic images, CC performed statistical analysis and participated to the manuscript preparation, R H supervised the application of the Fourier Transform and CLB carried out the design of the study and supervised the manuscript preparation.The pre-publication history for this paper can be accessed here:


Fibromatosis-like metaplastic carcinoma is a newly described metaplastic breast tumor, literature on which is still evolving.A 77-year-old lady presented with a 2 × 2 cm mass with irregular margins in the upper and outer quadrant of left breast. Fine needle aspiration cytology (FNAC) from the lump was inconclusive. A lumpectomy was performed and sent for frozen section, which revealed presence of spindle cells showing mild atypia in a sclerotic stroma. The tumor cells revealed prominent infiltration into the adjacent fat. A differential diagnosis of a low-grade sarcoma vs. a metaplastic carcinoma, favoring the former, was offered. Final histology sections revealed an infiltrating tumor with predominant spindle cells in a collagenous background, simulating a fibromatosis. Adjacent to the tumor were foci of benign ductal hyperplasia and a micropapilloma. Immunohistochemistry (IHC) showed diffuse co-expression of epithelial markers i.e. cytokeratins  and EMA along with a mesenchymal marker i.e. vimentin in the tumor cells. Myoepithelial markers (SMA and p63) showed focal positivity. A diagnosis of a low-grade fibromatosis-like carcinoma breast associated with a micropapilloma was formed.Fibromatosis-like carcinoma is a rare form of a metaplastic breast tumor. This diagnosis requires an index of suspicion while dealing with spindle cell breast tumors. The importance of making this diagnosis to facilitate an intra operative surgical planning is marred by diagnostic difficulties. In such cases, IHC is imperative in forming an objective diagnosis. Metaplastic breast tumors exhibit a wide morphologic spectrum, ranging from tumors with clearly visualized epithelial elements to heterologous tumors with non-epithelial elements like spindle cells, cartilage and bone -4. With A 77-year-old lady presented with the complaints of a left-sided breast lump of 1-month duration. She had been a heart patient and had been on treatment for the last 4 years. On clinical examination a 3 × 2 cm firm, mobile, non-tender lump was identified in the outer quadrant of her left breast. The overlying skin of the breast along with nipple and areola were unremarkable. There was no significant axillary or cervical lymphadenopathy. The other breast was normal. She underwent a mammographic examination, followed by fine needle aspiration cytology (FNAC) that was essentially inconclusive. Subsequently, she underwent a frozen section for a primary diagnosis.On mammography, a 2 × 2 cm ill-defined mass with irregular margins was identified in the left upper outer quadrant. No micro-calcifications were seen. The right-sided breast was normal. Figure .The lumpectomy specimen on cut surface revealed a firm, grey-white, fibrous, un-encapsulated nodular tumor measuring 2 × 1.2 × 0.8 cm with infiltrative borders. No area of calcification was identified. The closest margin was the base and was found to be 0.5 cm away from the tumor.Frozen sections revealed a tumor with predominant spindle cells showing mild atypia, amidst a sclerotic stroma and conspicuously infiltrated the adjacent fat. A diagnosis of a low-grade sarcoma was favored over a metaplastic carcinoma. Therefore, a sentinel lymph node biopsy and/or an axillary node dissection (ALND) were not conducted at the time of surgery.in-situ (DCIS) was seen in any of the sections. The two closest differential diagnoses considered were fibromatosis and a "fibromatosis like" metaplastic carcinoma. A wide panel of IHC antibody markers was performed . Thereafter, she has been on a regular 2 monthly follow-up; including her metastatic work-up with Positron emission tomography (PET-CT) of the body and bone scan. Due to a high cardiac risk, a second surgery for an ALND was not performed. Nevertheless, till 1 year and 4 months of her follow-up she has not been identified with any lymphadenopathy, recurrent lesion or metastatic lesions in her body.Spindle cell metaplastic breast tumors display a range of elements, including low-grade tumors to those with areas of high-grade sarcomas like fibrosarcomas and malignant fibrous histiocytomas -4. AmongThe present case observed in an elderly female who underwent a lumpectomy for a painless breast lump, exemplifies the diagnostic and management issues related to this tumor. The relatively bland nature of cells has prompted some authors to label it as a 'tumor' than a carcinoma .et al [et al [et al [This tumor has predilection for older women. In a classical premier series of 30 exclusive cases by Gobbi et al  and 24 cl [et al , the aveet al [et al [et al [On gross findings, they observed an average size of 2.7 cms with these tumors; mostly associated with unencapsulation and irregular borders . In the et al , who notl [et al . Among tl [et al ,7. As inl [et al  demonstret al [et al [Positive expression for myoepithelial markers in this case is further suggestive that these tumors might constitute as myoepithelial subtypes of a metaplastic carcinoma. A positive p63 expression, like in our case, has been lately identified in 86.3% cases of myoepithelial carcinomas in a study by Koker et al . Ultrastet al [Micropapillomas and papillomas have been described to be associated with an increased risk for subsequent development of a breast carcinoma and may form its antecedent lesion . Associaet al . Howeveret al .et al [et al [The optimal treatment options for this tumor remain unclear. However, most authors insist on a complete local treatment like lumpectomy with wide margins and adjuvant RT . Rarely,et al  and Kinkl [et al . Though An objective identification of this uncommon tumor with the help of a panel of IHC, along with the presence of a micropapilloma makes this case unique. Further, an uneventful follow-up for more than a year, despite avoidance of an axillary lymph node dissection suggests a relatively lesser metastatic potential of this tumor. A certain degree of index of suspicion in the pathologists' mind while dealing with spindle cell tumors of breast is helpful in making this diagnosis. Documentation of more of such cases with follow-up details would bring new light to the management and biological behavior of this unusual breast tumor.The author(s) declare that they have no competing interests.BR: Involved in the diagnosis of the case; design, preparation and drafting of the manuscript.TMS: Involved in the diagnosis; preparation of the manuscript and in the ultrastructural analysis.RDB: Treating breast oncosurgeon, provided the clinical and follow-up details.RFC: Overall supervision and has given the final approval of the manuscript.


While cI regret the inadvertent misquotation. My own data, my conclusions, and my admiration for Okura et al. are unchanged.


Bos indicus) are reported to be comparatively less affected than exotic and crossbred cattle. However, genetic basis of resistance in indigenous cattle is not well documented. The association studies of few of the genes associated with various diseases, namely, solute carrier family 11 member 1, Toll-like receptors 1, with TB; Caspase associated recruitment domain 15, SP110 with JD; CACNA2D1, CD14 with mastitis and interferon gamma, BoLA-DRB3.2 alleles with TTBDs, etc., are presented. Breeding for genetic resistance is one of the promising ways to control the infectious diseases. High host resistance is the most important method for controlling such diseases, but till today no breed is total immune. Therefore, work may be undertaken under the hypothesis that the different susceptibility to these diseases are exhibited by indigenous and crossbred cattle is due to breed-specific differences in the dealing of infected cells with other immune cells, which ultimately influence the immune response responded against infections. Achieving maximum resistance to these diseases is the ultimate goal, is technically possible to achieve, and is permanent. Progress could be enhanced through introgression of resistance genes to breeds with low resistance. The quest for knowledge of the genetic basis for infectious diseases in indigenous livestock is strongly warranted.Huge livestock population of India is under threat by a large number of endemic infectious  diseases. These diseases are associated with high rates of morbidity and mortality, particularly in exotic and crossbred cattle. Beside morbidity and mortality, economic losses by these diseases occur through reduced fertility, production losses, etc. Some of the major infectious diseases which have great economic impact on Indian dairy industries are tuberculosis (TB), Johne’s disease (JD), mastitis, tick and tick-borne diseases (TTBDs), foot and mouth disease, etc. The development of effective strategies for the assessment and control of infectious diseases requires a better understanding of pathogen biology, host immune response, and diseases pathogenesis as well as the identification of the associated biomarkers. Indigenous cattle ( The livestock sector plays an important role in supporting the livelihood of livestock keepers, consumers, traders, and laborers worldwide. The livestock is an important segment of expanding and diverse agricultural sector of Indian financial system. Approximately, 70% people of this country are either directly or indirectly involved in the occupation related to agriculture and livestock rearing . India’s2), so on and so forth. Genome-wide association studies have attempted to confirm associations found and identify new genes involved in pathogenesis and susceptibility.Susceptibility to the mentioned infectious diseases suggested to have a genetic component. These ailments are good candidates for genetic selection as effective vaccine is either not available or if available, either costly or currently are at trial stage. Further, these diseases are difficult to cure and cause significant economic losses. Selective breeding, to increase resistance against infectious disease, will prove to be a low cost and sustainable practice. In livestock, a number of candidate genes have been studied and selected on the basis of their association to resistance or susceptibility in certain other diseases and their known role in disease pathogenesis. These genes include solute carrier family 11 member 1 (SLC11A1), interferon gamma (IFN-γ), peptidoglycan recognition protein 1 (PGLYRP-1), Toll-like receptors (TLRs), Caspase associated recruitment domain 15 (CARD15), mannose binding lectin-1 (MBL-1), nitric oxide synthase  is a chronic infectious disease caused by esponses . The hosIngestion of the bacillus is followed by fusion of lysosomes with the phagosome to form phagolysosomes and it is there that the phagocytes attempt to destroy the bacillus . HoweverMycobacterium avium subspecies paratuberculosis (MAP) is highly pathogenic mycobacteria affecting dairy cattle and other domestic ruminants globally [globally . The inf1 and TH2) activate different host immune responses. Mycobacterium paratuberculosis infection appears to follow patterns similar to that of M. tuberculosis. These patterns entail an initial TH1 response (referred to as “tuberculoid”) that is characterized by a tissue infiltrate distinguished primarily by lymphocytes with few if any detectable organisms [1 response is also characterized by the production of the cytokine IFN-γ, one of the earliest detectable reactions to M. paratuberculosis infection, in addition to IL-2 and TNF-α. These cytokines are assumed to have a significant role in the CMI functions necessary to contain such an intracellular infection. During the early, subclinical stage of M. paratuberculosis infection, the TH1 T-cell activity appears to predominate. This subclinical phase of infection can last for months to years, as the bacilli are contained within macrophages and microscopic granulomas.The bacterium after crossing lumen of intestine is taken up by epithelioid macrophages which, once activated, elicit T-cell activation and clonal expansion . Two T-hrganisms . The TH1via a variety of mechanisms [The disease caused by FMD virus (FMDV), a member of the family Picornaviridae, is characterized by fever, profuse salivation, vesicles in the mouth and on the feet, and a drastic reduction in milk production. Sudden death in young stock may occur . In cattchanisms . Evidencchanisms .Rhipicephalus and Hyalomma - are most widely distributed in India [Ticks are among the most competent and versatile vectors of pathogens and are only second to mosquitoes as vectors of a number of human pathogens, such as viruses, bacteria, rickettsia, and spirochetes, and the most important vector of pathogens affecting cattle worldwide . The twoin India . In geneTheileria parva and Theileria annulata infected cattle, direct evidence for the existence of CTL activity against other tick-borne pathogens is still missing. Recently, it is observed by many that CD4+ T cells play a key role in the development of protective immunity against the TTBD. IFN-c produced by CD4+ T cells and NK cells activates macrophages for an enhanced phagocytosis and cytokine and nitric oxide production. These molecules either kill or inhibit the growth of the parasites. It is also advocated that memory T-helper cells provide help for the synthesis of opsonizing anti-parasite immunoglobulin (Ig) G2 antibodies. On the other hand, the overproduction of cytokines, particularly tumor necrosis factor alpha, leads to an exaggeration of the S52 (types of IgE) clinical symptoms and pathological reactions associated with TTBD [Evidence suggests the role of both innate and adaptive immune mechanisms against TTBD. While major histocompatibility complex (MHC-I) restricted cytotoxic T-lymphocyte (CTL) responses have been observed in ith TTBD .Theilerioses caused by Theileria species, where sporozoites injected by the ticks, which then enter lymphocytes and develop into schizonts in the lymph node draining the area of attachment of the tick, usually the parotid node. Infected lymphocytes are transformed to lymphoblasts which continue to divide synchronously with the schizonts so that each daughter cell is also infected [In India, tropical theileriosis and babesiosis are the major tick-borne infections. In babesioses, sporozoites are injected into the host and directly infect erythrocytes, where they develop into piroplasms resulting in two or sometimes four daughter cells that leave the host cell to infect other erythrocytes  that leainfected . EventuaEscherichia coli, Staphylococcus aureus, and Streptococcus agalactiae [In dairy industry, intramammary infections are among the most important diseases of cows that cause great economic losses . Mastitialactiae .Following entry of bacteria into the mammary gland, large numbers of neutrophils migrate from the blood into the milk to control infection. This relies on the appropriate expression of genes, such as receptors present on cell surface as CD14 and TLRs, triggering a diverse array of responses including the early release of immune effector molecules and chemokines, facilitating the appropriate influx of cells following infection .The genes involved  in the pathogenesis of these diseases may be exposed for possible variation which may further be associated with disease susceptibly or resistance and may be explored for variations, which can be exploited for selection for resistance/susceptibility. Since the unraveling of the genetic material and the rapid development of molecular genetics tools, the last 50 years has witnessed a tremendous growth in the knowledge base and utilization of genetic information in tackling human and animal diseases. The genetic material in livestock animal species harbors a huge collection of genetic variations, these variations are usually in the form of deletions/insertions of nucleotides, single nucleotide polymorphisms (SNPs), gene duplications, copy number polymorphisms, e.g., variable number of tandem repeats (VNTRs) and microsatellites .A genetic marker is a gene or DNA sequence with a known location on a chromosome and associated with a particular gene or trait. It is a variation, which may arise due to mutation or alteration in the genomic loci that can be observed . MarkersThe first approach in application of molecular markers has been the use of candidate genes. It is assumed that a gene involved in a certain trait could show a mutation causing variation in that trait, and any variations in the DNA sequences, that are found, are tested for association with variation in the phenotypic trait . Till noThe RFLP is defined by the existence of alternative alleles associated with restriction fragments that differ in size from each other. RFLP is the nucleotide base substitutions, insertions, deletions, duplications, and inversions within the whole genome, can remove or create new restriction sites . RFLP anet al. [The SSCP technique, discovered by Orita et al. , has beeSSR loci, referred as VNTRs and simple sequence length polymorphisms, are found throughout the nuclear genomes of most eukaryotes and to a lesser extent in prokaryotes . MicrosaIn 1996, Lander proposed a new molecular marker technology named SNP . When a Advances in molecular genetics are taking place leap and bound, and with the advent of new technology, detection of variation in markers is becoming easier with high precision. Among the more recent technology of detection of polymorphism is the real-time polymerase chain reaction (RT-PCR) and its use in establishing association with comparison of m-RNA expression in different pathological conditions.et al. [et al. [et al. [et al. [et al. [et al. [Deb et al.  from the [et al.  where he [et al.  with the [et al.  reported [et al.  with PCR [et al.  observed [et al. .et al. [HinfI enzyme, of CD14 gene (Chromosome 7) by Selvan et al. [et al. [Liu et al.  using PCet al. . PCR-RFLn et al.  in Karan [et al.  reportedet al. [et al. [Asaf et al.  in their [et al.  with coret al. [et al. [In microsatellite study, Guo et al.  analyzed [et al.  analyzed [et al.  detected [et al.  based onet al. [et al. [2 (chromosome 18) in cattle plays an important role in TB resistance. Wang et al. [M. bovis. Further, Qin et al. [StyI enzyme cut site in CARD15 gene and obtained SNP was found to be significantly associated with the susceptibility to TB of Yunnan plateau dairy cows. Cheng et al. [2 gene (chromosome 19), g.19958101T>G polymorphism by PCR-RFLP and concluded that this gene may contribute to the susceptibility of TB in cattle.In bovine SLC11A1 gene (chromosome 2), Cheng et al.  with the [et al.  detectedg et al.  with then et al.  investigg et al.  observedet al. [et al. [Sun et al.  performe [et al.  detected [et al. .et al. [et al. [et al. [Among the microsatellite Markers, as per the observation of Zanotti et al.  the geno [et al.  from the [et al.  reportedet al. [et al. [et al. [et al. [et al. [et al. [IFN-γ gene in Holstein, Jersey and Brahman-Angus crosses.Ruiz et al.  performe [et al.  in their [et al.  again us [et al.  reported [et al.  found th [et al.  reported [et al. , with thet al. [The microsatellite analysis done by Pinedo et al.  revealedet al. [et al. [et al. [Singh et al.  in theiret al. . Similar [et al.  reported [et al.  with seqet al. [et al. [et al. [et al. [T. annulata infection in crossbreds as compared to indigenous cattle. Recently in a study of global gene expression profile in PBMCs with the help of Microarray, NFKBID, BoLA-DQB, HOXA13, PAK1, TGFBR2, NFKBIA genes showed breed specific differences associated with T. annulata infection [Recent years have witnessed an emergence of various dreaded TTBDs  and lack of its effective control measures has compelled to look for certain markers to be included in selection programs for controlling the menace of TTBDs. IFN-γ is one such gene (chromosome 5) in which Maryam et al.  with seq [et al.  suggeste [et al.  reported [et al.  on the bnfection .et al. [One of the major questions which trouble all of us is what to do with large number of sporadic SNPs studies with small number of samples? Are these studies baseless or they can still be made useful? Recently, Schaub et al.  using enThe evidence presented above indicates a detectable genomic basis of the various infectious diseases of economic importance, and there is a strong case for the inclusion of genetic elements within disease control strategies, particularly in the light of constraints to the sustainability of other classical methods. Disease resistance traits are among the most difficult to include in the classical “Biometrical” farm animal genetic programs. A further complication is that disease resistance is most often an “all or none” trait. Although there may well be quantitative polygenic variation in resistance status, the observations are often limited to “Sick or healthy.” This, too, reduces heritability compared with other polygenic traits, such as milk production. There are many documented instances of breed and individual differences in genetic disease resistance among farm animals. The current studies in cattle for selection against mastitis and JD in India have shown some encouraging results and have motivated the scientist and workers working in this area to look for more and more variations and associate these with disease resistance or susceptibility. Thus, selection for genetic disease resistance provides a potential avenue for improving the health status of farm animals, increasing productivity and reducing the need for pharmaceutical intervention, thereby reducing cost and delaying the appearance of resistant pathogens.Breeding for genetic resistance is one of the promising ways to control the infectious diseases. High host resistance is the most important method for controlling such diseases, but no breed is totally resistant. Total resistance to these diseases is the ultimate goal, is technically possible to achieve, and is permanent. Progress could be enhanced through introgression of resistance genes to breeds with low resistance. The quest for knowledge of the genetic basis for infectious diseases in livestock is strongly warranted, given that 70 % of people are either directly or indirectly earning their livelihood in India by livestock based occupation.BMP prepared the initial version of the manuscript. GAP and JDC assisted in literature collection. JPG and DPP conceived the idea, revised the manuscript and made final critical scientific corrections. All authors read and approved the final manuscript.