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A large group of keratin genes (n=54 in the human genome) code for intermediate filament (IF)-forming proteins and show differential regulation in epithelial cells and tissues. Keratin expression can be highly informative about the type of epithelial tissue, differentiation status of constituent cells and biological context (e.g. normal versus diseased settings). The foundational principles underlying the use of keratin expression to gain insight about epithelial cells and tissues primarily originated in pioneering studies conducted in the 1980s. The recent emergence of single cell transcriptomics provides an opportunity to revisit these principles and gain new insight into epithelial biology. Re-analysis of single-cell RNAseq data collected from human and mouse skin has confirmed long-held views regarding the quantitative importance and pairwise regulation of specific keratin genes in keratinocytes of surface epithelia. Furthermore, such analyses confirm and extend the notion that changes in keratin gene expression occur gradually as progenitor keratinocytes commit to and undergo differentiation, and challenge the prevailing assumption that specific keratin combinations reflect a mitotic versus a post-mitotic differentiating state. Our findings provide a blueprint for similar analyses in other tissues, and warrant a more nuanced approach in the use of keratin genes as biomarkers in epithelia.

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian cancer, now as a treatment and as a maintenance therapy in the upfront and recurrent settings. However, patients often develop resistance to PARPis, underlining the importance of dissecting resistance mechanisms. Here, we report different dosing/timing schemes of PARPi treatment in BRCA2-mutant PEO1 cells, resulting in the simultaneous development of distinct resistance mechanisms. PARPi-resistant variants PEO1/OlaJR, established by higher initial doses and short-term PARPi treatment, develops PARPi resistance by rapidly restoring functional BRCA2 and promoting drug efflux activity. In contrast, PEO1/OlaR, developed by lower initial doses with long-term PARPi exposure, shows no regained BRCA2 function but a mesenchymal-like phenotype with greater invasion ability, and exhibits activated ATR/CHK1 and suppressed EZH2/MUS81 signaling cascades to regain HR repair and fork stabilization, respectively. Our study suggests that PARPi resistance mechanisms can be governed by treatment strategies and have a molecular basis on BRCA2 functionality. Further, we define different mechanisms that may serve as useful biomarkers to assess subsequent treatment strategies in PARPi-resistant ovarian cancer.

Graphical abstract, Highlights • Large GGGGCC repeat expansions within BAC vectors are highly unstable. • CRISPR-Cas9 screening of BAC vector clones to determine repeat length. • CRISPR-Cas9 cloning of GGGGCC repeat expansion regions into the linear pJazz vector. • pJazz dramatically stabilizes GGGGCC repeat expansions over 4 kb in length., Aberrant microsatellite repeat-expansions at specific loci within the human genome cause several distinct, heritable, and predominantly neurological, disorders. Creating models for these diseases poses a challenge, due to the instability of such repeats in bacterial vectors, especially with large repeat expansions. Designing constructs for more precise genome engineering projects, such as engineering knock-in mice, proves a greater challenge still, since these unstable repeats require numerous cloning steps in order to introduce homology arms or selection cassettes. Here, we report our efforts to clone a large hexanucleotide repeat in the C9orf72 gene, originating from within a BAC construct, derived from a C9orf72-ALS patient. We provide detailed methods for efficient repeat sizing and growth conditions in bacteria to facilitate repeat retention during growth and sub-culturing. We report that sub-cloning into a linear vector dramatically improves stability, but is dependent on the relative orientation of DNA replication through the repeat, consistent with previous studies. We envisage the findings presented here provide a relatively straightforward route to maintaining large-range microsatellite repeat-expansions, for efficient cloning into vectors.

Oral squamous cell cancers involving the masticatory space are staged as unresectable cancers and their treatment is difficult. Curative treatment with extensive surgery followed by adjuvant therapy is one of the treatment options. In this retrospective study, the survival of 123 patients (93 with T4a cancers, 30 with T4b cancers), treated during the period August 2009 to August 2015, was evaluated. The majority had bucco-alveolar cancers (62.6%), were male (61.8%), and were tobacco users (76.4%). The select group of T4b oral cancer patients were treated with surgery, which included infratemporal fossa clearance in all 30 patients, followed by adjuvant therapy. The masseter was the most commonly involved masticatory muscle, and 24 patients had fewer than three involved structures. Free margins were obtained in 90.2% of cases; 41.5% of cases were node-positive. One hundred and four patients (84.6%) completed adjuvant treatment. The median follow-up was 42 months. For node-negative patients with T4a and T4b cancers, the 5-year overall survival was 59% and 50.2%, respectively (P= 0.62), and 5-year disease-free survival was 64.6% and 53.5%, respectively (P= 0.01). In conclusion, the select group of patients with T4b oral cancers and less than three masticatory space structures involved had comparable outcomes to those with T4a cancers after treatment with surgery and adjuvant radiotherapy.

Precise localization of the "epileptogenic zone(EZ)" is the goal of presurgical investigations in patients with drug-resistant focal epilepsy. Intracranial electroencephalography recordings are required when noninvasive evaluation results are not consistent. Although subdural grid electrodes(SDG)have been widely used in Japan, stereoelectroencephalography(SEEG)has been recently introduced. The principle of SEEG is based on anatomo-electro-clinical correlations to investigate surgical hypotheses that are primarily driven by the analysis of seizure semiology as well as other noninvasive investigations. The most important element of the SEEG methodology is to formulate preimplantation electrode trajectories considering the anatomo-electro-clinical correlations of epileptic seizures. If the preimplantation hypotheses are insufficient or incorrect, SEEG recordings will not identify the EZ. A detailed analysis of seizure semiology with respect to anatomo-electro-clinical correlates, particularly including various deep structures, such as the insular, operculum, and cingulate cortex, forms the basis of the implantation strategy for SEEG. The strategy of implantation is not to map the lobes/lobules but the epileptic networks, which usually involve multiple lobes, indicating that the theory of SEEG is completely different from that of SDG. Herein, we introduce the basics of SEEG, especially presurgical evaluations, with a representative case presentation.

A series of copper(II) compounds 1-4 were synthesized and developed as fluorogenic probes to measure the cardiac marker homocysteine (Hcy) without any interference from other bioanalytes prevalent in human blood plasma including, cysteine and glutathione. UV-vis and EPR studies have provided confirmatory evidence for reduction-induced-emission-enhancement of the probe, which is responsible for the observed "off-to-on" behaviour towards Hcy. Water solubility, remarkable fluorescence enhancement (55-111 fold), and low detection ability (nearly 2.5 μM) make the probe suitable for clinical testing of cardiac samples. Investigation of 1 against a few reductive interferents testifies its specificity for Hcy. Results from clinical examination of cardiac samples by 1 when combined with the outcome of the reliability testing involving a clinically approved commercial immunoassay kit, validates the prospect of the molecular probe for direct measurement of Hcy in human plasma, which is unprecedented.

STUDY QUESTION Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting? SUMMARY ANSWER Consensus definitions for individual core outcomes, contextual statements and a standardized reporting table have been developed. WHAT IS KNOWN ALREADY Different definitions exist for individual core outcomes for infertility. This variation increases the opportunities for researchers to engage with selective outcome reporting, which undermines secondary research and compromises clinical practice guideline development. STUDY DESIGN, SIZE, DURATION Potential definitions were identified by a systematic review of definition development initiatives and clinical practice guidelines and by reviewing Cochrane Gynaecology and Fertility Group guidelines. These definitions were discussed in a face-to-face consensus development meeting, which agreed consensus definitions. A standardized approach to reporting was also developed as part of the process. PARTICIPANTS/MATERIALS, SETTING, METHODS Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus development methods. MAIN RESULTS AND THE ROLE OF CHANCE Forty-four potential definitions were inventoried across four definition development initiatives, including the Harbin Consensus Conference Workshop Group and International Committee for Monitoring Assisted Reproductive Technologies, 12 clinical practice guidelines and Cochrane Gynaecology and Fertility Group guidelines. Twenty-seven participants, from 11 countries, contributed to the consensus development meeting. Consensus definitions were successfully developed for all core outcomes. Specific recommendations were made to improve reporting. LIMITATIONS, REASONS FOR CAUTION We used consensus development methods, which have inherent limitations. There was limited representation from low- and middle-income countries. WIDER IMPLICATIONS OF THE FINDINGS A minimum data set should assist researchers in populating protocols, case report forms and other data collection tools. The generic reporting table should provide clear guidance to researchers and improve the reporting of their results within journal publications and conference presentations. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials statement, and over 80 specialty journals have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S) This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and a financial interest in NexHand. E.H.Y.N. reports research sponsorship from Merck. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their ‘traffic light’ system for infertility treatment ‘add-ons’. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER Core Outcome Measures in Effectiveness Trials Initiative: 1023.

Background and aims Melatonin, a pineal gland hormone is reported to have a protective effect against delirium. This systematic review and meta-analysis explores the effect of melatonin and melatonin receptor agonist, ramelteon on delirium prevention in adult hospitalized patients. Methods Randomized Controlled trials of melatonin/ramelteon published up to May 7, 2020 were identified from MEDLINE, PREMEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled trials, PubMed, and Google Scholar. The primary outcome was delirium incidence. The secondary outcomes were sleep quality, sedation score, sedatives requirement, delirium duration, length of hospital stay, length of Intensive Care Unit (ICU) stay, mortality and adverse events. A meta-analysis with a random-effects models was performed. Estimates were presented as Risk Ratio (RR) or Mean Differences (MD) with 95% Confidence Interval (CI). Findings Fourteen studies with 1712 participants were included. Melatonin/ramelteon significantly reduced delirium incidence (RR 0·61, 95% CI 0·42–0·89, p 0·009) with risk reduction of 49% in surgical patients and 34% in ICU patients. Non-significant reduction was found in medical patients. Melatonin/ramelteon were associated with improvement in sleep quality, increased sedation score and lower sedatives consumption. However, they did not reduce delirium duration, length of hospital stay, length of ICU stay and mortality. Hallucinations, nightmares and gastrointestinal disorders were prevalent in melatonin group. Interpretation Melatonin/ramelteon are associated with reduction in delirium incidence in hospitalized patients. However, this effect seems confined to surgical and ICU patients. The optimum dosage and formulation of melatonin, and treatment duration remain uncleared and open to further studies with larger sample sizes.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G2–M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells. PI3K/mTOR pathway inhibitors (PI3K/mTORi) showed supra-additive cytotoxicity with CHK1i. Combined treatment with CHK1i and PI3K/mTORi significantly attenuated cell viability and increased DNA damage, chromosomal breaks, and mitotic catastrophe compared with monotherapy. PI3K/mTORi decelerated fork speed by promoting new origin firing via increased CDC45, thus potentiating CHK1i-induced replication stress. PI3K/mTORi also augmented CHK1i-induced DNA damage by attenuating DNA homologous recombination repair activity and RAD51 foci formation. High expression of replication stress markers was associated with poor prognosis in patients with HGSOC. Our findings indicate that combined PI3K/mTORi and CHK1i induces greater cell death in HGSOC cells and in vivo models by causing lethal replication stress and DNA damage. This insight can be translated therapeutically by further developing combinations of PI3K and cell-cycle pathway inhibitors in HGSOC. Significance: Dual inhibition of CHK1 and PI3K/mTOR pathways yields potent synthetic lethality by causing lethal replication stress and DNA damage in HGSOC, warranting further clinical development.

Purpose: Examine patterns of medication use, changes in medication patterns over time, and investigate factors associated with medication patterns among older Australian women with Atrial Fibrillation (AF). Methods: It is a retrospective analysis of the 1921-26 birth cohort of the Australian Longitudinal Study on Women’s Health (ALSWH), diagnosed with AF between 2000-2015 (N = 1206). Survey data of these women was linked with national registries for medications and death. Latent Transition Analysis (LTA) identified distinct patterns of medication use and transitions among these patterns for 3 consecutive years following AF diagnosis. LTA with co-variates determined the factors associated with latent status membership. Results: One-tenth (9.6%, 11.7%, 11.4%) of the study population did not receive any medication for AF in all 3 years following AF diagnosis and about 60% did not receive any medication for the prevention of thromboembolism. Among those who received medications, almost three-quarters (76.6%, 68.4%, 68.5%) received some kind of combination of medications. LTA indicated at least 6 different patterns of AF medications. These patterns had transition probabilities >85% for most of the latent statuses. All factors but diabetes mellitus among the CHA2DS2-VA scoring scheme were independently associated with latent status membership at the time of AF diagnosis. Conclusions: Evaluation of pharmacological treatment indicates that prevention of thromboembolism is inadequate among women with AF. There exists wide variations in medication patterns. However, once in a particular pattern, women are likely to continue the same medications long-term. This underscores the importance of initial assessment of patient profile and stroke risk score in determining the treatment for AF. Failure to assess risk makes women susceptible to devastating AF complications.

Fatty acids in mitochondria, in sensu stricto, arise either as β-oxidation substrates imported via the carnitine shuttle or through de novo synthesis by the mitochondrial fatty acid synthesis (mtFAS) pathway. Defects in mtFAS or processes involved in the generation of the mtFAS product derivative lipoic acid (LA), including iron-sulfur cluster synthesis required for functional LA synthase, have emerged only recently as etiology for neurodegenerative disease. Intriguingly, mtFAS deficiencies very specifically affect CNS function, while LA synthesis and attachment defects have a pleiotropic presentation beyond neurodegeneration. Typical mtFAS defect presentations include optical atrophy, as well as basal ganglia defects associated with dystonia. The phenotype display of patients with mtFAS defects can resemble the presentation of disorders associated with coenzyme A (CoA) synthesis. A recent publication links these processes together based on the requirement of CoA for acyl carrier protein maturation. MtFAS defects, CoA synthesis- as well as Fe-S cluster-deficiencies share lack of LA as a common symptom.

Background Providing a timely and accurate diagnosis of dementia and delivering appropriate support following a diagnosis are essential to allow individuals and their families to plan for the future. Recent studies suggest that provision of diagnosis and post-diagnosis support is suboptimal. This study explored geriatricians’ views about strategies to improve quality of care across these domains. Methods An anonymous online survey of geriatricians and advanced trainees in one Australian state was conducted. An Expert Advisory Group of geriatricians, behavioural scientists and consumers proposed strategies to improve quality of care in relation to diagnosis and post-diagnosis support for people with dementia, which formed the survey items. Potential strategies were guided by, but not limited to, dementia and chronic care guidelines. Participants were asked the extent to which they agreed that implementing each of the proposed strategies would improve the quality of dementia care. Results Of 59 participants (response rate 42%), all agreed that improving accessibility of geriatricians would improve the accuracy and timeliness of diagnosis. Over 90% were supportive of strategies to improve capacity of general practitioners to accurately diagnose dementia. Between 97-100% agreed that information provided following diagnosis should encompass symptom progression, treatments, psychological supports, and advance care planning. Just over two-thirds thought that life expectancy should be discussed at this time. There were high levels of support for strategies already included in existing dementia care guidelines, however geriatricians also agreed with a range of possible strategies not currently included in guidelines. Conclusions Geriatricians perceive that timeliness and accuracy of dementia diagnosis may be improved by increasing access to geriatricians and training general practitioners in diagnosing dementia. They also believe it is appropriate to provide information at the time of diagnosis across a comprehensive range of areas, including potentially sensitive topics such as advance care planning. Future studies should explore the views of other groups of health care providers and consumers about these approaches. The strategies proposed should be considered for inclusion in future dementia care guidelines.

Aims Policymakers and researchers have little evidence on prevalence rates of intellectual disability (ID) or their changes over time to tailor healthcare interventions. Prevalence rates and trends of ID are especially lacking in regions with lower socio-demographic development. Additionally, the assessment of inequalities in the prevalence of ID across regions with varying socio-demographic development is understudied. This study assessed variations in prevalence rates of ID from 1990 to 2019 and the related inequalities between low and high socio-demographic index (SDI) regions. Methods This study used global data from 1990 to 2019 for individuals with ID from the 2019 Global Burden of Diseases study. Data analyses were performed from September 2021 to January 2022. Prevalence for individuals with ID was extracted by sex, age groups and SDI regions. Annual percentage change (APC) was estimated for each demographic group within SDI regions to assess their prevalence trends over 30 years. Relative and absolute inequalities were calculated between low and high SDI regions for the various age groups. Results In 2019, there were 107.62 million (1.74%) individuals with ID, with an APC of −0.80 (−0.88 to −0.72). There was a slightly higher prevalence among males (1.42%) than females (1.37%). The highest prevalence rates were found in the low-middle SDI regions (2.42%) and the lowest prevalence rates were in the high SDI regions (0.33%). There was a large reduction in the prevalence rate between the youngest age group v. the oldest age group in all the SDI regions and at all time points. The relative inequalities between low and high SDI regions increased over three decades. Conclusions While an overall decrease in global prevalence rate for ID was found, relative inequalities continue to increase with lower SDI regions needing more comprehensive support services. The demographic trends indicate a significantly higher mortality rate among those with ID v. the rest of the population. Our study highlights the necessity for policies and interventions targeting lower SDI regions to mobilise resources that better support individuals with ID and achieve sustainable development goals proposed by the United Nations.

Medication adherence is important for optimal management of chronic conditions, including hypertension and hypercholesterolemia. This study describes adherence to antihypertensive and statin medications, individually and collectively, and examines variation in adherence by demographic and geographic characteristics.The 2017 prescription drug event data for beneficiaries with Medicare Part D coverage were assessed. Beneficiaries with a proportion of days covered ≥80% were considered adherent. Adjusted prevalence ratios were estimated to quantify the associations between demographic and geographic characteristics and adherence. Adherence estimates were mapped by county of residence using a spatial empirical Bayesian smoothing technique to enhance stability. Analyses were conducted in 2019‒2021.Among the 22.5 million beneficiaries prescribed antihypertensive medications, 77.1% were adherent; among the 16.1 million prescribed statin medications, 81.9% were adherent; and among the 13.5 million prescribed antihypertensive and statin medications, 70.3% were adherent to both. Adherence varied by race/ethnicity: American Indian/Alaska Native (adjusted prevalence ratio=0.83, 95% confidence limit=0.82, 0.842), Hispanic (adjusted prevalence ratio=0.90, 95% confidence limit=0.90, 0.91), and non-Hispanic Black (adjusted prevalence ratio=0.87, 95% confidence limit=0.86, 0.87) beneficiaries were less likely to be adherent than non-Hispanic White beneficiaries. County-level adherence ranged across the U.S. from 25.7% to 88.5% for antihypertensive medications, from 36.0% to 93.8% for statin medications, and from 20.8% to 92.9% for both medications combined and tended to be the lowest in the southern U.S.This study highlights opportunities for efforts to remove barriers and support medication adherence, especially among racial/ethnic minority groups and within the regions at greatest risk for adverse cardiovascular outcomes.

Background Relative adrenal insufficiency (RAI) is common in compensated and decompensated chronic liver disease in the presence of sepsis. This study was performed to find out the prevalence of RAI in decompensated cirrhotic patients presenting with hepatic encephalopathy and variceal bleeding without any evidence of infection. Methods The study prospectively included 75 cirrhotic patients with signs of decompensation. The short Synacthen test (SST) was performed on all patients after ruling out infection. Patients with positive blood, urine, sputum, ascitic and pleural fluid cultures or evidence of infection on chest X-ray and those with elevated procalcitonin levels (>0.05 ng/ml) were excluded. RAI in critical illness was defined by a delta cortisol level (difference between basal and post-stimulation cortisol) of ≤9 μg/dl after SST. Results The mean age of the study population was 54 ± 11 years. Upper gastrointestinal bleed and hepatic encephalopathy were seen in 56.6% and 41.5%, respectively, and both were seen in 1.9%. Of the 75 patients, 55 (73%) were in Child-Turcotte-Pugh (CTP) class C and the mean model for end-stage liver disease (MELD) score was 21 ± 7. Forty-five patients (60%) met our criteria for RAI. Those with RAI had lower serum albumin (2.4 ± 0.5 g/dl vs 2.7 ± 0.5 g/dl, p = 0.03) and higher MELD scores (22 ± 7 vs 19 ± 6, p = 0.03). Prevalence of RAI in CTP class C was 65% (36 out of 55 patients) compared to 45% (9 out of 20 patients) in Child-Pugh stage A and B. Similarly, 82% (23 out of 28 patients) with MELD scores >25 had RAI compared to 54% with MELD scores Conclusion The present study showed RAI to be common in noninfected decompensated cirrhotic patients, but did not predict 3-month mortality. There were no other predictive factors in those with RAI. Hence, in patients with cirrhosis without infection, the clinical utility of routine adrenal function testing needs further elucidation.

Preeclampsia is a hypertensive disorder of pregnancy associated with vascular dysfunction and cardiovascular risk to offspring. We hypothesize that endothelial PPARγ (peroxisome proliferator–activated receptor-γ) provides cardiovascular protection in offspring from pregnancies complicated by hypertension. C57BL/6J dams were bred with E-V290M sires, which express a dominant-negative allele of PPARγ selectively in the endothelium. Arginine vasopressin was infused throughout gestation. Vasopressin elevated maternal blood pressure at gestational day 14 to 15 and urinary protein at day 17 consistent. Systolic blood pressure and vasodilation responses to acetylcholine were similar in vasopressin-exposed offspring compared to offspring from control pregnancies. We treated offspring with a subpressor dose of angiotensin II to test if hypertension during pregnancy predisposes offspring to hypertension. Male and female angiotensin II–treated E-V290M offspring from vasopressin-exposed but not control pregnancy exhibited significant impairment in acetylcholine-induced relaxation in carotid artery. Endothelial dysfunction in angiotensin II–treated E-V290M vasopressin-exposed offspring was attenuated by tempol, an effect which was more prominent in male offspring. Nrf2 (nuclear factor-E2-related factor) protein levels were significantly elevated in aorta from male E-V290M offspring, but not female offspring compared to controls. Blockade of ROCK (Rho-kinase) signaling and incubation with a ROCK2-specific inhibitor improved endothelial function in both male and female E-V290M offspring from vasopressin-exposed pregnancy. Our data suggest that interference with endothelial PPARγ in offspring from vasopressin-exposed pregnancies increases the risk for endothelial dysfunction on exposure to a cardiovascular stressor in adulthood. This implies that endothelial PPARγ provides protection to cardiovascular stressors in offspring of a pregnancy complicated by hypertension and perhaps in preeclampsia.

Potential heart and lung donors with a history of illicit drugs and/or smoking and alcohol are frequently offered, though there is no clear guidance on when it is safe to use these organs. A review of the literature on effects of drugs, alcohol and smoking on donor outcomes, and the effects of these on the intact heart and lung was undertaken. There has been a marked increase in deaths from opioid abuse in many developed countries, though recent evidence suggests that outcomes after cardiothoracic transplantation are equivalent to nonopioid donor causes of death. For donor smoking, there is an increased risk with lung transplantation; however, that risk is less when compared to further waiting on the transplant list for a nonsmoking alternative. Heavy alcohol consumption does not adversely affect heart transplantation, and there is no clear evidence of adverse outcomes after lung transplantation. There are no overall effects of cannabis or cocaine on survival after heart or lung transplantation. In all these cases, careful donor assessment can establish if a particular organ can be used. In most cases, use of drugs requires careful assessment, but is not in of itself a contraindication to cardiothoracic transplantation.

Neurodegenerative disease encompasses a wide range of disorders afflicting the central and peripheral nervous systems and is a major unmet biomedical need of our time. There are very limited treatments, and no cures, for most of these diseases, including Alzheimer’s Disease, Parkinson's Disease, Huntington Disease, and Motor Neuron Diseases. Mouse and other animal models provide hope by analysing them to understand pathogenic mechanisms, to identify drug targets, and to develop gene therapies and stem cell therapies. However, despite many decades of research, virtually no new treatments have reached the clinic. Increasingly, it is apparent that human heterogeneity within clinically defined neurodegenerative disorders, and between patients with the same genetic mutations, significantly impacts disease presentation and, potentially, therapeutic efficacy. Therefore, stratifying patients according to genetics, lifestyle, disease presentation, ethnicity, and other parameters may hold the key to bringing effective therapies from the bench to the clinic. Here, we discuss genetic and cellular humanised mouse models, and how they help in defining the genetic and environmental parameters associated with neurodegenerative disease, and so help in developing effective precision medicine strategies for future healthcare.

Early miscarriage (EM) is one of the most devastating obstetrical complications globally affecting the quality of women's life. In the present study, we aimed to identify proteins that correlate with and could act as biomarkers for EM. We performed 2-dimensional gel electrophoresis in chorionic villi samples followed by mass spectrometry for identification of differential protein expression with EM. Proteomic studies detected a total 124 protein spots, out of which 83 spots were differentially expressed between EM and controls in chorionic villi samples. Matrix assisted laser desorbtion/ionization-time of flight (MALDI-TOF) mass spectrometry analysis revealed Apolipoprotein A1 (APOA1) to be the most upregulated protein in the EM group that was validated by Western blotting and Enzyme-linked immunosorbent assay (ELISA) . We found low but not statistically significant level of APOA1 on 21st day of menstruation in comparison to the 7th day. APOA1 level was observed to be the lowest in the first trimester. Hence, this study suggests that low APOA1 expression is critical in establishing pregnancy and elevated APOA1 expression in chorionic villi correlates with EM. Similar observation in serum samples suggests its potential as a marker for the risk of EM.

Disease relapse in B-cell acute lymphoblastic leukemia (ALL), either due to development of acquired resistance after therapy or because of de novo resistance, remains a therapeutic challenge. In the present study, we have developed a cytarabine (Ara-C)-resistant REH cell line (REH/Ara-C) as a chemoresistance model. REH/Ara-C 1) was not crossresistant to vincristine or methotrexate; 2) showed a similar proliferation rate and cell surface marker expression as parental REH; 3) demonstrated decreased chemotaxis toward bone marrow stromal cells; and 4) expressed higher transcript levels of cytidine deaminase (CDA) and mitoNEET (CISD1) than the parental REH cell line. Based on these findings, we tested NL-1, a mitoNEET inhibitor, which induced a concentration-dependent decrease in cell viability with a comparable IC(50) value in REH and REH/Ara-C. Furthermore, NL-1 decreased cell viability in six different ALL cell lines and showed inhibitory activity in a hemosphere assay. NL-1 also impaired the migratory ability of leukemic cells, irrespective of the chemoattractant used, in a chemotaxis assay. More importantly, NL-1 showed specific activity in inducing death in a drug-resistant population of leukemic cells within a coculture model that mimicked the acquired resistance and de novo resistance observed in the bone marrow of relapsed patients. Subsequent studies indicated that NL-1 mediates autophagy, and inhibition of autophagy partially decreased NL-1–induced tumor cell death. Finally, NL-1 showed antileukemic activity in an in vivo mouse ALL model. Taken together, our study demonstrates that mitoNEET has potential as a novel antileukemic drug target in treatment refractory or relapsed ALL.

To better understand human health and disease, researchers create a wide variety of mouse models that carry human DNA. With recent advances in genome engineering, the targeted replacement of mouse genomic regions with orthologous human sequences has become increasingly viable, ranging from finely tuned humanisation of individual nucleotides and amino acids to the incorporation of many megabases of human DNA. Here, we examine emerging technologies for targeted genomic humanisation, we review the spectrum of existing genomically humanised mouse models and the insights such models have provided, and consider the lessons learned for designing such models in the future., Generation of transgenic mice has become routine in studying gene function and disease mechanisms, but often this is not enough to fully understand human biology. Here, the authors review the current state of the art of targeted genomic humanisation strategies and their advantages over classic approaches.

Microbial products have been used for the treatment of different diseases for many centuries. The serratiopeptidase enzyme provides a new hope for COVID-19-infected patients. Nowadays, anti-inflammatory drugs are easy to obtain at minimal expenditure from microbial sources. Serratia sp. is identified as one of the most efficient bacteria produced from serratiopeptidase. Screening for new and efficient bacterial strains from different sources has been of interest in recent years. Serratiopeptidase remains the most well-known anti-inflammatory drug of choice. Serratiopeptidase is a cheaper and safer anti-inflammatory drug alternative to NSAIDs. The multifaceted properties of serratiopeptidase may lead towards arthritis, diabetes, cancer and thrombolytic treatments. Existing serratiopeptidase treatments in combination with antibiotics are popular in the treatment of postoperative swelling. Although an exclusive number of serratiopeptidase-producing strains have been derived, there is an urge for new recombinant strains to enhance the production of the enzyme. This review explores the properties of serratiopeptidase, different therapeutic aspects, industrial production, and various analytical techniques used in enzyme recovery. In addition, the review highlights the therapeutic and clinical aspects of the serratiopeptidase enzyme to combat COVID-19-induced respiratory syndrome.

Mutations in the RNA-binding protein (RBP) FUS have been genetically associated with the motoneuron disease amyotrophic lateral sclerosis (ALS). Using both human induced pluripotent stem cells and mouse models, we found that FUS-ALS causative mutations affect the activity of two relevant RBPs with important roles in neuronal RNA metabolism: HuD/ELAVL4 and FMRP. Mechanistically, mutant FUS leads to upregulation of HuD protein levels through competition with FMRP for HuD mRNA 3’UTR binding. In turn, increased HuD levels overly stabilize the transcript levels of its targets, NRN1 and GAP43. As a consequence, mutant FUS motoneurons show increased axon branching and growth upon injury, which could be rescued by dampening NRN1 levels. Since similar phenotypes have been previously described in SOD1 and TDP-43 mutant models, increased axonal growth and branching might represent broad early events in the pathogenesis of ALS., Maria Giovanna Garone et al. use iPSC and mouse models to evaluate a mechanistic link between aberrant axonal phenotypes in ALS and the alteration of a cross-regulatory circuitry involving three RNA binding proteins: FUS, HuD and FMRP. Their results suggest NRN1 as a potential therapeutic target for ALS and provide further insight into the pathogenesis of this critical disorder.

B-cell acute lymphoblastic leukemia (ALL) is characterized by accumulation of immature hematopoietic cells in the bone marrow, a well-established sanctuary site for leukemic cell survival during treatment. While standard of care treatment results in remission in most patients, a small population of patients will relapse, due to the presence of minimal residual disease (MRD) consisting of dormant, chemotherapy-resistant tumor cells. To interrogate this clinically relevant population of treatment refractory cells, we developed an in vitro cell model in which human ALL cells are grown in co-culture with human derived bone marrow stromal cells or osteoblasts. Within this co-culture, tumor cells are found in suspension, lightly attached to the top of the adherent cells, or buried under the adherent cells in a population that is phase dim (PD) by light microscopy. PD cells are dormant and chemotherapy-resistant, consistent with the population of cells that underlies MRD. In the current study, we characterized the transcriptional signature of PD cells by RNA-Seq, and these data were compared to a published expression data set derived from human MRD B-cell ALL patients. Our comparative analyses revealed that the PD cell population is markedly similar to the MRD expression patterns from the primary cells isolated from patients. We further identified genes and key signaling pathways that are common between the PD tumor cells from co-culture and patient derived MRD cells as potential therapeutic targets for future studies.

Bladder cancer (BC) is the 10th most common malignancy worldwide and the patient experience is found to be worse than that for patients diagnosed with other cancer types. We aimed to develop a wellbeing intervention to help improve the bladder cancer patient experience by ameliorating their health-related Quality of Life (HRQoL). We followed the 3 phases of the modified Medical Research Council (MRC) Framework for development of complex interventions. Following a systematic review of the literature on mental, sexual, and physical wellbeing, we conducted discussion groups with patients and healthcare professionals on these 3 themes. A consultation phase was then conducted with all relevant stakeholders to co-design a wellbeing intervention as part of a feasibility study. A pragmatic wellbeing feasibility trial was designed based on the hypothesis that a wellbeing program will increase patient awareness and attendance to services available to them and will better support their needs to improve HRQoL. The primary feasibility endpoints are patient attendance to the services offered and changes in HRQoL. The principle of patient centered care has strengthened the commitment to provide a holistic approach to support BC patients. In this study, we developed a wellbeing intervention in collaboration with patients and healthcare professionals to meet an unmet need in terms of the BC patient experience.

Reperfusion therapy for acute myocardial infarction (MI) is lifesaving. However, the benefit of reperfusion therapy can be paradoxically diminished by reperfusion injury, which can increase MI size.Hemorrhage is known to occur in reperfused MIs, but whether hemorrhage plays a role in reperfusion-mediated MI expansion is not known.We studied cardiac troponin kinetics (cTn) of ST-segment elevation MI patients (n = 70) classified by cardiovascular magnetic resonance to be hemorrhagic (70%) or nonhemorrhagic following primary percutaneous coronary intervention. To isolate the effects of hemorrhage from ischemic burden, we performed controlled canine studies (n = 25), and serially followed both cTn and MI size with time-lapse imaging.CTn was not different before reperfusion; however, an increase in cTn following primary percutaneous coronary intervention peaked earlier (12 hours vs 24 hours; P 0.05) and was significantly higher in patients with hemorrhage (P 0.01). In hemorrhagic animals, reperfusion led to rapid expansion of myocardial necrosis culminating in epicardial involvement, which was not present in nonhemorrhagic cases (P 0.001). MI size and salvage were not different at 1 hour postreperfusion in animals with and without hemorrhage (P = 0.65). However, within 72 hours of reperfusion, a 4-fold greater loss in salvageable myocardium was evident in hemorrhagic MIs (P 0.001). This paralleled observations in patients with larger MIs occurring in hemorrhagic cases (P 0.01).Myocardial hemorrhage is a determinant of MI size. It drives MI expansion after reperfusion and compromises myocardial salvage. This introduces a clinical role of hemorrhage in acute care management, risk assessment, and future therapeutics.

Background Upper tract urothelial carcinoma (UTUC) is a rare urological cancer that is still an important public health concern in many areas around the world. Although UTUC has been linked to a number of risk factors, to our knowledge no systematic review has been published on the overall incidence and prevalence of de-novo UTUC. This review aimed to examine the global epidemiology of UTUC to provide clinicians and public health specialists a better understanding of UTUC. Methods A systematic search was conducted on MEDLINE, Embase, and the Web of Science using a detailed search strategy. Observational epidemiological studies describing the incidence and prevalence of de-novo UTUC in adults were included, and the Joanna Briggs Institute checklist was used for critical appraisal and data extraction of the studies selected. Results The systematic search identified 3506 papers, of which 59 papers were included for qualitative synthesis. The studies selected included data ranging from the years 1943 to 2018. A comprehensive qualitative synthesis of the data was performed. UTUC incidence generally varied according to age (higher with increasing age), sex (unclear), race (unclear), calendar time (increased, stable, or decreased according to region), geographical region (higher in Asian countries), occupation (higher in seamen and printers), and other population characteristics. Prevalence was only reported by one study, which showed UTUC to have the highest incidence of the rare urogenital cancers in Europe. Conclusion This systematic review highlights an increased incidence of UTUC in certain groups, including increasing age and certain occupations such as seamen. The incidence of UTUC also varies between certain geographical regions. The trend of UTUC incidence for sex, race, and calendar time is less clear due to a wide variety of metrics used by the studies identified. More studies are also required on the prevalence of UTUC to understand its disease burden. Trial registration This review was registered on PROSPERO (registration number CRD42019134255).

Background: India has been amongst the most affected nations during the SARS CoV2 pandemic, with sparse data on country wide spread of asymptomatic infections and antibody persistence. This longitudinal cohort study was aimed to evaluate SARS CoV2 seropositivity rate as a marker of infection and evaluate temporal persistence of antibodies with neutralization capability and to infer possible risk factors for infection. Methods: Council of Scientific and Industrial Research, India (CSIR) with its more than 40 laboratories and centers in urban and semi urban settings spread across the country piloted the pan country surveillance. 10427 adult individuals working in CSIR laboratories and their family members based on voluntary participation were assessed for antibody presence and stability was analyzed over 6 months utilizing qualitative Elecysys SARS CoV2 specific antibody kit and GENScript cPass SARS CoV2 Neutralization Antibody Detection Kit. Along with demographic information, possible risk factors were evaluated through self to be filled online forms with data acquired on blood group type, occupation type, addiction and habits including smoking and alcohol, diet preferences, medical history and transport type utilized. Symptom history and information on possible contact and compliance with COVID 19 universal precautions was also obtained. Findings:1058 individuals (10.14%) had antibodies against SARS CoV2. A follow up on 346 seropositive individuals after three months revealed stable to higher antibody levels against SARS CoV2 but declining plasma activity for neutralizing SARS CoV2 receptor binding domain and ACE2 interaction. A repeat sampling of 35 individuals, at six months, revealed declining antibody levels while the neutralizing activity remained stable compared to three months. Majority of seropositive individuals (75%) did not recall even one of nine symptoms since March 2020. Fever was the most common symptom with one fourth reporting loss of taste or smell. Significantly associated risks for seropositivity (Odds Ratio, 95% CI, p value) were observed with usage of public transport (1.79, 1.43 to 2∙24, 2.81561x10-6), occupational responsibilities such as security, housekeeping personnel etc. (2.23, 1.92 to 2.59, 6.43969x10-26), non smokers (1.52, 1.16 to 1.99, 0.02) and non vegetarianism (1.67, 1.41 to 1.99, 3.03821x10-8). An iterative regression analysis was confirmatory and led to only modest changes to estimates. Predilections for seropositivity was noted with specific ABO blood groups; O was associated with a lower risk. Interpretation: In a first of its kind study from India, we report the seropositivity in a country wide cohort and identify variable susceptible associations for contacting infection. Serology and Neutralizing Antibody response provides much sought for general insights on the immune response to the virus among Indians and will be an important resource for designing vaccination strategies. Funding: Council of Scientific and Industrial Research, India (CSIR)

Data science has been an invaluable part of the COVID-19 pandemic response with multiple applications, ranging from tracking viral evolution to understanding the vaccine effectiveness. Asymptomatic breakthrough infections have been a major problem in assessing vaccine effectiveness in populations globally. Serological discrimination of vaccine response from infection has so far been limited to Spike protein vaccines since whole virion vaccines generate antibodies against all the viral proteins. Here, we show how a statistical and machine learning (ML) based approach can be used to discriminate between SARS-CoV-2 infection and immune response to an inactivated whole virion vaccine (BBV152, Covaxin). For this, we assessed serial data on antibodies against Spike and Nucleocapsid antigens, along with age, sex, number of doses taken, and days since last dose, for 1823 Covaxin recipients. An ensemble ML model, incorporating a consensus clustering approach alongside the support vector machine model, was built on 1063 samples where reliable qualifying data existed, and then applied to the entire dataset. Of 1448 self-reported negative subjects, our ensemble ML model classified 724 to be infected. For method validation, we determined the relative ability of a random subset of samples to neutralize Delta versus wild-type strain using a surrogate neutralization assay. We worked on the premise that antibodies generated by a whole virion vaccine would neutralize wild type more efficiently than delta strain. In 100 of 156 samples, where ML prediction differed from self-reported uninfected status, neutralization against Delta strain was more effective, indicating infection. We found 71.8% subjects predicted to be infected during the surge, which is concordant with the percentage of sequences classified as Delta (75.6%-80.2%) over the same period. Our approach will help in real-world vaccine effectiveness assessments where whole virion vaccines are commonly used.

Background Thyroid carcinoma (TC) is extremely rare in children. We assessed the clinicopathological features, outcomes, recurrence pattern, and associated risk factors of differentiated thyroid carcinoma (DTC). Methods Children aged ≤14 years, pathologically diagnosed as DTC at a tertiary cancer institute between January 1998 and December 2015 were retrospectively analyzed. Survival outcomes were estimated using the Kaplan-Meier method. Results During 18 years, 125 children with DTC were treated with a male:female ratio of 1:2.3. The median age was 12 years (2-14 years). Anterior neck swelling was the commonest presentation (72.8%). Histopathology revealed papillary thyroid carcinoma (PTC) in 123 children (98.4%). Extrathyroidal extension was seen in 32 children (25.6%). Sixty-eight children (54.4%) had nodal metastases and seven had distant metastasis. Relapse developed in 12 children. All were salvaged with subsequent surgery and radioiodine therapy. Eight children had persistent disease and one had a second malignant neoplasm. The median follow-up period was 9 years 1 month (1-20 years). Five-year recurrence-free survival (RFS) was 94.8% and 5-year overall survival was 100%. Larger tumors (p-value = .001), extrathyroidal extension (p-value = .001), and nodal metastasis (p-value = .022) were significant predictors for RFS in univariate analysis. Conclusions Pediatric DTC showed aggressive behavior characterized by a high rate of extrathyroidal extension and nodal and pulmonary metastasis. Persistent disease should be distinguished from recurrent disease as DTCs with metastatic disease remain stable for long time and usually respond well to radioiodine therapy. Our study reaffirmed favorable prognosis despite aggressive presentation and even after relapse.

High levels of the intermediate filament protein keratin 17 (K17) are associated with poor prognoses for several human carcinomas. Studies in mouse models have shown that K17 expression is positively associated with growth, survival, and inflammation in skin and that lack of K17 delays onset of tumorigenesis. K17 occurs in the nucleus of human and mouse tumor keratinocytes where it impacts chromatin architecture, gene expression, and cell proliferation. We report here that K17 is induced following DNA damage and promotes keratinocyte survival. The presence of nuclear K17 is required at an early stage of the double-stranded break (DSB) arm of the DNA damage and repair (DDR) cascade, consistent with its ability to associate with key DDR effectors, including γ-H2A.X, 53BP1, and DNA-PKcs. Mice lacking K17 or with attenuated K17 nuclear import showed curtailed initiation in a two-step skin carcinogenesis paradigm. The impact of nuclear-localized K17 on DDR and cell survival provides a basis for the link between K17 induction and poor clinical outcomes for several human carcinomas.

Introduction: Large vessels are often encountered during endobronchial ultrasound (EBUS). Safety of traversing the vessels weighed against a more invasive procedure can be a dilemma. Material and methods: We describe a case series of 8 patients who underwent transvascular needle aspiration during EBUS, to access a lesion in the absence of an alternate safe window. A 21 gauge EBUS needle was used to traverse either the main or a major branch of the pulmonary artery. Results: Malignancy was suspected at ROSE in five cases. Granuloma and necrosis noted in 2 cases were confirmed as tubercu-losis on culture. Diagnostic yield of EBUS-TVNA was 87.5% (7/8). No complications were noted in the immediate post-operative period as well as during 6 months of follow up. Conclusion: EBUS-TVNA in carefully selected patients is a feasible alternative to more invasive procedures with excellent yield. Appropriate intraoperative, perioperative and postoperative monitoring and care must be available in the case of fatal bleeds.

This study documents the monitorability using different anesthesia regimes and accuracy of muscle motor evoked potentials (mMEPs) in children ≤2 years of age undergoing tethered cord surgery (TCS).Intraoperative mMEP monitoring was attempted in 100 consecutive children, ≤2 years of age, undergoing TCS. MEP monitoring was done under 4 different anesthetic regimes: (Total intravenous anesthesia (TIVA); balanced anesthesia with sevoflurane and ketamine; balanced anesthesia with isoflurane and ketamine; and balanced anesthesia with sevoflurane). Factors analyzed for their effect on monitorability were: age, neurological deficits, type of anesthesia, and the number of pulses used for stimulation.Baseline mMEPs were obtained in 87% children. Monitorability of mMEPs was similar in children ≤1 year and 1-2 years of age (85.7% and 87.5%). In multivariate analysis, anesthesia regime was the only significant factor predicting presence of baseline mMEPs. Children undergoing TIVA (p=0.02) or balanced anesthesia with a combination of propofol, sevoflurane, and ketamine (p=0.05) were most likely to have baseline mMEPs. mMEPs had a sensitivity of 97.4%, specificity of 96.4%, negative predictive value of 98.2% and accuracy of 96.8%.Baseline mMEPs were obtained in85% of children ≤2 years of age including those who had motor deficits. TIVA and balanced anesthesia with sevoflurane and ketamine are ideal for mMEP monitoring. mMEPs have a high accuracy although, false positive and false negative results can occasionally be experienced.

A number of patients with advanced-stage epithelial ovarian cancer do survive beyond 5 years. The long-term follow-up data are limited, especially for the Indian setting. We evaluated the 10-year survival outcome and influencing clinicopathological factors.A retrospective analysis of advanced-stage epithelial ovarian cancer patients who underwent primary cytoreductive surgery (PCS) or interval cytoreductive surgery (ICS) from 2005 to 2008 was conducted. Survival analysis was performed with the Kaplan-Meier method, and the Cox proportional hazards model was used for prognostic clinicopathological factors analysis.Ninety-four patients with a median age of 54.5 (18-79) years were evaluated. The median follow-up period was 11.2 years. The overall survival (OS) rates at 5, 7, and 10 years were 37%, 23%, and 18%, respectively. The median OS (MOS) was 46 (95% confidence interval [CI], 36-55.8) months and progression-free survival (PFS) was 19.5 (15.3-23.6) months. Long-term survival was significantly predicted by R0 resection (complete cytoreduction with no macroscopic residual disease) and PFS20 months while prolonged PFS was influenced by age ≤55 years and R0 resection. For the R0 resection group, patients who underwent PCS had better overall survival in comparison with ICS [72.1(25.2-119) months vs 47.4 (34.9-59.9)months] on 10 years follow-up but was not significant statistically.Patients with age ≤55 years, R0 resection, PFS20 months have a better 10-year survival outcome. Among R0 resection, patients undergoing PCS have clinically a better outcome on 10-year follow-up.

Health assessments have potential to improve health of older people. This study compares long-term health care utilisation, physical functioning, and mortality for women aged 75 years or over who have had a health assessment and those who have not. Prospective data on health service use, physical functioning, and deaths among a large cohort of women born 1921–26 were analysed. Propensity score matching was used to produce comparable groups of women according to whether they had a health assessment or not. The study population included 6128 (67.3%) women who had an assessment, and 2971 (32.7%) women who had no assessment. Propensity matching produced 2101 pairs. Women who had an assessment had more use of other health services, longer survival, and were more likely to survive with high physical functioning compared to women with no assessment. Among women who had good baseline physcial functioning scores, women who had an assessment had significantly lower odds of poor outcomes at 1000 days follow-up compared to women who had no assessment (OR: 0.67, 95%CI: 0.52, 0.85). This large observational study shows the real-world potential for assessments to improve health outcomes for older women. However, they also increased health service use. This increased healthcare is likely to be an important mechanism in improving the women’s health outcomes.

To estimate SF-6D utility scores for older women with atrial fibrillation (AF); calculate and compare mean utility scores for women with AF with various demographic, health behaviours, and clinical characteristics; and develop a multivariable regression model to determine factors associated with SF-6D utility scores.This study evaluated N = 1432 women diagnosed with AF from 2000 to 2015 of the old cohort (born 1921-26) of the Australian Longitudinal Study on Women's Health (ALSWH) who remained alive for at least 12 months post first recorded AF diagnosis. Self-reported data on demographics, health behaviours, health conditions, and SF-36 were obtained from the ALSWH surveys, corresponding to within three years of the date of the first record of AF diagnosis. Linked Pharmaceutical Benefits Scheme (PBS) data determined the use of oral anticoagulants and comorbid conditions, included in CHAThe mean health utility was estimated to be 0.638 ± 0.119 for the complete dataset and 0.642 ± 0.120 for the dataset where missing values were handled using MI. Using the MI technique, living in regional and remote areas ([Formula: see text]) and the use of oral anticoagulants ([Formula: see text] were positively associated with health utility compared to living in major cities and no use of anticoagulants, respectively. Difficulty to manage on available income [Formula: see text], no/low physical activity [Formula: see text], disability [Formula: see text], history of stroke ([Formula: see text] and history of arthritis [Formula: see text] were negatively associated with health utility.This study presents health utility estimates for older women with AF. These estimates can be used in future clinical and economic research. The study also highlights better health utilities for women living in regional and remote areas, which requires further exploration.

Context Management of non–muscle-invasive bladder cancer (NMIBC) is costly and associated with negative health-related quality-of-life effects, in part because of the frequent need for repeated transurethral resections under general/regional anaesthesia. Outpatient-based diathermy or laser ablation is another option, but evidence for its efficacy is mixed and its use is controversial. Objective To systematically review evidence regarding the efficacy and safety of outpatient diathermy and laser ablation for the treatment of recurrent NMIBC. Evidence acquisition The EMBASE, MEDLINE/PubMed, and Cochrane Library were searched from inception to June 26, 2020. All studies evaluating the use of diathermy or laser ablation for bladder tumours (new or recurrent) in an outpatient setting under local anaesthetic were included. Two reviewers independently screened all articles, searched the reference lists of retrieved articles, and performed the data extraction. The quality of evidence and risk of bias were assessed using the GRADE and ROBINS-I tools. Evidence synthesis The search yielded 1328 studies. After excluding duplicates, 1319 titles and abstracts were screened and 17 studies (1584 patients) were eligible for inclusion in the final review. The majority of patients had small, low-grade tumours, but there was heterogeneity in the inclusion criteria. Overall, laser ablation and diathermy resulted in mean recurrence rates of 47% and 32% at follow-up of 22–38 mo, respectively, with a mean progression rate of 3–12% (low certainty of evidence). Both procedures were well tolerated, with low pain scores and low periprocedural complication rates (moderate certainty of evidence). Conclusions Outpatient diathermy and laser ablation have good short-term efficacy in patients with low-grade NMIBC and reduce the need for intervention under general/regional anaesthesia. The procedures are well tolerated with low complication rates. The overall certainty of evidence is low, with heterogeneity between studies and methodological limitations. However, we have highlighted the need for randomised trials with long-term follow-up using standardised risk classification and outcome measures. Despite these limitations, the findings will aid in patient counselling regarding this less invasive treatment option that avoids the morbidity of transurethral resection. Patient summary Outpatient diathermy and laser ablation have good success rates in treating recurrent low-grade bladder tumours in the short term, avoiding the need for more invasive procedures under general/regional anaesthesia, with low rates of side effects. Further studies are needed to determine whether these treatments remain safe and effective in the long term.

Extramedullary plasmacytoma (EMP) is an uncommon presentation and usually occurs in conjunction with multiple myeloma (MM). An EMP without developing MM at any point is an extremely rare presentation, and only seven such cases have been reported in the literature to date.We present a case of EMP, who presented with multiple recurrent lesions in rare sites like nasal cavity, testis and skin without the involvement of bone marrow at any point of disease course. He was treated with multiagent chemotherapy (DT-PACE) and continues to be in remission at 29 months post-chemotherapy, which is the longest amongst all the cases reported so far.There are no clearly defined guidelines to treat EMP. Our case had a clinical presentation at very unusual sites and was treated with DT-PACE regimen as against the previous seven reported cases and had the most prolonged period of remission.

The PRKAG2 syndrome is a rare autosomal dominant phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM), characterized by ventricular pre-excitation, progressive conduction system disease and left ventricular hypertrophy. This study describes the phenotype, genotype and clinical outcomes of a South-Asian PRKAG2 cardiomyopathy cohort over a 7-year period. Clinical, electrocardiographic, echocardiographic, and cardiac MRI data from 22 individuals with PRKAG2 variants (68% men; mean age 39.5 ± 18.1 years), identified at our HCM centre were studied prospectively. At initial evaluation, all of the patients were in NYHA functional class I or II. The maximum left ventricular wall thickness was 22.9 ± 8.7 mm and left ventricular ejection fraction was 53.4 ± 6.6%. Left ventricular hypertrophy was present in 19 individuals (86%) at baseline. 17 patients had an WPW pattern (77%). After a mean follow-up period of 7 years, 2 patients had undergone accessory pathway ablation, 8 patients (36%) underwent permanent pacemaker implantation (atrio-ventricular blocks—5; sinus node disease—2), 3 patients developed atrial fibrillation, 11 patients (50%) developed progressive worsening in NYHA functional class, and 6 patients (27%) experienced sudden cardiac death or equivalent. PRKAG2 cardiomyopathy must be considered in patients with HCM and progressive conduction system disease.

OBJECTIVES To determine if the presence of non-urothelial variant histology (NUVH) is associated with a poorer prognosis following radical cystectomy (RC) compared to pure urothelial carcinoma (PUC). PATIENTS AND METHODS A prospectively maintained database of all patients undergoing RC at a high-volume regional tertiary bladder cancer service between January 2010 and January 2017 was retrospectively analysed looking for patients with NUVH. Multivariate Cox proportional hazards regression analysis was used to determine disease recurrence, overall survival and bladder cancer-specific survival, as well as lymph node positivity. Association of tumour stage was determined using chi-squared analysis. RESULTS In total, 430 patients underwent RC of which 73 (17%) had NUVH and 357 (83%) had PUC. The median (range) follow-up was 45.0 (8.5-100.2) months. The presence of NUVH was associated with both increased overall (hazard ratio [HR] 1.86, 95% confidence interval [CI] 1.21-2.85) and bladder cancer-specific mortality (HR 1.81, 95% CI 1.91-3.01), as well as disease recurrence (HR 1.71, 95% CI 1.06-2.75) in multivariate analysis. Squamous cell variant was also associated with increased overall mortality (HR 1.91, 95% CI 1.16-3.13), cancer-specific mortality (HR 2.03, 95% CI 1.21-3.42) and disease recurrence (HR 2.08, 95% CI 1.23-3.52), although this was not seen in other variant subtypes. Lymph node positivity was not associated with NUVH in multivariate analysis (HR 1.28, 95% CI 0.59-2.75), but NUVH was associated with advanced tumour stage on chi-squared analysis (P < 0.001). CONCLUSION Our results showed a risk of shorter survival in NUVH compared to PUC. This suggests NUVH as an independent predictor of worse outcomes. As a result, patients with NUVH should be counselled preoperatively that overall and disease-specific outcomes are worse postoperatively and about the possible need for adjuvant treatment.

Effects of different boundary conditions prescribed across the boundaries of radiofrequency ablation (RFA) models of liver cancer are investigated for the case where the tumour is at the liver boundary. Ground and Robin-type conditions (electrical field) and body temperature and thermal insulation (thermal field) conditions are examined. 3D models of the human liver based on publicly-available CT images of the liver are developed. An artificial tumour is placed inside the liver at the boundary. Simulations are carried out using the finite element method. The numerical results indicated that different electrical and thermal boundary conditions led to different predictions of the electrical potential, temperature and thermal coagulation distributions. Ground and body temperature conditions presented an unnatural physical conditions around the ablation site, which results in more intense Joule heating and excessive heat loss from the tissue. This led to thermal damage volumes that are smaller than the cases when the Robin type or the thermal insulation conditions are prescribed. The present study suggests that RFA simulations in the future must take into consideration the choice of the type of electrical and thermal boundary conditions to be prescribed in the case where the tumour is located near to the liver boundary.

Goldfish farming gained more attention among the ornamental fishes in aquaculture industry. The occurrence of bacterial infections and further antimicrobial treatment lead to the major crisis of antibiotic resistance in aquaculture. We have isolated diverse enterobacteriaceae groups which affect the goldfish and identified their response towards 46 antimicrobials of 15 different classes. Thirteen significant bacterial isolates such as Edwardsiella tarda, Serratia marcescens, Klebsiella aerogenes, Proteus penneri, P. hauseri, Enterobacter cloacae, E. cancerogenus, E. ludwigii, Citrobacter freundii, E. coli, Kluyvera cryocrescens, Plesiomonas shigelloides and Providencia vermicola were recovered from the infected fish with the Shannon-wiener diversity index of 2.556. Multiple antibiotic resistance (MAR) index was found to be maximum for P. penneri (0.87) and minimum for C. freundii and E. cloacae (0.22), highlighting the hyper antibiotic selection pressure in the farm. The minimum concentration of antibiotics required to inhibit most of the resistant isolates was found to be 256 mcg/ml. All the isolates were susceptible towards ciprofloxacin. Plasmid curing and further AMR tests could reveal the location of antibiotic resistance genes mainly as plasmids which determine the large extent of AMR spread through horizontal gene transfer. This study is the first of its kind to investigate the antimicrobial resistance profile of enterobacteriaceae recovered from goldfish, before and after plasmid curing.

Menopause is associated with changes consistent with cardiovascular aging. The effects of cardiac disease are multifaceted, affecting endothelial function, coronary artery physiology and metabolic dysfunction leading to structural changes in the coronary anatomy. A systematic review of literature from 1986 to 2019 was conducted using PubMed and Google Scholar. The search was directed to retrieve papers that addressed the changes in cardiovascular physiology in menopause and the current therapies available to treat cardiovascular manifestations of menopause. The metabolic and clinical factors secondary to menopause, such as dyslipidemia, insulin resistance, fat redistribution and systemic hypertension, contribute to the accelerated risk for cardiovascular aging and disease. Atherosclerosis appears to be the end result of the interaction between cardiovascular risk factors and their accentuation during the perimenopausal period. Additionally, complex interactions between oxidative stress and levels of L-arginine and ADMA may also influence endothelial dysfunction in menopause. The increased cardiovascular risk in menopause stems from the exaggerated effects of changing physiology on the cardiovascular system affecting peripheral, cardiac and cerebrovascular beds. The differential effects of menopause on cardiovascular disease at the subclinical, biochemical and molecular levels form the highlights of this review.

In order to explore the properties of any species in solution, the actual, i.e. equilibrium concentration of the free species should be taken into account. Researchers have not paid attention to the deprotonation equilibrium between HSO4- and SO42- while probing bisulfate ion. In this study, we have addressed this concern and developed two zwitterions, CG (coumarin-integrated glycine) and CA (coumarin-integrated alanine), for the selective detection of HSO4- at a picomolar level (50 to 325 pM) with very high binding affinity (∼108 M-1) in pure water at physiological pH. The principle of HSO4- recognition was established via UV-vis and fluorescence techniques. DFT calculations suggested that the H-bonding interactions between the probes and HSO4- are the driving force for this unforeseen selectivity. The membrane penetration ability and nontoxicity of CG/CA enable them to function as staining agents in living brine shrimps and bacteria. The use of these probes for the estimation of HSO4- in various day-to-day edible foods and drugs along with urine samples is unprecedented. The significance and novelty of this study lies in the application and development of assays for estimating bisulfate in several real-world samples that are predominantly aqueous in nature, which are the first of their kind.

To explore the prevalence of temporomandibular dysfunction (TMD) among working Australian adults and examine whether workplace effort-reward imbalance is associated with TMD.Data were from Australia's National Survey of Adult Oral Health (NSAOH) 2004-06, a cross-sectional stratified clustered sample of Australian adults. The NSAOH data included information from a Computer Assisted Telephone Interview, self-complete questionnaire and oral epidemiological examination. Data included demographics, socio-economic characteristics, caries experience, diagnostic criteria for TMD, the Perceived Stress Scale (PSS) and a modified version of the Effort-Reward Imbalance instrument (ERI) where ERI ratio is the weighted ratio of workplace effort/reward subscales. Subpopulation analysis for working adults was conducted including complex sample descriptive statistics, bivariate and multivariable logistic regression models.NSAOH had 4014 participants with 2329 (65.1%, SE=1.3%) working adults included in the subpopulation analysis. Among working adults, TMD prevalence was 9.4% (SE=1.0%), which was slightly less than population prevalence (PR=9.9%, SE=0.8%), and was higher for females (PR=12.4%, SE=1.4%), people aged ⟨35 years (PR=11.2%, SE=2.2%) and uninsured (PR=11.8%, SE=1.7%). TMD prevalence was associated with the ERI ratio (OR=2.5, 95% CI: 1.3-4.5) and PSS scores (OR=1.1, 95% CI: 1.0-1.09) in bi-variate associations. In multivariable logistic regression, TMD was associated with being female (OR=2.1, 95% CI:1.3-3.6), university qualified (OR=0.43, 95%CI: 0.21-0.88) and with the ERI ratio (OR=2.63, 95% CI: 1.47-4.72).Greater effort-reward imbalance in the workplace is a psychosocial risk factor for TMD. This finding might need to be considered by clinicians managing TMD patients with need for investigating the efficacy of workplace stress management interventions.