Evidence of a Hardening in the Cosmic Ray Proton Spectrum at around 166 TeV Observed by the GRAPES-3 Experiment.

We present the measurement of the cosmic ray proton spectrum from 50 TeV to 1.3 PeV using 7.81×10^{6} extensive air shower events recorded by the ground-based GRAPES-3 experiment between 1 January 2014 and 26 October 2015 with a live time of 460 day. Our measurements provide an overlap with direct observations by satellite and balloon-based experiments. The electromagnetic and muon components in the shower were measured by a dense array of plastic scintillator detectors and a tracking muon telescope, respectively. The relative composition of the proton primary from the air shower data containing all primary particles was extracted using the multiplicity distribution of muons which is a sensitive observable for mass composition. The observed proton spectrum suggests a spectral hardening at ∼166 TeV and disfavors a single power law description of the spectrum up to the Knee energy (∼3 PeV).

DNA methylation: an emerging paradigm of gene regulation under drought stress in plants.

Drought is an enormous threat to global crop production. In order to ensure food security for the burgeoning population, we must develop drought tolerant crop varieties. This necessitates the identification of drought-responsive genes and understanding the mechanisms involved in their regulation. DNA methylation is a widely studied mechanism of epigenetic regulation of gene expression, which is known to play vital role in conferring tolerance to various biotic and abiotic stress factors. The recent advances in next-generation sequencing (NGS) technologies, has allowed unprecedented access to genome-wide methylation marks, with single base resolution. The most important roles of DNA methylation have been studied in terms of gene body methylation (gbM), which is associated with regulation of both transcript abundance and its stability. The availability of mutants for the various genes encoding enzymes involved in methylation of DNA has allowed ascertainment of the biological significance of methylation. Even though a vast number of reports have emerged in the recent past, where both genome-wide methylation landscape and locus specific changes in DNA methylation have been studied, a conclusive picture with regards to the biological role of DNA methylation is still lacking. Compounding this, is the lack of sufficient evidence supporting the heritability of these epigenetic changes. Amongst the various epigenetic variations, the DNA methylation changes are observed to be the most stable. This review describes the drought-induced changes in DNA methylation identified across different plant species. We also briefly describe the stress memory contributed by these changes. The identification of heritable, drought-induced methylation marks would broaden the scope of crop improvement in the future.

Nivolumab induced pulmonary sarcoid-like granulomas with a concurrent pleural schwannoma: A pathologic-radiologic correlation of a rare condition mimicking metastatic melanoma.

Nivolumab is an anti-PD-1 antibody. The mechanism of action of nivolumab is inhibition of binding between PD-1 and PD-1 ligand. This causes activation of antigen-specific T cells that were previously unresponsive to cancer cells. This unique mechanism of action attributes the widespread use of nivolumab for the treatment of a variety of neoplastic conditions. On the other hand, this mode of action is associated with adverse effects as well. Schwannoma, also called neurilemmoma, is a benign peripheral nerve sheath tumor. Pleural schwannomas are very rare and very few cases have been reported in the medical English literature so far. Herein, we report a very rare case of concurrent presence of Nivolumab induced pulmonary sarcoid-like granulomas along with primary benign pleural schwannoma in a 49-year-old male. He was diagnosed with malignant melanoma of the right upper arm for which he underwent surgery and was receiving adjuvant chemotherapy. He developed pneumonitis during chemotherapy, and on imaging multiple reticular and nodular interstitial infiltrates were seen along with an incidental pleural mass with a high suspicion for metastasis. Wedge biopsy of the interstitial infiltrates was done and they were found to be pulmonary granulomas related to the nivolumab therapy he was receiving. The patient underwent excision of the pleural mass which showed histopathological and immunohistochemical features of schwannoma. The two conditions are unrelated and rarely encountered simultaneously. The radiologic and pathologic correlation along with differential diagnosis of these conditions are discussed.

Influence of maternal body mass index on interobserver variability of fetal ultrasound biometry and amniotic-fluid assessment in late pregnancy.

OBJECTIVE: To determine the interobserver reproducibility of fetal ultrasound biometric and amniotic-fluid measurements in the third trimester of pregnancy, according to maternal body mass index (BMI) category. METHODS: This was a prospective cohort study of women with a singleton gestation beyond 34 weeks, recruited into four groups according to BMI category: normal (18.0-24.9 kg/m2 ), overweight (25.0-29.9 kg/m2) , obese (30.0-39.9 kg/m2 ) and morbidly obese (≥ 40 kg/m2 ). Multiple pregnancies, women with diabetes and pregnancies with a fetal growth, structural or genetic abnormality were excluded. In each woman, fetal biometric (biparietal diameter (BPD), head circumference, abdominal circumference (AC), femur length (FL) and estimated fetal weight) and amniotic-fluid (amniotic-fluid index (AFI) and maximum vertical pocket (MVP)) measurements were obtained by two experienced sonographers or physicians, blinded to gestational age and each other's measurements. Differences in measurements between observers were expressed as gestational age-specific Z-scores. The interobserver intraclass correlation coefficient (ICC) and Cronbach's reliability coefficient (CRC) were calculated. Bland-Altman analysis was used to assess the degree of reproducibility. RESULTS: In total, 110 women were enrolled prospectively (including 1320 measurements obtained by 17 sonographers or physicians). Twenty (18.2%) women had normal BMI, 30 (27.3%) women were overweight, 30 (27.3%) women were obese and 30 (27.3%) women were morbidly obese. Except for AFI (ICC, 0.65; CRC, 0.78) and MVP (ICC, 0.49; CRC, 0.66), all parameters had a very high level of interobserver reproducibility (ICC, 0.72-0.87; CRC, 0.84-0.93). When assessing reproducibility according to BMI category, BPD measurements had a very high level of reproducibility (ICC ≥ 0.85; CRC > 0.90) in all groups. The reproducibility of AC and FL measurements increased with increasing BMI, while the reproducibility of MVP measurements decreased. Among the biometric parameters, the difference between the BMI categories in measurement-difference Z-score was significant only for FL. Interobserver differences for biometric measurements fell within the 95% limits of agreement. CONCLUSION: Obesity does not seem to impact negatively on the reproducibility of ultrasound measurements of fetal biometric parameters when undertaken by experienced sonographers or physicians who commonly assess overweight, obese and morbidly obese women. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Quality assessment of cancer patient education materials: the current state of systemic therapy patient education in fourteen cancer centres across Ontario, Canada.

PURPOSE: Most patients diagnosed with cancer are administered systemic therapy and these patients are counselled and given printed education (PE) materials. High rates of low health literacy highlight the need to evaluate the quality of these PE materials. METHODS: A current state assessment of the quality of PE materials was conducted in Ontario, Canada. Patient education leaders from 14 cancer centres submitted print materials on the topic of systemic cancer therapy to the assessment team. To report adherence to PE quality and health literacy best practices, the following validated measures were used: readability (FRY, SMOG and Flesch Reading Ease), understandability and actionability (Patient Education Materials Assessment Tool (PEMAT)). Materials at grade level 6 or lower and with PEMAT scores greater than 80% were considered to meet health literacy best practices. RESULTS: A total of 1146 materials were submitted; 366 met inclusion criteria and 83 were selected for assessment. Most materials scored below the 80% target for understandability (x̄ = 73%, 31-100%) and actionability (x̄ = 68%, 20-100%), and above the recommended grade 6 readability level (x̄ = grade 9) meaning that the majority did not meet quality standards or best practices. CONCLUSION: Results suggest that there is significant opportunity to improve the quality of PE materials distributed by cancer centres. The quality of PE materials is a critical safety and equity consideration when these materials convey important safety and self-care directives.

Autologous stem cell transplantation for untreated transformed indolent B-cell lymphoma in first remission: an international, multi-centre propensity-score-matched study.

High-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are used as consolidation in first remission (CR1) in some centres for untreated, transformed indolent B-cell lymphoma (Tr-iNHL) but the evidence base is weak. A total of 319 patients with untreated Tr-iNHL meeting prespecified transplant eligibility criteria [age <75, LVEF ≥45%, no severe lung disease, CR by positron emission tomography or computed tomography ≥3 months after at least standard cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) intensity front-line chemotherapy] were retrospectively identified. Non-diffuse large B-cell lymphoma transformations were excluded. About 283 (89%) patients had follicular lymphoma, 30 (9%) marginal-zone lymphoma and six (2%) other subtypes. Forty-nine patients underwent HDC/ASCT in CR1, and a 1:2 propensity-score-matched cohort of 98 patients based on age, stage and high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements (HGBL-DH) was generated. After a median follow-up of 3·7 (range 0·1-18·3) years, ASCT was associated with significantly superior progression-free survival [hazard ratio (HR) 0·51, 0·27-0·98; P = 0·043] with a trend towards inferior overall survival (OS; HR 2·36;0·87-6·42; P = 0·1) due to more deaths from progressive disease (8% vs. 4%). Forty (41%) patients experienced relapse in the non-ASCT cohort - 15 underwent HDC/ASCT with seven (47%) ongoing complete remission (CR); 10 chimeric antigen receptor-modified T-cell (CAR-T) therapy with 6 (60%) ongoing CR; 3 allogeneic SCT with 2 (67%) ongoing CR. Although ASCT in CR1 improves initial duration of disease control in untreated Tr-iNHL, the impact on OS is less clear with effective salvage therapies in this era of CAR-T.

Novel Classification of Posttraumatic Ear Deformities and its Surgical Management.

Background Classification of posttraumatic ear deformities and its reconstruction is an uphill task for a reconstructive surgeon as they present in various combinations. In our study, we have described ear deformity as per a new classification and reconstructed the ear accordingly. Method Posttraumatic ear deformity was described under the following four headings: (a) zone of defect, (b) size of defect, (c) missing components, and (d) condition of surrounding skin. Twenty-six posttraumatic ear deformities were operated using postauricular skin flap (14), temporoparietal fascial (TPF) flaps (8), preauricular skin flap (1), intralesional excision (2), and primary closure with chondrocutaneous advancement in one patient. Costal cartilage was used for reconstruction of framework wherever required. Framework elevation was done 4 to 6 months postoperatively. Results Posttraumatic ear deformity was more common in males. Bite injury and road traffic accidents were the common causes. Zones I, II and III were most frequently involved. Four patients complained about size, contour, and projection of reconstructed ear. Three patients were not satisfied by the appearance of junction between reconstructed and residual ear. Four patients in whom the reconstruction was done with TPF, costal cartilage, and thin (SSG) split skin grafts complained of hyperpigmentation of reconstructed ear. Conclusion Classification of posttraumatic ear deformity and its reconstruction is a surgical challenge. Unscarred postauricular skin and TPF flaps are the workhorse flaps for reconstruction of acquired ear deformities. Our classification helps in describing the defect, documenting it, planning reconstruction, and aiding in assessing postoperative outcomes.

Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome.

Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H1R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H1R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H1R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H1R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.

Late onset systemic sclerosis with seronegativity: a rare presentation of an uncommon disease.

Systemic sclerosis (SSc) is an uncommon connective tissue disorder characterized by multisystem involvement with fibrosis of skin and internal organs. Antibody formation is one of the hallmarks of SSc. Antinuclear antibodies (ANA) are positive in 97% of patients with SSc. We report a rare case where the patient was negative for ANA, Anti-topoisomerase I, Anti-centromere and Anti-RNA polymerase III antibodies.

Sciatic Nerve to Pudendal Nerve Transfer: Anatomical Feasibility for a New Proposed Technique.

Aim Restoration of bladder and bowel continence after pudendal nerve anastomosis has been shown successfully in animal models and may be applicable in humans. Aim of this cadaveric study was to assess feasibility of pudendal nerve neurotization using motor fascicles from sciatic nerve. Methods Pudendal and sciatic nerves were exposed via gluteal approach in 5 human cadavers (10 sites). Size of pudendal and sciatic nerves and the distance between two nerves was measured. Results There were four male and one female cadavers. Mean age was 62 (range, 50-70) years. Mean pudendal nerve diameter was 2.94 mm (right side) and 2.82 mm (left side). Mean sciatic nerve diameter was 11.2 mm (right side) and 14.2 mm (left side). The distance between two nerves was 23.4 mm on both sides. Conclusion Transfer of the motor fascicles from sciatic nerve to pudendal nerve to restore the bladder and bowel continence is feasible.

Discrepancies between biomarkers of primary breast cancer and subsequent brain metastases: an international multicenter study.

PURPOSE: Discordances between the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), expression between primary breast tumors and their subsequent brain metastases (BM) were investigated in breast cancer patients. METHODS: We collected retrospective data from 11 institutions in 8 countries in a predefined-standardized format. Receptor status (positive or negative) was determined according to institutional guidelines (immunohistochemically and/or fluorescence in situ hybridization). The study was subject to each institution's ethical research committee. RESULTS: A total of 167 breast cancer patients with BM were included. 25 patients out of 129 with a complete receptor information from both primary tumor and BM (ER, PR, HER2) available, had a change in receptor status: 7 of 26 (27%) ER/PR-positive/HER2-negative primaries (3 gained HER2; 4 lost expression of ER/PR); 10 of 31 (32%) ER/PR-positive/HER2-positive primaries (4 lost ER/PR only; 3 lost HER2 only; 3 lost both ER/PR and HER2); one of 33 (3%) ER/PR-negative receptor/HER2-positive primaries (gained ER); and 7 of 39 (18%) triple-negative primaries (5 gained ER/PR and 2 gained HER2). CONCLUSIONS: The majority of breast cancer patients with BM in this series had primary HER2-enriched tumors, followed by those with a triple-negative profile. One out of 5 patients had a receptor discrepancy between the primary tumor and subsequent BM. Therefore, we advise receptor status assessment of BM in all breast cancer patients with available histology as it may have significant implications for therapy.

Characteristics, outcomes, prognostic factors and treatment of patients with T-cell prolymphocytic leukemia (T-PLL).

BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive disease. In this study, we report our experience from 119 patients with T-PLL. PATIENTS AND METHODS: We reviewed the clinico-pathologic records of 119 consecutive patients with T-PLL, who presented to our institution between 1990 and 2016. RESULTS: One hundred and nineteen patients with T-PLL were analysed. Complex karyotype and aberrations in chromosome 14 were seen in 65% and 52% patients, respectively. Seventy-five patients (63%) were previously untreated and 43 (37%) were initially treated outside our institution. Sixty-three previously untreated patients (84%) received frontline therapies. Overall, 95 patients (80%) have died. Median overall survival (OS) from diagnosis was 19 months [95% confidence interval (CI) 16-26 months]. Using recursive partitioning (RP), we found that patients with hemoglobin < 9.3 g/dl, lactate dehydrogenase (LDH) ≥ 1668 IU/l, white blood cell ≥ 208 K/l and ß2M ≥ 8 mg/l had significantly inferior OS and patients with hemoglobin < 9.3 g/dl had inferior progression-free survival (PFS). In multivariate analysis, we identified that presence of pleural effusion [hazard ratio (HR) 2.08 (95% CI 1.11-3.9); P = 0.02], high LDH (≥ 1668 IU/l) [HR 2.5 (95% CI 1.20-4.24); P < 0.001)], and low hemoglobin (< 9.3 g/dl) [HR 0.33 (95% CI 0.14-0.75); P = 0.008] were associated with shorter OS. Fifty-five previously untreated patients received treatment with an alemtuzumab-based regimen (42 monotherapy and 13 combination with pentostatin). Overall response rate, complete remission rate (CR) for single-agent alemtuzumab and alemtuzumab combined with pentostatin were 83%, 66% and 82%, 73% respectively. In patients who achieved initial CR, stem cell transplantation was not associated with longer PFS and OS. CONCLUSION: Outcomes in T-PLL remain poor. Multicenter collaborative effort is required to conduct prospective studies.

Co-circulation and co-infections of all dengue virus serotypes in Hyderabad, India 2014.

The burden of dengue virus infections increased globally during recent years. Though India is considered as dengue hyper-endemic country, limited data are available on disease epidemiology. The present study includes molecular characterization of dengue virus strains occurred in Hyderabad, India, during the year 2014. A total of 120 febrile cases were recruited for this study, which includes only children and 41 were serologically confirmed for dengue positive infections using non-structural (NS1) and/or IgG/IgM ELISA tests. RT-PCR, nucleotide sequencing and evolutionary analyses were carried out to identify the circulating serotypes/genotypes. The data indicated a high percent of severe dengue (63%) in primary infections. Simultaneous circulation of all four serotypes and co-infections were observed for the first time in Hyderabad, India. In total, 15 patients were co-infected with more than one dengue serotype and 12 (80%) of them had severe dengue. One of the striking findings of the present study is the identification of serotype Den-1 as the first report from this region and this strain showed close relatedness to the Thailand 1980 strains but not to any of the strains reported from India until now. Phylogenetically, all four strains of the present study showed close relatedness to the strains, which are reported to be high virulent.

Trend of Japanese encephalitis in Uttar Pradesh, India from 2011 to 2013.

As indicated by the sporadic Japanese encephalitis (JE) cases reported from the districts of Uttar Pradesh (UP), India, the disease is endemic in the state despite the fact that a JE vaccination programme has been ongoing in the state since 2006. Hence, the present study was undertaken to study the annual trend of JE in UP during January 2011 to December 2013. CSF and/or serum samples collected from acute encephalitis syndrome (AES) cases were referred to the virology laboratory at King George's Medical University, Lucknow and were tested for anti-JEV IgM antibodies by JEV MAC-ELISA kit. The study reveals that 26·9%, 9·9% and 14·8% of AES cases were positive for anti-JEV IgM in the years 2011, 2012 and 2013, respectively. Of the total JE confirmed cases, 30% were adults. Males were more commonly affected than females. A distinct peak of JE was seen in the monsoon and post-monsoon season, although sporadic cases were also reported in other months. JE vaccination by district in UP is discussed. This study reports that the proportion of JE positives in AES cases is decreasing in UP although the number of AES cases has not decreased. The study also discusses the probable causes of this decrease, including JE vaccination and natural periodicity due to herd immunity.

Systemic lupus erythematosus presenting as fulminant lupus pneumonitis: a rare case report.

We report a case of 19 year-old female patient diagnosed as systemic lupus erythematosus (SLE) presented with fever and diffuse cutaneous lesions. During the hospital stay she had acute pneumonia, pleural effusion and respiratory failure, which required intensive care unit (ICU) care and mechanical ventilator support. A fulminant course of the disease, decreased values of complement levels and positive antinuclear antibodies (ANA) in pleural fluid and repeated negative sputum for acid-fast bacillus, blood cultures enabled diagnosis of fulminant lupus pneumonitis. Fulminant lupus pneumonitis is a rare but potentially life threatening complication of SLE. Management requires involvement of multiple specialties and rigorous efforts in reviving the patient.

The prevalence of severe pain, its etiopathological characteristics and treatment profile of patients referred to a tertiary cancer care pain clinic.

Pain is the most feared symptom in cancer. About 52-77% patients suffer pain despite World Health Organization (WHO) recommendations. Out of total, one-third patients suffer moderate to severe pain. This study was undertaken to determine the prevalence, etiopathogenesis and characteristics of severe pain and treatment response among pain clinic referrals in a busy tertiary care cancer center. This study found a high prevalence (31.5%) of severe pain. A total of 251 patients who had complete pain data were analyzed for etiopathological characteristics and treatment response. Head and neck cancer contributed the highest prevalence among all regions. Oncologists prescribed non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol with or without mild opioids to 14% patients and pain clinic physicians prescribed opioids and overall 63.7% patients had a better response after pain clinic referral, even then, morphine was not prescribed to many deserving patients. Doctors need pain education about opioids to remove any fear of prescribing opioids in presence of severe pain.

Laparoscopic common bile duct exploration.

BACKGROUND: Laparoscopic common bile duct exploration (LCBDE) is a safe and effective single-stage treatment for choledocholithiasis in the elective setting. The outcomes after LCBDE in the emergency setting are unknown. The aim of this study was to compare the outcomes following elective and emergency LCBDE for choledocholithiasis. METHODS: Details of all patients who underwent LCBDE for choledocholithiasis between August 2003 and August 2013 were analysed retrospectively. The primary outcome measure was common bile duct (CBD) stone clearance rate. Secondary outcome measures were conversion rate, morbidity, mortality and length of hospital stay. RESULTS: Some 215 consecutive patients (57 male; median age 65 (range 14-92) years) underwent LCBDE. Some 121 procedures were performed electively and 94 as an emergency. Forty-five patients (48 per cent) presented with obstructive jaundice or cholangitis in the emergency LCBDE group compared with 15 (12·4 per cent) in the elective group (P < 0·001). The CBD stone clearance rate was similarly high in both groups (96 versus 96·7 per cent respectively; P = 0·557). There were no significant differences in conversion rate (6 versus 4·1 per cent), morbidity (5 versus 6·6 per cent), mortality (2 versus 0 per cent) or median length of stay (3 days) between groups. Two patients died, both following emergency LCBDE. CONCLUSION: LCBDE can be performed safely and effectively in both elective and emergency settings.

NAC transcription factor genes: genome-wide identification, phylogenetic, motif and cis-regulatory element analysis in pigeonpea (Cajanus cajan (L.) Millsp.).

The NAC (NAM, ATAF and CUC) proteins are plant-specific transcription factors implicated in development and stress responses. In the present study 88 pigeonpea NAC genes were identified from the recently published draft genome of pigeonpea by using homology based and de novo prediction programmes. These sequences were further subjected to phylogenetic, motif and promoter analyses. In motif analysis, highly conserved motifs were identified in the NAC domain and also in the C-terminal region of the NAC proteins. A phylogenetic reconstruction using pigeonpea, Arabidopsis and soybean NAC genes revealed 33 putative stress-responsive pigeonpea NAC genes. Several stress-responsive cis-elements were identified through in silico analysis of the promoters of these putative stress-responsive genes. This analysis is the first report of NAC gene family in pigeonpea and will be useful for the identification and selection of candidate genes associated with stress tolerance.