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Abstract Multiplexed assays of variant effect are powerful methods to profile the consequences of rare variants on gene expression and organismal fitness. Yet, few studies have integrated several multiplexed assays to map variant effects on gene expression in coding sequences. Here, we pioneered a multiplexed assay based on polysome profiling to measure variant effects on translation at scale, uncovering single-nucleotide variants that increase or decrease ribosome load. By combining high-throughput ribosome load data with multiplexed mRNA and protein abundance readouts, we mapped the cis-regulatory landscape of thousands of catechol-O-methyltransferase (COMT) variants from RNA to protein and found numerous coding variants that alter COMT expression. Finally, we trained machine learning models to map signatures of variant effects on COMT gene expression and uncovered both directional and divergent impacts across expression layers. Our analyses reveal expression phenotypes for thousands of variants in COMT and highlight variant effects on both single and multiple layers of expression. Our findings prompt future studies that integrate several multiplexed assays for the readout of gene expression.

Background: Temperature variability (TV) is associated with increased mortality risk. However, it is still unknown whether intra-day or inter-day TV has different effects. Objectives: We aimed to assess the association of intra-day TV and inter-day TV with all-cause, cardiovascular, and respiratory mortality. Methods: We collected data on total, cardiovascular, and respiratory mortality and meteorology from 758 locations in 47 countries or regions from 1972 to 2020. We defined inter-day TV as the standard deviation (SD) of daily mean temperatures across the lag interval, and intra-day TV as the average SD of minimum and maximum temperatures on each day. In the first stage, inter-day and intra-day TVs were modelled simultaneously in the quasi-Poisson time-series model for each location. In the second stage, a multi-level analysis was used to pool the location-specific estimates. Results: Overall, the mortality risk due to each interquartile range [IQR] increase was higher for intra-day TV than for inter-day TV. The risk increased by 0.59% (95% confidence interval [CI]: 0.53, 0.65) for all-cause mortality, 0.64% (95% CI: 0.56, 0.73) for cardiovascular mortality, and 0.65% (95% CI: 0.49, 0.80) for respiratory mortality per IQR increase in intra-day TV0–7 (0.9 °C). An IQR increase in inter-day TV0–7 (1.6 °C) was associated with 0.22% (95% CI: 0.18, 0.26) increase in all-cause mortality, 0.44% (95% CI: 0.37, 0.50) increase in cardiovascular mortality, and 0.31% (95% CI: 0.21, 0.41) increase in respiratory mortality. The proportion of all-cause deaths attributable to intra-day TV0–7 and inter-day TV0–7 was 1.45% and 0.35%, respectively. The mortality risks varied by lag interval, climate area, season, and climate type. Conclusions: Our results indicated that intra-day TV may explain the main part of the mortality risk related to TV and suggested that comprehensive evaluations should be proposed in more countries to help protect human health.

Assessing the association between temperature frequency and mortality can provide insights into human adaptation to local ambient temperatures. We collected daily time-series data on mortality and temperature from 757 locations in 47 countries/regions during 1979–2020. We used a two-stage time series design to assess the association between temperature frequency and all-cause mortality. The results were pooled at the national, regional, and global levels. We observed a consistent decrease in the risk of mortality as the normalized frequency of temperature increases across the globe. The average increase in mortality risk comparing the 10th to 100th percentile of normalized frequency was 13.03% (95% CI: 12.17–13.91), with substantial regional differences (from 4.56% in Australia and New Zealand to 33.06% in South Europe). The highest increase in mortality was observed for high-income countries (13.58%, 95% CI: 12.56–14.61), followed by lower-middle-income countries (12.34%, 95% CI: 9.27–15.51). This study observed a declining risk of mortality associated with higher temperature frequency. Our findings suggest that populations can adapt to their local climate with frequent exposure, with the adapting ability varying geographically due to differences in climatic and socioeconomic characteristics.

Objectives Studies show that anxiety and depression are widespread across patients presenting to outpatient services for medical illnesses. We expect similar or even higher prevalence in patients with breast complaints owing to the relevance of breasts in terms of sexuality, identity and confidence. Thus, this study was proposed to estimate the prevalence and identify risk factors for being at risk for anxiety and depression in patients seeking breast services.Design Descriptive, cross-sectional study.Setting Tertiary care teaching hospital in Mumbai, Western India.Participants Patients seeking breast services for either benign or malignant conditions.Outcome measures Proportion of those at risk for clinical depression (defined as a score of ≥10 on Patient Health Questionnaire-9) and proportion of those at risk for clinical anxiety warranting further clinical evaluation (defined as a score of ≥10 on Generalized Anxiety Disorder-7) and their predictors.Results A total of 208 patients were screened, and 192 consenting patients were enrolled. The prevalence of those at risk for anxiety requiring further clinical evaluation was 46.4% (95% CI 39.2% to 53.7%) and for those at risk for major depression that warrants further clinical evaluation by a mental health provider was 29.7% (95% CI 23.3% to 36.7%). The predictors of anxiety were age (adjusted odds ratio (aOR) 1.053; 95% CI 1.024 to 1.083; p

Intracranial granulomas are a major cause of seizures in India, the most common etiologies being neurocysticercosis and tuberculosis. However, other pathologies including rare low-grade tumors may mimic these granulomas on imaging. In this article, we presented the case of a young woman patient with drug-resistant epilepsy. On imaging, there was a small calcified lesion in the brain parenchyma. In view of concordant electroclinical and imaging data on presurgical evaluation, the lesion was excised and the patient was seizure free. On histopathological evaluation, it was found to be a polymorphous low-grade neuroepithelial tumor of the young (PLNTY) – a rare, recently reported entity that can mimic an intracranial granuloma on imaging.

Abstract Microsatellite-stable colorectal cancer (MSS-CRC) is highly refractory to immunotherapy. Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve MSS-CRC patient outcomes. Here, we demonstrate that high tumor expression of the core autophagy gene ATG16L1 is associated with poor clinical response to anti-PD-L1 therapy in KRAS-mutant tumors from IMblaze370 (NCT02788279), a large phase III clinical trial of atezolizumab (anti-PD-L1) in advanced metastatic MSS-CRC. Deletion of Atg16l1 in engineered murine colon cancer organoids inhibits tumor growth in primary (colon) and metastatic (liver and lung) niches in syngeneic female hosts, primarily due to increased sensitivity to IFN-γ-mediated immune pressure. ATG16L1 deficiency enhances programmed cell death of colon cancer organoids induced by IFN-γ and TNF, thus increasing their sensitivity to host immunity. In parallel, ATG16L1 deficiency reduces tumor stem-like populations in vivo independently of adaptive immune pressure. This work reveals autophagy as a clinically relevant mechanism of immune evasion and tumor fitness in MSS-CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.

Background Vascular malformations (VMs) of the central nervous system comprise a variety of lesions that could affect the arteries, veins, or capillaries. Materials and Methods We analyzed the histopathological features of all the VMs diagnosed at our centre over a decade. Results Intracranial VM included arteriovenous malformation (AVM) (53%), cerebral cavernous malformations (CCMs) (45%), capillary telangiectasia (2%), venous angioma (0.5%), and arteriovenous fistula (AVF) (0.5%). In spinal VMs, capillary telangiectasia (40%) were the most common, followed by cavernomas (34%), AVF (16%), and AVMs and venous angiomas (5%). Clinical presentation varied from focal deficit to features of raised intracranial tension. Conclusion Imaging and histopathology plays an important role in the diagnosis and management of VMs. Histopathological examination is essential for characterization of the VMs, which influences the prognosis.

Background: The epidemiological evidence on the interaction between heat and ambient air pollution on mortality is still inconsistent. Objectives: To investigate the interaction between heat and ambient air pollution on daily mortality in a large dataset of 620 cities from 36 countries. Methods: We used daily data on all-cause mortality, air temperature, particulate matter ≤ 10 μm (PM10), PM ≤ 2.5 μm (PM2.5), nitrogen dioxide (NO2), and ozone (O3) from 620 cities in 36 countries in the period 1995–2020. We restricted the analysis to the six consecutive warmest months in each city. City-specific data were analysed with over-dispersed Poisson regression models, followed by a multilevel random-effects meta-analysis. The joint association between air temperature and air pollutants was modelled with product terms between non-linear functions for air temperature and linear functions for air pollutants. Results: We analyzed 22,630,598 deaths. An increase in mean temperature from the 75th to the 99th percentile of city-specific distributions was associated with an average 8.9 % (95 % confidence interval: 7.1 %, 10.7 %) mortality increment, ranging between 5.3 % (3.8 %, 6.9 %) and 12.8 % (8.7 %, 17.0 %), when daily PM10 was equal to 10 or 90 μg/m3, respectively. Corresponding estimates when daily O3 concentrations were 40 or 160 μg/m3 were 2.9 % (1.1 %, 4.7 %) and 12.5 % (6.9 %, 18.5 %), respectively. Similarly, a 10 μg/m3 increment in PM10 was associated with a 0.54 % (0.10 %, 0.98 %) and 1.21 % (0.69 %, 1.72 %) increase in mortality when daily air temperature was set to the 1st and 99th city-specific percentiles, respectively. Corresponding mortality estimate for O3 across these temperature percentiles were 0.00 % (-0.44 %, 0.44 %) and 0.53 % (0.38 %, 0.68 %). Similar effect modification results, although slightly weaker, were found for PM2.5 and NO2. Conclusions: Suggestive evidence of effect modification between air temperature and air pollutants on mortality during the warm period was found in a global dataset of 620 cities.

Background: Short-term associations between heat and cardiovascular disease (CVD) mortality have been examined mostly in large cities. However, different vulnerability and exposure levels may contribute to spatial heterogeneity. This study assessed heat effects on CVD mortality and potential vulnerability factors using data from three European countries, including urban and rural settings. Methods: We collected daily counts of CVD deaths aggregated at the small-area level in Norway (small-area level: municipality), England and Wales (lower super output areas), and Germany (district) during the warm season (May-September) from 1996 to 2018. Daily mean air temperatures estimated by spatial–temporal models were assigned to each small area. Within each country, we applied area-specific Quasi-Poisson regression using distributed lag nonlinear models to examine the heat effects at lag 0–1 days. The area-specific estimates were pooled by random-effects meta-analysis to derive country-specific and overall heat effects. We examined individual- and area-level heat vulnerability factors by subgroup analyses and meta-regression, respectively. Results: We included 2.84 million CVD deaths in analyses. For an increase in temperature from the 75th to the 99th percentile, the pooled relative risk (RR) for CVD mortality was 1.14 (95% CI: 1.03, 1.26), with the country-specific RRs ranging from 1.04 (1.00, 1.09) in Norway to 1.24 (1.23, 1.26) in Germany. Heat effects were stronger among women [RRs (95% CIs) for women and men: 1.18 (1.08, 1.28) vs. 1.12 (1.00, 1.24)]. Greater heat vulnerability was observed in areas with high population density, high degree of urbanization, low green coverage, and high levels of fine particulate matter. Conclusion: This study provides evidence for the heat effects on CVD mortality in European countries using high-resolution data from both urban and rural areas. Besides, we identified individual- and area-level heat vulnerability factors. Our findings may facilitate the development of heat-health action plans to increase resilience to climate change.

Background: Obesity and associated primary amenorrhea are common presentations in the endocrinology outpatient department. Hypothalamic obesity is rare, and Langerhans cell histiocytosis (LCH) causing hypothalamic dysfunction is even more rare. Clinical Description: A 16-year-old girl presented with rapid weight gain over preceding 2 years, associated with headache for 2 months and primary amenorrhea. On examination, she had a weight and body mass index corroborating with obesity, while her height was age-appropriate. In addition, she had acanthosis nigricans but no Cushingoid features or intellectual disability. Systemic examination was normal. Management and Outcome: Considering a possibility of neuroendocrine cause of obesity, investigations were carried out. Bone age was delayed. Hormonal work-up revealed low estradiol, luteinizing hormone, and follicular stimulating hormone while thyroid function tests, growth hormone, and cortisol were normal, suggestive of hypogonadotropic hypogonadism. Magnetic resonance imaging of the brain revealed a mass in the hypothalamus region with a normal pituitary gland and stalk which was confirmed to be LCH on a stereotactic biopsy. Fluorodeoxyglucose-positron emission tomography showed no other sites of abnormal uptake. Thus, the child was diagnosed with a low-risk single-system LCH and treated accordingly. Conclusion: This case creates the awareness regarding the rare possibility of isolated hypothalamic involvement in LCH, causing obesity and primary amenorrhea, confirmed by biopsy.

Reduction in key air pollutants, especially particulate carbon, can help mitigate Arctic warming with associated benefits for global climate and human health, according to Earth system model simulations under future emissions scenarios.

Background: Evidence on the potential interactive effects of heat and ambient air pollution on cause-specific mortality is inconclusive and limited to selected locations. Objectives: We investigated the effects of heat on cardiovascular and respiratory mortality and its modification by air pollution during summer months (six consecutive hottest months) in 482 locations across 24 countries. Methods: Location-specific daily death counts and exposure data (e.g., particulate matter with diameters ≤ 2.5 µm [PM2.5]) were obtained from 2000 to 2018. We used location-specific confounder-adjusted Quasi-Poisson regression with a tensor product between air temperature and the air pollutant. We extracted heat effects at low, medium, and high levels of pollutants, defined as the 5th, 50th, and 95th percentile of the location-specific pollutant concentrations. Country-specific and overall estimates were derived using a random-effects multilevel meta-analytical model. Results: Heat was associated with increased cardiorespiratory mortality. Moreover, the heat effects were modified by elevated levels of all air pollutants in most locations, with stronger effects for respiratory than cardiovascular mortality. For example, the percent increase in respiratory mortality per increase in the 2-day average summer temperature from the 75th to the 99th percentile was 7.7% (95% Confidence Interval [CI] 7.6–7.7), 11.3% (95%CI 11.2–11.3), and 14.3% (95% CI 14.1–14.5) at low, medium, and high levels of PM2.5, respectively. Similarly, cardiovascular mortality increased by 1.6 (95%CI 1.5–1.6), 5.1 (95%CI 5.1–5.2), and 8.7 (95%CI 8.7–8.8) at low, medium, and high levels of O3, respectively. Discussion: We observed considerable modification of the heat effects on cardiovascular and respiratory mortality by elevated levels of air pollutants. Therefore, mitigation measures following the new WHO Air Quality Guidelines are crucial to enhance better health and promote sustainable development.

A modified version of the PGDx elioTM Plasma Resolve assay was validated as a laboratory-developed test (LDT) for clinical use in the Molecular Diagnostics Laboratory at Fox Chase Cancer Center. The test detects single nucleotide variants (SNVs) and small insertions and deletions (indels) in 33 target genes using fragmented genomic DNA extracted from plasma. The analytical performance of this assay was assessed with reference standard DNA and 29 samples from cancer patients and detected 66 SNVs and 23 indels. Using 50 ng of input DNA, the sensitivity was 95.5% to detect SNVs at 0.5% allele frequency, and the specificity was 92.3%. The sensitivity to detect indels at 1% allele frequency was 70.4%. A cutoff of 0.25% variant allele frequency (VAF) was set up for diagnostic reporting. An inter-laboratory study of concordance with an orthologous test resulted in a positive percent agreement (PPA) of 91.7%.

Inflammatory neuropathies are a group of acquired neuropathies which could be due to autoimmune, infectious, paraneoplastic, or paraproteinemic etiology. The etiological diagnosis of inflammatory neuropathy is not simple, and often requires combination of clinical, electrophysiological, and histopathological findings to arrive at a precise diagnosis which is important for management of the disorder. Whereas there are comprehensive and sensitive panel of serological tests available for diagnosis of the infectious, paraneoplastic, paraproteinemic neuropathies, the diagnosis of immune-mediated demyelinating neuropathies remain a considerable challenge as there is both clinical and pathological overlap. Newer non-invasive methodologies such as high-resolution ultrasound, magnetic resonance imaging (MRI), and importantly, serological testing for antibodies are emerging, and it is essential for the practicing pathologist to be up-to-date with emerging modalities. In this review, we focus on the approach to diagnosis of immune-mediated demyelinating neuropathies.

Autoimmune encephalitis is a group of non-infectious immune-mediated inflammatory disorders manifesting with epilepsy and encephalitis syndromes that are associated with autoantibodies in the serum and/or cerebrospinal fluid (CSF). Pathogenic autoantibodies have been discovered against intracellular onconeural antigens, surface neuronal, or synaptic antigens with distinctive pathogenesis that underlie differences in response to immunotherapy. The onconeural antigens incite cytotoxic T-cell-mediated neuronal destruction, whereas surface antigens trigger direct damage by autoantibodies via complement mediated pathways, and hence respond well to immunomodulatory therapy, in contrast to poor response in the former. Neuroimaging, electroencephalogram, and CSF findings being non-specific, detection of autoantibodies is essential for a confirmatory diagnosis. Detection methods available include tissue-based assay, cell-based assays, immunoblot, cell culture, flow cytometry, and enzyme-linked immunosorbent assays. In this review, we discuss the various testing modalities available for onconeural and cell surface antibodies, their sensitivity and specificity and the emerging role of the pathologist in the diagnosis of autoimmune encephalitis. Early diagnosis is crucial for instituting treatment and preventing morbidity and mortality.

Infections constitute an important and common category of diseases, particularly in less developed countries. Infections present with a broad spectrum of clinical and radiologic features dictated by the cell and tissue tropism and host response elicited, posing a considerable diagnostic challenge. Early diagnosis and treatment are crucial in preventing mortality and morbidity. Recourse is often made to biopsy for ascertaining the diagnosis, and hence the pathologist plays a vital role in patient management. Therefore, knowledge of the histopathologic changes is necessary to recognize the histological changes and guide the diagnostic workup and management. Each microbial agent elicits a distinctive pattern of inflammatory tissue response, which can serve as a clue to the etiological agent. Based on the causative organism, microbial, and host factors, the inflammatory response may be acute or chronic, necrotic or non-necrotic. The inflammation can be of varied patterns – lymphohistiocytic, granulomatous, inflammatory demyelinating, fibrosing, or showing minimal inflammation. The pattern of necrosis also differs based on the causative organism. Typically, pyogenic bacteria are associated with suppurative inflammation, tuberculosis with caseous granulomatous, and fungi with suppurative granulomatous inflammation. Viral infections are associated with lymphohistiocytic non-necrotizing inflammation and, based on cell tropism, can cause demyelination (e.g., JCV) and/or viral inclusions. Parasitic infections (protozoal or metazoal) display a broad spectrum of inflammatory changes that overlap with other types of infections. This review briefly describes pathological patterns and associated pathogens and provides an algorithmic approach based on pattern recognition that may be useful for the practicing pathologist.

The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5) features several changes in the classification, diagnostic criteria, nomenclature, and grading of diffuse gliomas. Adult-type diffuse gliomas are genetically defined and include astrocytoma, isocitrate dehydrogenase (IDH)-mutant, oligodendroglioma, IDH-mutant and 1p/19q codeleted, and glioblastoma, IDH-wildtype. This review briefly discusses two tumor types: astrocytoma, IDH-mutant, and oligodendroglioma, IDH-mutant and 1p/19q codeleted, with emphasis on relevant changes in their classification and defining molecular genetic alterations. A simplified approach to the diagnosis of these tumors is provided.

Precise surgical excision of brain tumors depends on the surgeon’s ability to accurately differentiate tumors from healthy brain tissues. We have developed an automated system integrated with biochips, an actuation unit, and electronics to measure the electrical resistivity of ex vivo human brain tissues for differentiating normal and tumor. The electrical resistivity of fresh (n = 48), formalin-fixed for one week (n = 48), and long-term (six months) formalin-fixed (n = 27) healthy human brain samples from different anatomical regions and tumor samples (glioma n = 6; fresh, formalin-fixed for one week, and formalin-fixed for six months) were measured using the automated system. The resistivity of glioma (22.4 ± $1.6~\Omega$ .cm) was significantly lesser than the normal region (98.6 ± $1.4~\Omega$ .cm) for fresh tissue samples (p = 5e-8). The trend of lower resistivity of glioma compared to normal was preserved after one week and six months of formalin fixation. We also report the effects of heterogeneity of normal brain tissue and formalin-fixation on the electrical properties of tissues. White matter regions were found to have higher resistivity compared to grey matter regions. The heterogeneity associated with grey matter regions was lower than the white matter regions. Formalin-fixation was observed to increase the magnitude of resistivity measured while retaining the observed trend across the different regions of the brain and tumors. The study shows that the electrical resistivity could potentially be used as an additional biomarker for delineating normal from the tumor.

Feedbacks between air pollutants and meteorology play a crucial role in the direction of the response of future climate and air pollution. These feedbacks are important to understand and quantify the potential impact of adaptation and mitigation policies setup for protecting the population against air pollution and heat stress. We review the interactions between climate and air pollution, with special focus on the projections of air pollution under different future climate scenarios and time horizons, based on a literature review of research articles and reports from the last decade. The assessment focuses on 1) the specific impacts of climate change on air pollution and natural particle and precursor emissions in Europe in the near future (2030), by mid-century (2050) and by end of the century (2100), 2) impacts on air pollution due to changes in emissions vs. changes in climate, 3) feedbacks from air pollution on climate, 4) impacts of climate change on wildland fires and air pollutant levels, and 5) the role of adaptation and mitigation policies on climate change and air pollution. Available literature to a large extent suggests that ozone concentrations will likely increase in the second half of the century by up to 9 ppb [−4 + 9.3], while in the first half of the century, changes are much smaller and are up to ±1.5 ppb. These changes are mainly attributed to increased temperatures and emissions of biogenic volatile organic compounds, but also depends on the models and scenarios used in these studies. On the other hand, the predicted changes in particle concentrations and chemical composition are uncertain and much smaller. Similar to ozone, larger changes in the particle concentrations are projected in the second half of the century. The main conclusion from this review is that the estimated changes in pollutant levels in the future vary significantly depending on the applied model systems, as well as the different emission or meteorological scenarios used in the different studies. Nevertheless, studies generally agree on the overall trend of the changes in pollutant levels due to climate change, in particular in the second half of the century.

Abstract Background Diffuse leptomeningeal glioneuronal tumor (DLGNT) has been recently described in the literature. The complete neuroimaging spectrum and histopathological characteristics of this entity are yet to be elucidated. In an endemic region, diffuse leptomeningeal enhancement on neuroimaging with associated communicating hydrocephalus is usually suggestive of infective meningitis and the patients are started on empirical anti-microbial therapy. However, it is important to consider other differential diagnosis of leptomeningeal enhancement in such cases, particularly if the clinical condition does not improve on anti-microbial therapy. An early diagnosis of a neoplastic etiology may be of particular importance as the treatment regimens vary considerably depending on the underlying disease condition. Case presentation In this case report, we describe a case of DLGNT with high-grade histopathological features which was initially managed as tubercular meningitis based on the initial neuroimaging findings. Due to worsening of the clinical course and subsequent imaging findings at follow-up, a diagnosis of DLGNT was considered and subsequently proven to be DLGNT with features of anaplasia on histopathological examination of leptomeningeal biopsy specimen. Conclusion This case highlights the importance of recognizing certain subtle finding on MRI which may help in an early diagnosis of DLGNT which is crucial for appropriate treatment.

We consider channel estimation for an uplink massive multiple-input multiple-output (MIMO) system where the base station (BS) uses an array with low-resolution (1-2 bit) analog-to-digital converters and a spatial Sigma-Delta ( $\Sigma \Delta $ ) architecture to shape the quantization noise away from users in some angular sector. We develop a linear minimum mean squared error (LMMSE) channel estimator based on the Bussgang decomposition that reformulates the nonlinear quantizer model using an equivalent linear model plus quantization noise. We also analyze the uplink achievable rate with maximal ratio combining (MRC), zero-forcing (ZF) and LMMSE receivers and provide a lower bound for the achievable rate with the MRC receiver. Numerical results show superior channel estimation and sum spectral efficiency performance using the $\Sigma \Delta $ architecture compared to conventional 1- or 2-bit quantized massive MIMO systems.

Summary: Background: Increased mortality risk is associated with short-term temperature variability. However, to our knowledge, there has been no comprehensive assessment of the temperature variability-related mortality burden worldwide. In this study, using data from the MCC Collaborative Research Network, we first explored the association between temperature variability and mortality across 43 countries or regions. Then, to provide a more comprehensive picture of the global burden of mortality associated with temperature variability, global gridded temperature data with a resolution of 0·5° × 0·5° were used to assess the temperature variability-related mortality burden at the global, regional, and national levels. Furthermore, temporal trends in temperature variability-related mortality burden were also explored from 2000–19. Methods: In this modelling study, we applied a three-stage meta-analytical approach to assess the global temperature variability-related mortality burden at a spatial resolution of 0·5° × 0·5° from 2000–19. Temperature variability was calculated as the SD of the average of the same and previous days’ minimum and maximum temperatures. We first obtained location-specific temperature variability related-mortality associations based on a daily time series of 750 locations from the Multi-country Multi-city Collaborative Research Network. We subsequently constructed a multivariable meta-regression model with five predictors to estimate grid-specific temperature variability related-mortality associations across the globe. Finally, percentage excess in mortality and excess mortality rate were calculated to quantify the temperature variability-related mortality burden and to further explore its temporal trend over two decades. Findings: An increasing trend in temperature variability was identified at the global level from 2000 to 2019. Globally, 1 753 392 deaths (95% CI 1 159 901–2 357 718) were associated with temperature variability per year, accounting for 3·4% (2·2–4·6) of all deaths. Most of Asia, Australia, and New Zealand were observed to have a higher percentage excess in mortality than the global mean. Globally, the percentage excess in mortality increased by about 4·6% (3·7–5·3) per decade. The largest increase occurred in Australia and New Zealand (7·3%, 95% CI 4·3–10·4), followed by Europe (4·4%, 2·2–5·6) and Africa (3·3, 1·9–4·6). Interpretation: Globally, a substantial mortality burden was associated with temperature variability, showing geographical heterogeneity and a slightly increasing temporal trend. Our findings could assist in raising public awareness and improving the understanding of the health impacts of temperature variability. Funding: Australian Research Council, Australian National Health & Medical Research Council.

Abstract Background Though parenchymal neurocysticercosis is common and a major contributor to burden of seizures in most parts of the world, intraventricular neurocysticercosis (IVNCC) comprises 10–20% of cases and poses a diagnostic challenge to the clinician. Case presentation We report an adult female presenting with intermittent occipital headache, used to be worse in lying down position, and aggravated with head movements, and there was mild relief in the sitting position. Her physical examination was unremarkable, and laboratory tests were within normal limits. Her multimodal neuroimaging showed cystic lesion in the fourth ventricle suggestive of neurocysticercosis. Patient underwent neuroendoscopic removal of the cyst, and the final diagnosis was confirmed on histopathology. Post removal of cyst patient had complete resolution of her symptoms. Discussion Intraventricular neurocysticercosis can present as acute hydrocephalus which may clinically manifest as Bruns’ syndrome in which sudden attacks of headache vertigo and nausea or vomiting are precipitated by abrupt head movements which was observed in our patient. Multimodal neuroimaging supported by histopathology helped in confirmation of the diagnosis, thus averting an inadvertent use of unnecessary medications in such patients. Furthermore, neuroendoscopy has evolved as minimally invasive technique for extirpation of fourth ventricular cysts.

Extradural spinal nerve root hemangioblastoma is a rare entity with very few cases reported in the literature. A comprehensive picture of the treatments and outcomes of the same is thus not available. A systematic search was done according to PRISMA guidelines. Search criteria included terms: spinal extradural hemangioblastoma, extradural hemangioblastoma, and spinal root hemangioblastoma. The parameters considered were treatment, motor, and sensory outcome, association with von-Hippel-Lindau (VHL) syndrome. Twenty-two studies (19 full text articles) were available for the review. A total of 39 cases of extradural spinal nerve root hemangioblastoma have been reported. These cases had a median age of 44 years with male predominance (2:1) and up to 48% occur in the thoracic level, similar to our case. Thirty-six percent of patients were associated with VHL syndrome. Surgical resection was the primary modality of treatment with embolization used in selected cases (20%). They had mean follow-up of 23 (±11) months. The prognosis was better than the intradural counterpart with no motor deficit and sensory deficit in only 9%. Preoperative identification of the extradural nature of this pathology and complete excision at the first surgery offers excellent outcomes compared to intradural lesion. Targeted embolization may be used in cases anticipated with high blood loss.

Summary: Background: Exposure to cold or hot temperatures is associated with premature deaths. We aimed to evaluate the global, regional, and national mortality burden associated with non-optimal ambient temperatures. Methods: In this modelling study, we collected time-series data on mortality and ambient temperatures from 750 locations in 43 countries and five meta-predictors at a grid size of 0·5° × 0·5° across the globe. A three-stage analysis strategy was used. First, the temperature–mortality association was fitted for each location by use of a time-series regression. Second, a multivariate meta-regression model was built between location-specific estimates and meta-predictors. Finally, the grid-specific temperature–mortality association between 2000 and 2019 was predicted by use of the fitted meta-regression and the grid-specific meta-predictors. Excess deaths due to non-optimal temperatures, the ratio between annual excess deaths and all deaths of a year (the excess death ratio), and the death rate per 100 000 residents were then calculated for each grid across the world. Grids were divided according to regional groupings of the UN Statistics Division. Findings: Globally, 5 083 173 deaths (95% empirical CI [eCI] 4 087 967–5 965 520) were associated with non-optimal temperatures per year, accounting for 9·43% (95% eCI 7·58–11·07) of all deaths (8·52% [6·19–10·47] were cold-related and 0·91% [0·56–1·36] were heat-related). There were 74 temperature-related excess deaths per 100 000 residents (95% eCI 60–87). The mortality burden varied geographically. Of all excess deaths, 2 617 322 (51·49%) occurred in Asia. Eastern Europe had the highest heat-related excess death rate and Sub-Saharan Africa had the highest cold-related excess death rate. From 2000–03 to 2016–19, the global cold-related excess death ratio changed by −0·51 percentage points (95% eCI −0·61 to −0·42) and the global heat-related excess death ratio increased by 0·21 percentage points (0·13–0·31), leading to a net reduction in the overall ratio. The largest decline in overall excess death ratio occurred in South-eastern Asia, whereas excess death ratio fluctuated in Southern Asia and Europe. Interpretation: Non-optimal temperatures are associated with a substantial mortality burden, which varies spatiotemporally. Our findings will benefit international, national, and local communities in developing preparedness and prevention strategies to reduce weather-related impacts immediately and under climate change scenarios. Funding: Australian Research Council and the Australian National Health and Medical Research Council.

Defective autophagy is strongly associated with chronic inflammation. Loss-of-function of the core autophagy gene Atg16l1 increases risk for Crohn’s disease in part by enhancing innate immunity through myeloid cells such as macrophages. However, autophagy is also recognized as a mechanism for clearance of certain intracellular pathogens. These divergent observations prompted a re-evaluation of ATG16L1 in innate antimicrobial immunity. In this study, we found that loss of Atg16l1 in myeloid cells enhanced the killing of virulent Shigella flexneri (S.flexneri), a clinically relevant enteric bacterium that resides within the cytosol by escaping from membrane-bound compartments. Quantitative multiplexed proteomics of murine bone marrow-derived macrophages revealed that ATG16L1 deficiency significantly upregulated proteins involved in the glutathione-mediated antioxidant response to compensate for elevated oxidative stress, which simultaneously promoted S.flexneri killing. Consistent with this, myeloid-specific deletion of Atg16l1 in mice accelerated bacterial clearance in vitro and in vivo. Pharmacological induction of oxidative stress through suppression of cysteine import enhanced microbial clearance by macrophages. Conversely, antioxidant treatment of macrophages permitted S.flexneri proliferation. These findings demonstrate that control of oxidative stress by ATG16L1 and autophagy regulates antimicrobial immunity against intracellular pathogens.

The refractory seizures have significant impact on the quality of life and increase long term neurologic and non-neurologic complications. Implantation of Stereotactic Electroencephalography (SEEG) leads is one of the newer surgical techniques intended to localize seizure foci with higher accuracy than the conventional methods. Most of the commonly utilized anesthetic agents depress EEG waveforms affecting intra operative monitoring during these surgeries. Hence, the anesthetic goals include a stable induction and maintenance with agents which have minimal effect on EEG. This article discusses the peri-operative considerations of multiple anti-epileptic medications, recent advances in anesthetic management, and important post-operative concerns.

An intestinal nematode, with clinical presentations ranging from asymptomatic state to catastrophic outcomes, Strongyloides stercoralis can be a potential cause of mortality, especially in patients with immunosuppressed state. Here, we present a patient with relatively short duration of immunosuppression, developing systemic strongyloidiasis and eventually succumbed after a brief duration of ailment. The index case satisfied the description of a case of hyperinfection. However, there existed a challenge in ruling out dissemination in her since she could not be evaluated completely due to a fulminant course.

Members of the Msi family of RNA-binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers, where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here, we demonstrate that, in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA-binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers.

Particulate matter air pollution is widely considered as the leading environmental cause of premature mortality. However, there are substantial differences in the estimated health burden between the assessments. The aim of this work is to quantify the deaths attributable to ambient air pollution in Nordic countries applying selected assessment tools and approaches, and to identify the main disparities. We quantified and compared the estimated deaths from three health risk assessment tools and from a set of different concentration-response functions. A separate analysis was conducted for the impacts of spatial resolution of the exposure model on the estimated deaths. We found that the death rate (deaths per million) attributable to PM2.5 and O3 were the highest in Denmark and the lowest in Iceland. In the five Nordic countries, the results between the three tools ranged from 8500 to 11,400 for PM2.5 related deaths, and for ozone from 230 to 260 deaths in 2015. Substantially larger differences were found between five concentration-response functions. The shape of concentration-response functions, and applied theoretical thresholds led to substantial differences in the estimated deaths. Nordic countries are especially sensitive to theoretical thresholds due to low exposures. Sensitivity analysis demonstrated that when using spatial exposure assessment methods, high spatial resolution is necessary to avoid underestimation of exposures and health effects.

Arterial stiffening is a risk factor for cardiovascular disease, but how arteries stay supple is unknown. Here, we show that apolipoprotein E (apoE) and apoE-containing high-density lipoprotein (apoE-HDL) maintain arterial elasticity by suppressing the expression of extracellular matrix genes. ApoE interrupts a mechanically driven feed-forward loop that increases the expression of collagen-I, fibronectin, and lysyl oxidase in response to substratum stiffening. These effects are independent of the apoE lipid-binding domain and transduced by Cox2 and miR-145. Arterial stiffness is increased in apoE null mice. This stiffening can be reduced by administration of the lysyl oxidase inhibitor BAPN, and BAPN treatment attenuates atherosclerosis despite highly elevated cholesterol. Macrophage abundance in lesions is reduced by BAPN in vivo, and monocyte/macrophage adhesion is reduced by substratum softening in vitro. We conclude that apoE and apoE-containing HDL promote healthy arterial biomechanics and that this confers protection from cardiovascular disease independent of the established apoE-HDL effect on cholesterol.

Bilateral ovarian tumour in a girl presents the dilemma of conservative versus aggressive approach towards these tumours. When faced with suspicious tumour and complete replacement of the ovaries bilaterally, bilateral oophorectomy is a viable option, though the certain possibility of infertility and lifelong hormonal supplementation is unavoidable. We report a case of bilateral ovarian masses in a young girl, which on histopathological examination showed mature teratoma with aggregates of proliferating capillary and cavernous sized vessels in the tumour wall. Such associations are rare and must be differentiated from a vascular neoplasm.

To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo.

p27(kip1) (p27) is a cdk-inhibitory protein with an important role in the proliferation of many cell types. SCF(Skp2) is the best studied regulator of p27 levels, but Skp2-mediated p27 degradation is not essential in vivo or in vitro. The molecular pathway that compensates for loss of Skp2-mediated p27 degradation has remained elusive. Here, we combine vascular injury in the mouse with genome-wide profiling to search for regulators of p27 during cell cycling in vivo. This approach, confirmed by RT-qPCR and mechanistic analysis in primary cells, identified miR-221/222 as a compensatory regulator of p27. The expression of miR221/222 is sensitive to proteasome inhibition with MG132 suggesting a link between p27 regulation by miRs and the proteasome. We then examined the roles of miR-221/222 and Skp2 in cell cycle inhibition by prostacyclin (PGI(2)), a potent cell cycle inhibitor acting through p27. PGI(2) inhibited both Skp2 and miR221/222 expression, but epistasis, ectopic expression, and time course experiments showed that miR-221/222, rather than Skp2, was the primary target of PGI(2). PGI(2) activates Gs to increase cAMP, and increasing intracellular cAMP phenocopies the effect of PGI(2) on p27, miR-221/222, and mitogenesis. We conclude that miR-221/222 compensates for loss of Skp2-mediated p27 degradation during cell cycling, contributes to proteasome-dependent G1 phase regulation of p27, and accounts for the anti-mitogenic effect of cAMP during growth inhibition.

We present a model comparison study that combines multiple integrated assessment models with a reduced-form global air quality model to assess the potential co-benefits of global climate mitigation policies in relation to the World Health Organization (WHO) goals on air quality and health. We include in our assessment, a range of alternative assumptions on the implementation of current and planned pollution control policies. The resulting air pollution emission ranges significantly extend those in the Representative Concentration Pathways. Climate mitigation policies complement current efforts on air pollution control through technology and fuel transformations in the energy system. A combination of stringent policies on air pollution control and climate change mitigation results in 40% of the global population exposed to PM levels below the WHO air quality guideline; with the largest improvements estimated for India, China, and Middle East. Our results stress the importance of integrated multisector policy approaches to achieve the Sustainable Development Goals.

Byline: Paul. Paramita, Rao. Shilpa, B. Nandeesh, T. Yasha, Santosh. Vani Background: The WHO 2017 classification of endocrine tumors incorporates lineage-specific transcription factors (TF) and hormone expression for the classification [...]