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OBJECTIVE:: To further investigate the mortality risk of employees who worked in the petroleum refinery industry, we updated an earlier investigation by extending the mortality follow-up by an additional 14 years through 2003. METHODS:: The cohort consisted of 10,621 employees with an average follow-up of 34 years. We used the standardized mortality ratio (SMR) adjusted for age, race, and calendar years as a measure of risk. RESULTS:: Overall mortality (SMR = 0.77, 95% confidence interval [CI], 0.74-0.79), all cancer mortality (SMR = 0.87, 95% CI = 0.82-0.93), and most cause-specific mortalities for the total study population were lower than or similar to that of the population of Harris County, Texas. This study did not show a significant increase in leukemia in the total population or in any of the subgroups. The only statistically significant excess of mortality found in this study was an increase in mesothelioma among maintenance employees; the SMR was 4.78 (95% CI = 2.54-8.17) among employees who worked for a minimum of one year and was 7.51 (95% CI = 3.75-13.45) among those with 10 or more years of employment and 20 or more years of latency. CONCLUSIONS:: After more than half a century of follow-up, employees at this facility continue to show more favorable mortality outcomes than the general local population. Overall, no statistically significant increase of leukemia or of any of the specific cell types was found. The increased mesothelioma is likely related to past exposure to asbestos. [ABSTRACT FROM AUTHOR]

Background/Objectives: In type 2 diabetes (T2D), collective damage to the eyes, kidneys, and peripheral nerves constitutes microvascular complications, which significantly affect patients' quality of life. This study aimed to prospectively evaluate the risk of microvascular complications in newly diagnosed T2D patients in Dubai, UAE. Methods: Supervised automated machine learning in the Auto-Classifier model of the IBM SPSS Modeler package was used to predict microvascular complications in a training data set of 348 long-term T2D patients with complications using 24 independent variables as predictors and complications as targets. Three automated model scenarios were tested: Full All-Variable Model; Univariate-Selected Model, and Backward Stepwise Logistic Regression Model. An independent cohort of 338 newly diagnosed T2D patients with no complications was used for the model validation. Results: Long-term T2D patients with complications (duration = ~14.5 years) were significantly older (mean age = 56.3 ± 10.9 years) than the newly diagnosed patients without complications (duration = ~2.5 years; mean age = 48.9 ± 9.6 years). The Bayesian Network was the most reliable algorithm for predicting microvascular complications in all three scenarios with an area under the curve (AUC) of 77-87%, accuracy of 68-75%, sensitivity of 86-95%, and specificity of 53-75%. Among newly diagnosed T2D patients, 22.5% were predicted positive and 49.1% negative across all models. Logistic regression applied to the 16 significant predictors between the two sub-groups showed that BMI, HDL, adjusted for age at diagnosis of T2D, age at visit, and urine albumin explained >90% of the variation in microvascular measures. Conclusions: the Bayesian Network model effectively predicts microvascular complications in newly diagnosed T2D patients, highlighting the significant roles of BMI, HDL, age at diagnosis, age at visit, and urine albumin.

Antibody-mediated immunity is crucial in the vertebrate immune system. Nanobodies, also known as VHH or single-domain antibodies (sdAbs), are emerging as promising alternatives to full-length antibodies due to their compact size, precise target selectivity, and stability. However, the limited availability of nanobodies (Nbs) for numerous antigens (Ags) presents a significant obstacle to their widespread application. Understanding the interactions between Nbs and Ags is essential for enhancing their binding affinities and specificities. Experimental identification of these interactions is often costly and time-intensive. To address this issue, we introduce NABP-BERT, a deep-learning model based on the BERT architecture, designed to predict NANOBODY®-Ag binding solely from sequence information. Furthermore, we have developed a general pretrained model with transfer capabilities suitable for protein-related tasks, including protein-protein interaction tasks. NABP-BERT focuses on the surrounding amino acid contexts and outperforms existing methods, achieving an AUROC of 0.986 and an AUPR of 0.985., (© The Author(s) 2024. Published by Oxford University Press.)

In 2014, Nigeria faced a near-existential threat when Ebola was introduced to Lagos, a city of over 20 million people. Dr. Stella Ameyo Adadevoh (1956-2014), a physician at First Consultant Hospital, played a pivotal role in preventing the spread of the virus by making the crucial decision to quarantine the index case, Patrick Sawyer, despite intense governmental pressure to release him. This review explores Dr. Adadevoh's life, her heroic actions during the Ebola crisis, and the lasting impact of her work on Nigeria's public health system. It also highlights the ethical and professional challenges she faced, including balancing patient autonomy with the need for public safety. Through her brave decision-making, Dr. Adadevoh sacrificed herself to save countless lives and ensured Nigeria's swift containment of the deadly virus, leaving behind an inspirational legacy of medical ethics, leadership, and courage that continues to influence public health policy today. This paper highlights the lessons learned from her actions, emphasizing the critical role of decisive leadership in managing infectious disease outbreaks and the profound selflessness and courage she demonstrated., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Modibbo et al.)

As part of the response to the highly pathogenic avian influenza A(H5N1) virus outbreak in U.S. cattle and poultry and the associated human cases, CDC and partners are monitoring influenza A virus levels and detection of the H5 subtype in wastewater. Among 48 states and the District of Columbia that performed influenza A testing of wastewater during May 12-July 13, 2024, a weekly average of 309 sites in 38 states had sufficient data for analysis, and 11 sites in four states reported high levels of influenza A virus. H5 subtype testing was conducted at 203 sites in 41 states, with H5 detections at 24 sites in nine states. For each detection or high level, CDC and state and local health departments evaluated data from other influenza surveillance systems and partnered with wastewater utilities and agriculture departments to investigate potential sources. Among the four states with high influenza A virus levels detected in wastewater, three states had corresponding evidence of human influenza activity from other influenza surveillance systems. Among the 24 sites with H5 detections, 15 identified animal sources within the sewershed or adjacent county, including eight milk-processing inputs. Data from these early investigations can help health officials optimize the use of wastewater surveillance during the upcoming respiratory illness season., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. John Anderson reports support from the Council of State and Territorial Epidemiologists (CSTE) for travel to the 2023 Advanced Molecular Detection Days and the 2024 Advanced Molecular Detection Academy. Alexandria B. Boehm reports institutional support from the Sergey Brin Family Foundation and grant support from the U.S. National Science Foundation for research coordination network for wastewater-based epidemiology and from the Sloan Foundation for public health partnerships and wastewater-based epidemiology, and membership on the state of California wastewater-based epidemiology committee of the State Water Board. Ruth Lynfield reports support from the Infectious Diseases Society of America, CSTE, the National Foundation for Infectious Diseases, and the American Academy of Pediatrics to attend state epidemiology meetings, ID Week, CSTE Board meetings and CSTE annual conference, National Foundation for Infectious Diseases meeting, and the Committee on Infectious Diseases meeting. Marlene K. Wolfe reports a subaward gift to Stanford University, a grant from the Rockefeller Foundation for implementation of wastewater-based epidemiology in Bangladesh and Ghana and a subaward from Ceres Nanosciences (subaward from National Institutes of Health funding) for wastewater monitoring research, and support from the American Society of Microbiology for an invited talk at a conference. No other potential conflicts of interest were disclosed.

In this study, in vitro and in silico approaches were employed to assess the toxicity of marjoram ( Origanum majorana ) and rosemary ( Rosmarinus officinalis ) essential oils (EOs) to A. ipsilon larvae. The study determined the activities of ATPases in the larvae after treatment with the LC 20 and LC 70 of each EO. α-esterase and glutathione-S-transferase (GST) activities were also determined after treatment with LC 10 and LC 30 of each EO. Furthermore, molecular docking was employed to determine the binding affinity of terpinene-4-ol and α-pinene, the major constituents of O. majorana , and R. officinalis EOs, respectively, compared to the co-crystallized ligand of α-esterase, diethyl hydrogen phosphate (DPF). Toxicity assays revealed that O. majorana EO was more toxic than R. officinalis EO to the A. ipsilon larvae at 96 h post-treatment. However, the LC 20 and LC 70 of the latter significantly inhibited the activity of the Na + -K + pump at almost all intervals. The same concentrations significantly inhibited the Mg 2+ /Ca 2+ -ATPase and Ca 2+ pump at 96 h post-treatment. In contrast, O. majorana EO showed a variable effect on the Na+-K+ pump across different time intervals. On the other hand, LC 10 and LC 30 of both EOs showed varied effects on α-esterase and GST over time. Molecular docking revealed energy scores of -4.51 and -4.29 kcal/mol for terpinene-4-ol and α-pinene, respectively, compared to a score of -4.67 for PDF. Our study demonstrated the toxicity of the tested EOs to A. ipsilon , suggesting their potential efficacy as insecticides.

Background: Recognition of enhancer-promoter Interactions (EPIs) is crucial for human development. EPIs in the genome play a key role in regulating transcription. However, experimental approaches for classifying EPIs are too expensive in terms of effort, time, and resources. Therefore, more and more studies are being done on developing computational techniques, particularly using deep learning and other machine learning techniques, to address such problems. Unfortunately, the majority of current computational methods are based on convolutional neural networks, recurrent neural networks, or a combination of them, which don't take into consideration contextual details and the long-range interactions between the enhancer and promoter sequences. A new transformer-based model called EPI-Trans is presented in this study to overcome the aforementioned limitations. The multi-head attention mechanism in the transformer model automatically learns features that represent the long interrelationships between enhancer and promoter sequences. Furthermore, a generic model is created with transferability that can be utilized as a pre-trained model for various cell lines. Moreover, the parameters of the generic model are fine-tuned using a particular cell line dataset to improve performance., Results: Based on the results obtained from six benchmark cell lines, the average AUROC for the specific, generic, and best models is 94.2%, 95%, and 95.7%, while the average AUPR is 80.5%, 66.1%, and 79.6% respectively., Conclusions: This study proposed a transformer-based deep learning model for EPI prediction. The comparative results on certain cell lines show that EPI-Trans outperforms other cutting-edge techniques and can provide superior performance on the challenge of recognizing EPI., (© 2024. The Author(s).)

The whitefly, Bemisia tabaci (Genn.), is one of the most dangerous polyphagous pests in the world. Eco-friendly compounds and new chemical insecticides have gained recognition for whitefly control. In this study, the toxicity and biochemical impact of flometoquin, flonicamid, and sulfoxaflor, alone or combined with lemongrass essential oil (EO), against B. tabaci was studied. In addition, a molecular docking study was conducted to assess the binding affinity of the tested compounds to AchE. Based on the LC values, the descending order of the toxicity of the tested compounds to B. tabaci adults was as follows: sulfoxaflor > flonicamid > flometoquin > lemongrass EO. The binary mixtures of each of the tested compounds with lemongrass EO exhibited synergism in all combinations, with observed mortalities ranging from 15.09 to 22.94% higher than expected for an additive effect. Sulfoxaflor and flonicamid, alone or in combination with lemongrass EO, significantly inhibited AchE activity while only flonicamid demonstrated a significant impact on α-esterase, and none of the tested compounds affected cytochrome P450 or GST. However, the specific activity of P450 was significantly inhibited by the lemongrass/sulfoxaflor mixture while α-esterase activity was significantly inhibited by the lemongrass/flometoquin mixture. Moreover, the lemongrass EO and all the tested insecticides exhibited significant binding affinity to AchE with energy scores ranging from -4.69 to -7.06 kcal/mol. The current findings provide a foundation for utilizing combinations of essential oils and insecticides in the integrated pest management (IPM) of B. tabaci .

Spurious hyperphosphatemia, also known as pseudo-hyperphosphatemia, refers to artifactually elevated serum phosphate values that do not correspond to their actual systemic levels. Vascular access poses a significant challenge for individuals undergoing hemodialysis (HD) due to chronic kidney disease, primarily attributed to the elevated incidence of complications, such as infections or thrombosis associated with catheter use. To mitigate clotting risk during the inter-dialysis intervals, in recent years, a strategy involving the application of concentrated heparin (recombinant tissue plasminogen activator (rt-PA) e.g. alteplase) has been used. These infusions have a very high content of phosphorus, and if it is not removed sufficiently before collecting blood samples through the central venous catheter, it can cause erroneously high phosphate levels. Here we report two cases of pseudo-hyperphosphatemia caused by contaminated blood samples obtained from an HD catheter from the pediatric nephrology department. Absurd values found in routine samples led us to investigate the reason for these results. Further investigations carried out by the laboratory biochemistry department showed that all the analytical checks and proficiency testing performance were within acceptable limits. We hypothesized that there was a pre-analytical error such as possible contamination with the high phosphate content of heparin and alteplase solution in the catheter, contributing to the increased phosphate levels in these samples., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Ahmed et al.)

Background: Research in modifiable behaviors, like exercise, on risk for dementia is increasing. Although many studies focus on older adults, brain pathology for Alzheimer's Disease can begin in middle age, suggesting an ideal target for intervention., Methods: We conducted a systematic review from exercise intervention studies on cognitive function among healthy, middle-aged participants (45-65). We searched multiple databases (PubMed, PsycINFO, MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar) for studies using standard, validated, neuropsychological measures following either single- or multi-session interventions in cognitively-unimpaired, middle-aged adults., Results: We identified 13 eligible studies. There was notable heterogeneity across studies, with varying design, measures, interventions, and results. Results from single-session studies showed improvement in response inhibition, while results for cognitive flexibility were mixed. No significant changes were found on measures of attention, working memory, or processing speed. Results from multi-session studies were more varied. Verbal memory was found to improve while performance on tests of attention and working memory, processing speed, and executive function were mixed., Conclusion: Importantly, for both single-session and multi-session studies, there was no standard set of neuropsychological tests administered, making it more difficult to synthesize the findings into a single narrative. We end with a discussion on future directions and implementation.

This study focuses on the synthesis of magnetic fly ash composites and its application for the removal of methylene blue (MB) from wastewater. By-product of oil power plants, oil fly ash, was treated with magnetic nanoparticles after chemical surface modification and dubbed modified fly ash (MFA). MFA was characterized by X-ray fluorescence, diffractogram analysis, scanning electron microscopy, energy-dispersive X-ray (EDX), and Fourier transform infrared (FT-IR) and N 2 physisorption. MB (methylene blue) was removed from an aqueous solution using the response surface modelling (RSM) technique, which was used for optimization reasons. All four independent factors were investigated to see how they affected the removal process: adsorbent dosage; contact time; pH; and beginning dye concentration. The rate of MB removal was strongly influenced by the pH of the solution. The Langmuir and Freundlich models were used to examine equilibrium data A for MB adsorption onto the MFA in linear and nonlinear forms. Langmuir gave a better fit. The adsorption kinetics shown by increased kinetic statistics were better characterized by a pseudo-second-order MFA model. As far as thermodynamic characteristics go, adsorption is endothermic and occurs spontaneously. It has been proven that MFA may be used as an adsorbent to remove MB dye with high efficiency, and the quadratic model has been proved to be statistically significant., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited channelopathy. In this review, we summarize the epidemiology, pathophysiology, clinical characteristics, diagnostics, genetic mutations, standard treatment, and the emergence of potential gene therapy. This inherited cardiac arrhythmia presents in a bimodal distribution with no association between sex or ethnicity. Six different CPVT genes have been identified, however, most of the cases are related to a heterozygous, gain-of-function mutation on the ryanodine receptor-2 gene (RyR2) and calsequestrin-2 gene (CASQ2) that causes delayed after-depolarization. The diagnosis is clinically based, seen in patients presenting with syncope after exercise or stress-related emotions, as well as cardiac arrest with full recovery or even sudden cardiac death. Standard treatment relies on beta-blockers, with add-on therapy, flecainide, and cardiac sympathetic denervation as second-line treatments. An implantable cardioverter-defibrillator is indicated for patients who have suffered a cardiac arrest. Potential gene therapy has emerged in the last 20 years and accelerated because of associated viral vector application in increasing the efficiency of prolonged cardiac gene expression. Nevertheless, human trials for gene therapy for CPVT have been limited as the population is rare, and an excessive amount of funding is required., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Henriquez et al.)

Background: Colorectal cancers are the fourth most diagnosed cancer and the second leading cancer in number of deaths. Many clinical variables, pathological features, and genomic signatures are associated with patient risk, but reliable patient stratification in the clinic remains a challenging task. Here we assess how image, clinical, and genomic features can be combined to predict risk., Methods: We developed and evaluated integrative deep learning models combining formalin-fixed, paraffin-embedded (FFPE) whole slide images (WSIs), clinical variables, and mutation signatures to stratify colon adenocarcinoma (COAD) patients based on their risk of mortality. Our models were trained using a dataset of 108 patients from The Cancer Genome Atlas (TCGA), and were externally validated on newly generated dataset from Wayne State University (WSU) of 123 COAD patients and rectal adenocarcinoma (READ) patients in TCGA (N = 52)., Findings: We first observe that deep learning models trained on FFPE WSIs of TCGA-COAD separate high-risk (OS < 3 years, N = 38) and low-risk (OS > 5 years, N = 25) patients (AUC = 0.81 ± 0.08, 5 year survival p < 0.0001, 5 year relative risk = 1.83 ± 0.04) though such models are less effective at predicting overall survival (OS) for moderate-risk (3 years < OS < 5 years, N = 45) patients (5 year survival p-value = 0.5, 5 year relative risk = 1.05 ± 0.09). We find that our integrative models combining WSIs, clinical variables, and mutation signatures can improve patient stratification for moderate-risk patients (5 year survival p < 0.0001, 5 year relative risk = 1.87 ± 0.07). Our integrative model combining image and clinical variables is also effective on an independent pathology dataset (WSU-COAD, N = 123) generated by our team (5 year survival p < 0.0001, 5 year relative risk = 1.52 ± 0.08), and the TCGA-READ data (5 year survival p < 0.0001, 5 year relative risk = 1.18 ± 0.17). Our multicenter integrative image and clinical model trained on combined TCGA-COAD and WSU-COAD is effective in predicting risk on TCGA-READ (5 year survival p < 0.0001, 5 year relative risk = 1.82 ± 0.13) data. Pathologist review of image-based heatmaps suggests that nuclear size pleomorphism, intense cellularity, and abnormal structures are associated with high-risk, while low-risk regions have more regular and small cells. Quantitative analysis shows high cellularity, high ratios of tumor cells, large tumor nuclei, and low immune infiltration are indicators of high-risk tiles., Interpretation: The improved stratification of colorectal cancer patients from our computational methods can be beneficial for treatment plans and enrollment of patients in clinical trials., Funding: This study was supported by the National Cancer Institutes (Grant No. R01CA230031 and P30CA034196). The funders had no roles in study design, data collection and analysis or preparation of the manuscript., Competing Interests: Declaration of interests Fahad Shabbir Ahmed is a co-founder of ALGORISMUS, LLC and CDS Dental Material, LLC. The other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Protective oxide layers on Ti-6Al-3Mo-2Nb-2Sn-2Zr-1.5Cr (TC21) alloy with equiaxed microstructure considerably influence micro-hardness and hot corrosion resistance. The present work's thermal oxidation of TC21 alloy was performed at 600, 700, and 800 °C for 5, 20, and 50 h durations. Hot corrosion methods in NaCl and NaCl + Na 2 SO 4 salt media were applied to raw (unoxidized) and oxidized samples at 600 and 800 °C for 50 h. Hot corrosion was conducted at 600 °C for 5 cycles with 10-h steps. The best oxide layer thickness was observed at 800 °C, which increased with increased oxidation time and temperature. The surface hardness of the oxide layer at 800 °C was 900 ± 60 HV 0.05 owing to the formation of TiO 2 and Al 2 O 3 phases. Raw material hardness was 342 ± 20 HV 0.05 , increasing threefold due to thermal oxidation. In the case of NaCl, weight loss dominated all samples except at 800 °C for 5 h. In the case of NaCl + Na 2 SO 4 , weight gain occurred at 600 and 800 °C for 5 h. Weight loss occurred for the raw samples and those processed at 800 °C for 20 and 50 h, where the oxide layer flaked off. Surface hardness increased upon hot corrosion testing because of the formation of brittle phases, such as TiO 2 and Na 4 Ti 5 O 12 . Samples that oxidized at 800 °C for 5 h had the highest hardness and corrosion resistance., (© 2023. The Author(s).)

Moderate- to vigorous intensities of physical activity are recommended for health promotion, including brain health. Regular physical activity is considered a modifiable factor to delay -perhaps prevent- onset of dementias such as Alzheimer's disease. Little is known about the benefits of light physical activity. We analyzed data from a 998 community-dwelling, cognitively unimpaired participants from the Maine-Syracuse Longitudinal Study (MSLS) and investigated the role of light physical activity, defined by walking pace, across two time points. Results revealed light levels of walking pace were associated with higher performance at the first timepoint and less decline by time 2 in the domains of verbal abstract reasoning and visual scanning and tracking, which includes both processing speed and executive function skills. When examining change over time ( N  = 583), increasing walking pace was associated with less decline at time two for the domains of visual scanning and tracking, working memory, visual spatial ability, and working memory, but not verbal abstract reasoning. These findings highlight the relevance of light physical activity and the need to investigate its contribution to cognitive function. From a public health perspective, this may encourage more adults to adopt a light level of exercise and still reap health benefits.

Background: Prescribed agricultural burning is a common land management practice, but little is known about the health effects from the resulting smoke exposure., Objective: To examine the association between smoke from prescribed burning and cardiorespiratory outcomes in the U.S. state of Kansas., Methods: We analyzed a zip code-level, daily time series of primary cardiorespiratory emergency department (ED) visits for February-May (months when prescribed burning is common in Kansas) in the years 2009-2011 (n = 109,220). Given limited monitoring data, we formulated a measure of smoke exposure using non-traditional datasets, including fire radiative power and locational attributes from remote sensing data sources. We then assigned a population-weighted potential smoke impact factor (PSIF) to each zip code, based on fire intensity, smoke transport, and fire proximity. We used Poisson generalized linear models to estimate the association between PSIF on the same day and in the past 3 days and asthma, respiratory including asthma, and cardiovascular ED visits., Results: During the study period, prescribed burning took place on approximately 8 million acres in Kansas. Same-day PSIF was associated with a 7% increase in the rate of asthma ED visits when adjusting for month, year, zip code, meteorology, day of week, holidays, and correlation within zip codes (rate ratio [RR]: 1.07; 95% confidence interval [CI]: 1.01, 1.13). Same-day PSIF was not associated with a combined outcome of respiratory ED visits (RR [95% CI]: 0.99 [0.97, 1.02]), or cardiovascular ED visits (RR [95% CI]: 1.01 [0.98, 1.04]). There was no consistent association between PSIF during the past 3 days and any of the outcomes., Significance: These results suggest an association between smoke exposure and asthma ED visits on the same day. Elucidating these associations will help guide public health programs that address population-level exposure to smoke from prescribed burning., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Changes in adipose tissue distribution in liver cirrhosis are poorly characterized and may affect clinical outcomes., Methods: Adult liver transplant (LT) January 2008-August 2017 recipients with abdominal MRI within 6 months pre-LT were retrospectively assessed. Visceral adipose tissue, subcutaneous adipose tissue, and skeletal muscle area (cm2) were determined at L3. Visceral-to-subcutaneous adipose tissue ratio (VSR) was used to define relative adipose distribution, stratified by sex. Correlation was tested with Pearson. Body composition measures were compared by Child-Turcotte-Pugh (CTP) class, before and after LT, and evaluated as predictors of clinical outcomes., Results: A total of 318 patients were studied. Mean age was 56 years, 33.64% were female, and 47.80% had CTP C cirrhosis. CTP C was associated with a 0.42-point increase in VSR compared with CTP A (95% CI = 0.13-0.71, p < 0.01), adjusting for age, sex, diabetes, and HCC. Among the 79 (24.84%) patients with repeat MRI 1-2 years after LT, VSR significantly improved from before LT (1.31 vs. 0.95, p < 0.01). In adjusted analysis, CTP C was associated with a 0.86-point decrease in post-LT VSR compared with pre-LT VSR (95% CI = -1.27 to -0.44, p < 0.01). Body mass index poorly correlated with VSR before and after LT. Elevated pre-LT VSR trended toward an association with a 7.17-point decrease in pre-LT glomerular filtration rate (95% CI = -14.35 to -0.02, p = 0.05), adjusting for CTP C, age, sex, diabetes, hypertension, pre-LT sarcopenia, and hepatocellular carcinoma. Elevated pre-LT VSR did not affect 3-year post-LT mortality (log-rank p = 0.24)., Conclusions: Poorly represented by body mass index, visceral adiposity is increased in cirrhosis and is associated with CTP class. However, this adipose redistribution may be modifiable by LT., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: The South Asian Association for Regional Cooperation (SAARC) covers Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka. We conducted a comparative analysis of the trade-off between the health policies for the prevention of COVID-19 spread and the impact of these policies on the economies and livelihoods of the South Asia populations., Methods: We analyzed COVID-19 data on epidemiology, public health and health policy, health system capacity, and macroeconomic indicators from January 2020 to March 2021 to determine temporal trends by conducting joinpoint regression analysis using average weekly percent change (AWPC)., Results: Bangladesh had the highest statistically significant AWPC for new COVID-19 cases (17.0; 95% CI = 7.7-27.1, P < 0.001), followed by the Maldives (12.9; 95% CI = 5.3-21.0, P < 0.001) and India (10.0; 95% CI = 8.4-11.5, P < 0.001). The AWPC for COVID-19 deaths was significant for India (6.5; 95% CI = 4.3-8.9, P < 0.001) and Bangladesh (6.1; 95% CI = 3.7-8.5, P < 0.001). Nepal (55.79%), and India (34.91%) had the second- and third-highest increase in unemployment, while Afghanistan (6.83%) and Pakistan (16.83%) had the lowest. The rate of change of real GDP had the highest decrease for Maldives (557.51%), and India (297.03%); Pakistan (46.46%) and Bangladesh (70.80%), however, had the lowest decrease. The government response stringency index for Pakistan had a see-saw pattern with a sharp decline followed by an increase in the government health policy restrictions that approximated the test-positivity trend., Conclusions: Unlike developed economies, the South Asian developing countries experienced a trade-off between health policy and their economies during the COVID-19 pandemic. South Asian countries (Nepal and India), with extended periods of lockdowns and a mismatch between temporal trends of government response stringency index and the test-positivity or disease incidence, had higher adverse economic effects, unemployment, and burden of COVID-19. Pakistan demonstrated targeted lockdowns with a rapid see-saw pattern of government health policy response that approximated the test-positivity trend and resulted in lesser adverse economic effects, unemployment, and burden of COVID-19., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose the following activities and/or relationships: FBI reports grant from NorthStar Anesthesia, and personal fees for consultancy from Silicon Valley Innovation Center, Infineon Technologies AG, unrelated to this publication. All other authors declare no relevant interests., (Copyright © 2023 by the Journal of Global Health. All rights reserved.)

Introduction: Sleep disorder is often the first symptom of age-related cognitive decline associated with Alzheimer's disease (AD) observed in primary care. The relationship between sleep and early AD was examined using a patented sleep mattress designed to record respiration and high frequency movement arousals. A machine learning algorithm was developed to classify sleep features associated with early AD., Method: Community-dwelling older adults (N = 95; 62-90 years) were recruited in a 3-h catchment area. Study participants were tested on the mattress device in the home bed for 2 days, wore a wrist actigraph for 7 days, and provided sleep diary and sleep disorder self-reports during the 1-week study period. Neurocognitive testing was completed in the home within 30-days of the sleep study. Participant performance on executive and memory tasks, health history and demographics were reviewed by a geriatric clinical team yielding Normal Cognition (n = 45) and amnestic MCI-Consensus (n = 33) groups. A diagnosed MCI group (n = 17) was recruited from a hospital memory clinic following diagnostic series of neuroimaging biomarker assessment and cognitive criteria for AD., Results: In cohort analyses, sleep fragmentation and wake after sleep onset duration predicted poorer executive function, particularly memory performance. Group analyses showed increased sleep fragmentation and total sleep time in the diagnosed MCI group compared to the Normal Cognition group. Machine learning algorithm showed that the time latency between movement arousals and coupled respiratory upregulation could be used as a classifier of diagnosed MCI vs. Normal Cognition cases. ROC diagnostics identified MCI with 87% sensitivity; 89% specificity; and 88% positive predictive value., Discussion: AD sleep phenotype was detected with a novel sleep biometric, time latency, associated with the tight gap between sleep movements and respiratory coupling, which is proposed as a corollary of sleep quality/loss that affects the autonomic regulation of respiration during sleep. Diagnosed MCI was associated with sleep fragmentation and arousal intrusion., (© 2023. The Author(s).)

Measles is an acute febrile viral illness with a characteristic rash. It is usually present in children. Due to the vaccine's development and wide use, serious complications are quite infrequent in vaccine-covered areas., Case Presentation: A 36-year-old immunocompetent woman presented with a fever and a macular rash affecting the face and upper trunk. She was found to have transaminitis and later developed bilateral pulmonary infiltrates with decreased oxygen saturation. After extensive work, the measles PCR returned positive results. The patient was treated conservatively until she recovered., Discussion: Measles pneumonitis is a rare complication that usually occurs in immunosuppressed patients. Due to the coronavirus disease pandemic, diagnosis can be difficult, especially if the presentation is not classic., Conclusion: We report this case to emphasize the importance of correct diagnosis and proper management., Competing Interests: The authors declare no conflicts of interest.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Targeting the interaction of leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) and its ligands has been shown to reinstate antitumor immunity. In addition, the introduction of the LAIR-1 decoy protein, LAIR-2, sensitizes previously resistant lung tumors to programmed death-1 (PD-1) blockade, indicating the potential of LAIR-1 as an alternative marker for anti-PD-1 resistance in lung cancer. Here, we assessed LAIR-1 as compared with programmed death-ligand 1 (PD-L1) expression in various tumors, with a focus on non-small cell lung cancer (NSCLC) and its histologic subtypes using multiplexed quantitative immunofluorescence (mQIF) in 287 (discovery cohort) and 144 (validation cohort) patients with NSCLC. In addition, using multispectral imaging technology on mQIF images, we evaluated the localization of LAIR-1 on various cell types. We observed that CD14 + , CD68 + , and CD163 + monocytes and CK + tumor cells predominantly expressed LAIR-1 more than other cell types. Furthermore, LAIR-1 expression in the tumor compartment was significantly higher in patients with lung adenocarcinoma (LUAD) than those with lung squamous cell carcinoma subtype (**, P = 0.003). Our results indicated that high tumor LAIR-1 expression in patients with LUAD is negatively associated with OS (overall survival, HR = 2.4; *, P = 0.02) highlighting its prognostic value in LUAD but not in other subtypes. The Pearson correlation between LAIR-1 and PD-L1 is 0.31; however, mutual exclusive staining pattern (i.e., several cases were positive for LAIR-1 and negative for PD-L1) was observed. Altogether, our data suggest that the combination therapy of anti-PD-1/PD-L1 with anti-LAIR-1 or the anti-LAIR-1 monotherapy alone may be promising cancer immunotherapeutic strategies., Significance: The spatial, quantitative assessment of LAIR-1 in NSCLC shows positive association of OS with high LAIR-1 + /CD68 + cell densities and negative association of OS with high LAIR-1 expression in LUAD tumor subtype., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: CD40, a TNF receptor family member, is expressed by a variety of immune cells and is involved in the activation of both adaptive and innate immune responses. Here, we used quantitative immunofluorescence (QIF) to evaluate CD40 expression on the tumor epithelium of solid tumors in large patient cohorts of lung, ovarian, and pancreatic cancers., Methods: Tissue samples from nine different solid tumors (bladder, breast, colon, gastric, head and neck, non-small cell lung cancer (NSCLC), ovarian, pancreatic and renal cell carcinoma), constructed in tissue microarray format, were initially assessed for CD40 expression by QIF. CD40 expression was then evaluated on the large available patient cohorts for three of the tumor types demonstrating high CD40 positivity rate; NSCLC, ovarian and pancreatic cancer. The prognostic impact of CD40 expression on tumor cells was also investigated., Results: CD40 expression on tumor cells was found to be common, with 80% of the NSCLC population, 40% of the ovarian cancer population, and 68% of the pancreatic adenocarcinoma population displaying some degree of CD40 expression on cancer cells. All of three of these cancer types displayed considerable intra-tumoral heterogeneity of CD40 expression, as well as partial correlation between expression of CD40 on tumor cells and on surrounding stromal cells. CD40 was not found to be prognostic for overall survival in NSCLC, ovarian cancer, or pancreatic adenocarcinoma., Conclusions: The high percentage of tumor cells expressing CD40 in each of these solid tumors should be considered in the development of therapeutic agents designed to target CD40., (© 2023. The Author(s).)

Reducing nematicide dose rates could be a useful strategy for mitigating their negative effects on health and the environment. In this study, enzymatic activities and the parasitic ability of Meloidogyne incognita after exposure to sub-lethal concentrations (0.25, 1, 2, and 5 ppm) of ethoprophos, fenamiphos, and oxamyl were investigated. Although the tested concentrations did not show nematicidal properties in vitro, they reduced root galls by at least 30% at 0.25 ppm and up to 67% at 5 ppm in pots, besides disrupting nematode fertility. For all three nematicides at 2 ppm, a chemotaxis assay showed that ≤ 11% of the nematode population was successfully oriented to the host roots, compared to 44% in the control. Ethoprophos and fenamiphos at 5 ppm showed poor inhibitory effects on acetylcholinesterase (AChE) activity (5.6% and 12.5%, respectively). In contrast, the same nematicides were shown to be strong ATPase inhibitors, causing 82.4% and 82.8% inhibition, respectively. At the same concentration, oxamyl moderately inhibited AChE and ATPase-specific activities, the inhibition being 22.5% and 35.2%, respectively. This study suggests that the use of very low nematicide concentrations could be a promising strategy for nematode management. Furthermore, it has also highlighted the role of ATPases as a possible target site for suppressing nematode activity in the development of future nematicides., (© 2023. The Author(s).)

In the current study on TC21 Ti-alloy (6.5Al-3Mo-1.9Nb-2.2Sn-2.2Zr-1.5Cr), the thermal oxidation formed oxide layers that considerably influenced mechanical properties (hardness and wear). TC21 specimens were oxidized at 600, 700, 800, and 900 °C for 5, 20, and 50 h. NaCl-induced hot corrosion testing was carried out on raw (un-oxidized) and oxidized specimens at 600 and 800 °C for 50 h. The cyclic testing was performed at 600 °C for durations of 5, 10, 20, 30, 40, and 50 h. The average thickness of the layer grew with increasing oxidation time and temperature. A thin oxide layer (average 0.16 µm) was generated by oxidation at a temperature of 600 °C for a duration of 5 h, and at 800 °C, a large oxide layer of 10.8 µm thickness was formed. The most significant surface hardness of 1000 ± 150 HV 0.05 was produced for the layer oxidized at 900 °C. On the other hand, the lowest hardness of 360 ± 150 HV 0.05 was recorded for the raw materials. Best wear resistance had been achieved for specimens oxidized at 800 °C. During NaCl hot corrosion test, the weight loss of the raw specimen was 6.4 mg/cm 2 due to the flaking off of the corrosion product. However, for specimens oxidized at 600 °C for 50 h, weight loss after corrosion testing was 0.54 mg/cm 2 , less than that of the specimen before corrosion. Oxidized specimens at 800 °C exhibited the best mechanical characteristics and corrosion resistance., (© 2022. The Author(s).)

Background: Countries making up the Nordic region - Denmark, Finland, Iceland, Norway, and Sweden - have minimal socioeconomic, cultural, and geographical differences between them, allowing for a fair comparative analysis of the health policy and economy trade-off in their national approaches towards mitigating the impact of the COVID-19 pandemic., Methods: This study utilized publicly available COVID-19 data of the Nordic countries from January 2020 to January 3, 2021. COVID-19 epidemiology, public health and health policy, health system capacity, and macroeconomic data were analysed for each Nordic country. Joinpoint regression analysis was performed to identify changes in temporal trends using average monthly percent change (AMPC) and average weekly percent change (AWPC)., Results: Sweden's health policy, being by far the most relaxed response to COVID-19, was found to have the largest COVID-19 incidence and mortality, and the highest AWPC increases for both indicators (13.5, 95% CI = 5.6, 22.0, P < 0.001; 6.3, 95% CI = 3.5, 9.1, P < 0.001). Denmark had the highest number of COVID-19 tests per capita, consistent with their approach of increased testing as a preventive strategy for disease transmission. Iceland had the second-highest number of tests per capita due to their mass-testing, contact tracing, quarantine and isolation response. Only Norway had a significant increase in unemployment (AMPC = 2.8%, 95% CI = 0.7-4.9, P < 0.009) while the percentage change in real Gross Domestic Product (GDP) was insignificant for all countries., Conclusions: There was no trade-off between public health policy and economy during the COVID-19 pandemic in the Nordic region. Sweden's relaxed and delayed COVID-19 health policy response did not benefit the economy in the short term, while leading to disproportionate COVID-19 hospitalizations and mortality., Competing Interests: Competing interests: Irfan FB reports grant from NorthStar Anesthesia, and personal fees for consultancy from Silicon Valley Innovation Center, Infineon Technologies AG, unrelated to this publication. Saleh KJ reports royalties from patents with BBraun; and personal fees for consultancy from Saleh Medical Consulting PLC, Aesculap AG; Medical Director of Legend Health and Sphere Orthopaedics, unrelated to this publication. The authors have completed the ICMJE Unified Competing Interest Form (available upon request from the corresponding author) and declare no further competing interests., (Copyright © 2022 by the Journal of Global Health. All rights reserved.)

Software Test Case Prioritization (TCP) is an effective approach for regression testing to tackle time and budget constraints. The major benefit of TCP is to save time through the prioritization of important test cases first. Existing TCP techniques can be categorized as value-neutral and value-based approaches. In a value-based fashion, the cost of test cases and severity of faults are considered whereas, in a value-neutral fashion these are not considered. The value-neutral fashion is dominant over value-based fashion, and it assumes that all test cases have equal cost and all software faults have equal severity. But this assumption rarely holds in practice. Therefore, value-neutral TCP techniques are prone to produce unsatisfactory results. To overcome this research gap, a paradigm shift is required from value-neutral to value-based TCP techniques. Currently, very limited work is done in a value-based fashion and to the best of the authors' knowledge, no comprehensive review of value-based cost-cognizant TCP techniques is available in the literature. To address this problem, a systematic literature review (SLR) of value-based cost-cognizant TCP techniques is presented in this paper. The core objective of this study is to combine the overall knowledge related to value-based cost-cognizant TCP techniques and to highlight some open research problems of this domain. Initially, 165 papers were reviewed from the prominent research repositories. Among these 165 papers, 21 papers were selected by using defined inclusion/exclusion criteria and quality assessment procedures. The established questions are answered through a thorough analysis of the selected papers by comparing their research contributions in terms of the algorithm used, the performance evaluation metric, and the results validation method used. Total 12 papers used an algorithm for their technique but 9 papers didn't use any algorithm. Particle Swarm Optimization (PSO) Algorithm is dominantly used. For results validation, 4 methods are used including, Empirical study, Experiment, Case study, and Industrial case study. The experiment method is dominantly used. Total 6 performance evaluation metrics are used and the APFDc metric is dominantly used. This SLR yields that value-orientation and cost cognition are vital in the TCP process to achieve its intended goals and there is great research potential in this research domain., Competing Interests: The authors have declared that no competing interests exist.

Methoxyfenozide (M) is one of the selective insecticides used in integrated pest management (IPM) programs for lepidopteran pests. However, recent studies reported a development of M-resistance, which prompted us to look for alternatives. Here, we investigate the potency of a mixture of M with spinetoram (Sp) on M-resistant insects. In the laboratory, a selection pressure with M has carried out on Spodoptera littoralis (Lepidoptera: Noctuidae) strains. A dipping technique was used to evaluate the toxicity of a sublethal concentration of M and Sp. on S. littoralis larvae, and the same concentrations were used to assess the toxic impact of their combination on susceptible (SUS) and M-selected (MS) strains. The toxicity of M/Sp mixtures was computed using a combination index equation, and a potentiation effect was observed in the two tested strains. Synergism tests revealed that piperonyl butoxide had considerable synergistic effects on M toxicity in the MS strain. The results revealed that the M/Sp mixture's negative effect on both monooxygenases and esterases is most likely the cause of its potentiation effect on the SUS and MS strains. It was concluded that M/Sp mixtures are effective against M-resistant S. littoralis strains, so these can be used in IPM programs., (© 2022. The Author(s).)

In this commentary, we briefly describe our methodology in conducting a remote qualitative investigation with essential workers from southwest Kansas, and then describe some key considerations, challenges, and lessons learned in recruiting and conducting interviews remotely. From August 4, 2020 through August 26, 2020, Centers for Disease Control and Prevention (CDC) staff conducted five phone interviews with culturally and linguistically diverse employees in southwest Kansas to understand COVID-19 knowledge, attitudes, and practices and communication preferences. Our experience details the potential challenges of the federal government in recruiting individuals from these communities and highlights the possibilities for more effectively engaging health department and community partners to support investigation efforts. Optimizing recruitment strategies with additional participation from community partners, developing culturally and linguistically appropriate data collection tools, and providing supportive resources and services may augment participation from refugee, immigrant, and migrant (RIM) communities in similar remote investigations.

Melioidosis, caused by the bacterium Burkholderia pseudomallei, is an uncommon infection that is typically associated with exposure to soil and water in tropical and subtropical environments. It is rarely diagnosed in the continental United States. Patients with melioidosis in the United States commonly report travel to regions where melioidosis is endemic. We report a cluster of four non-travel-associated cases of melioidosis in Georgia, Kansas, Minnesota, and Texas. These cases were caused by the same strain of B. pseudomallei that was linked to an aromatherapy spray product imported from a melioidosis-endemic area., (Copyright © 2022 Massachusetts Medical Society.)

Background: Case-based surveillance of pediatric coronavirus disease 2019 (COVID-19) cases underestimates the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among children and adolescents. Our objectives were to estimate monthly SARS-CoV-2 antibody seroprevalence and calculate ratios of SARS-CoV-2 infections to reported COVID-19 cases among children and adolescents in 8 US states., Methods: Using data from the Nationwide Commercial Laboratory Seroprevalence Survey, we estimated monthly SARS-CoV-2 antibody seroprevalence among children aged 0-17 years from August 2020 through May 2021. We calculated and compared cumulative incidence of SARS-CoV-2 infection extrapolated from population-standardized seroprevalence of antibodies to SARS-CoV-2, cumulative COVID-19 case reports since March 2020, and infection-to-case ratios among persons of all ages and children aged 0-17 years for each state., Results: Of 41 583 residual serum specimens tested, children aged 0-4, 5-11, and 12-17 years accounted for 1619 (3.9%), 10 507 (25.3%), and 29 457 (70.8%), respectively. Median SARS-CoV-2 antibody seroprevalence among children increased from 8% (range, 6%-20%) in August 2020 to 37% (range, 26%-44%) in May 2021. Estimated ratios of SARS-CoV-2 infections to reported COVID-19 cases in May 2021 ranged by state from 4.7-8.9 among children and adolescents to 2.2-3.9 for all ages combined., Conclusions: Through May 2021 in selected states, the majority of children with serum specimens included in serosurveys did not have evidence of prior SARS-CoV-2 infection. Case-based surveillance underestimated the number of children infected with SARS-CoV-2 more than among all ages. Continued monitoring of pediatric SARS-CoV-2 antibody seroprevalence should inform prevention and vaccination strategies., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

The current standard of care for many patients with HER2-positive breast cancer is neoadjuvant chemotherapy in combination with anti-HER2 agents, based on HER2 amplification as detected by in situ hybridization (ISH) or protein immunohistochemistry (IHC). However, hematoxylin & eosin (H&E) tumor stains are more commonly available, and accurate prediction of HER2 status and anti-HER2 treatment response from H&E would reduce costs and increase the speed of treatment selection. Computational algorithms for H&E have been effective in predicting a variety of cancer features and clinical outcomes, including moderate success in predicting HER2 status. In this work, we present a novel convolutional neural network (CNN) approach able to predict HER2 status with increased accuracy over prior methods. We trained a CNN classifier on 188 H&E whole slide images (WSIs) manually annotated for tumor Regions of interest (ROIs) by our pathology team. Our classifier achieved an area under the curve (AUC) of 0.90 in cross-validation of slide-level HER2 status and 0.81 on an independent TCGA test set. Within slides, we observed strong agreement between pathologist annotated ROIs and blinded computational predictions of tumor regions / HER2 status. Moreover, we trained our classifier on pre-treatment samples from 187 HER2+ patients that subsequently received trastuzumab therapy. Our classifier achieved an AUC of 0.80 in a five-fold cross validation. Our work provides an H&E-based algorithm that can predict HER2 status and trastuzumab response in breast cancer at an accuracy that may benefit clinical evaluations., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Associations between fermented dairy products and blood pressure are unclear. The current study therefore examined the association between yogurt and blood pressure in hypertensive and non-hypertensive individuals. Cross-sectional analyses were undertaken on 915 community-dwelling adults from the Maine-Syracuse Longitudinal Study. Habitual yogurt consumption was measured using a food frequency questionnaire. The primary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure. Secondary outcomes included BMI (kg m -2 ), total cholesterol (mg dL -1 ), glucose (mg dL -1 ), HDL (mg dL -1 ), LDL (mg dL -1 ), triglycerides (mg dL -1 ), and plasma homocysteine (μmol L -1 ). Multivariable regression analyses revealed significant inverse associations between yogurt and both SBP ( p < 0.05) and MAP ( p < 0.05) in hypertensive (n = 564) but not non-hypertensive participants (n = 351). Future observational and intervention studies should continue to focus on at-risk individuals to examine the potential benefits of yogurt., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Objectives: To describe the demographics, clinical characteristics, and hospital course among persons <21 years of age with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated death., Methods: We conducted a retrospective case series of suspected SARS-CoV-2-associated deaths in the United States in persons <21 years of age during February 12 to July 31, 2020. All states and territories were invited to participate. We abstracted demographic and clinical data, including laboratory and treatment details, from medical records., Results: We included 112 SARS-CoV-2-associated deaths from 25 participating jurisdictions. The median age was 17 years (IQR 8.5-19 years). Most decedents were male (71, 63%), 31 (28%) were Black (non-Hispanic) persons, and 52 (46%) were Hispanic persons. Ninety-six decedents (86%) had at least 1 underlying condition; obesity (42%), asthma (29%), and developmental disorders (22%) were most commonly documented. Among 69 hospitalized decedents, common complications included mechanical ventilation (75%) and acute respiratory failure (82%). The sixteen (14%) decedents who met multisystem inflammatory syndrome in children (MIS-C) criteria were similar in age, sex, and race and/or ethnicity to decedents without MIS-C; 11 of 16 (69%) had at least 1 underlying condition., Conclusions: SARS-CoV-2-associated deaths among persons <21 years of age occurred predominantly among Black (non-Hispanic) and Hispanic persons, male patients, and older adolescents. The most commonly reported underlying conditions were obesity, asthma, and developmental disorders. Decedents with coronavirus disease 2019 were more likely than those with MIS-C to have underlying medical conditions., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Background: Vitiligo is an acquired pigmentation disorder due to loss of melanocytes. Topical tacrolimus is effective in vitiligo treatment with minimal effect on extra-facial lesions., Objective: To assess different methods of enhancing the absorption of topical tacrolimus in extra-facial vitiligo sites using microneedling and occlusion., Methods: This study included 20 adult patients of both sexes with non-segmental vitiligo. Four extra-facial vitiligo lesions in each patient were randomly labeled A, B, C, and D and treated as follows: area A: tacrolimus ointment (0.03%) application twice/day, area B: microneedling once/week and tacrolimus ointment application directly after microneedling and twice/day the rest of the week, area C: microneedling once/week alone, and area D: tacrolimus ointment application twice/day under occlusion by polyethylene foil. The evaluation was done clinically by calculating the re-pigmentation percent after 6 months of treatment., Results: Responders in area B were 45%, and 35% in area C, and 25% in both areas A and D. No statistically significant difference was detected regarding the re-pigmentation percent between the four areas (p > 0.05). No correlations were detected between re-pigmentation percent and patients' data., Conclusion: Combination of microneedling and topical tacrolimus has an edge over monotherapy in vitiligo, and further studies are needed to verify such results., (© 2021 Wiley Periodicals LLC.)

Purpose: Although tumor-infiltrating lymphocytes (TIL) assessment has been acknowledged to have both prognostic and predictive importance in triple-negative breast cancer (TNBC), it is subject to inter and intraobserver variability that has prevented widespread adoption. Here we constructed a machine-learning based breast cancer TIL scoring approach and validated its prognostic potential in multiple TNBC cohorts., Experimental Design: Using the QuPath open-source software, we built a neural-network classifier for tumor cells, lymphocytes, fibroblasts, and "other" cells on hematoxylin-eosin (H&E)-stained sections. We analyzed the classifier-derived TIL measurements with five unique constructed TIL variables. A retrospective collection of 171 TNBC cases was used as the discovery set to identify the optimal association of machine-read TIL variables with patient outcome. For validation, we evaluated a retrospective collection of 749 TNBC patients comprised of four independent validation subsets., Results: We found that all five machine TIL variables had significant prognostic association with outcomes ( P ≤ 0.01 for all comparisons) but showed cell-specific variation in validation sets. Cox regression analysis demonstrated that all five TIL variables were independently associated with improved overall survival after adjusting for clinicopathologic factors including stage, age, and histologic grade ( P ≤ 0.0003 for all analyses)., Conclusions: Neural net-driven cell classifier-defined TIL variables were robust and independent prognostic factors in several independent validation cohorts of TNBC patients. These objective, open-source TIL variables are freely available to download and can now be considered for testing in a prospective setting to assess clinical utility. See related commentary by Symmans, p. 5446 ., (©2021 American Association for Cancer Research.)

Background: The nextwave of COVID-19 pandemic is anticipated to be worse than the initial one and will strain the healthcare systems even more during the winter months. Our aim was to develop a novel machine learning-based model to predict mortality using the deep learning Neo-V framework. We hypothesized this novel machine learning approach could be applied to COVID-19 patients to predict mortality successfully with high accuracy., Methods: We collected clinical and laboratory data prospectively on all adult patients (≥18 years of age) that were admitted in the inpatient setting at Aga Khan University Hospital between February 2020 and September 2020 with a clinical diagnosis of COVID-19 infection. Only patients with a RT-PCR (reverse polymerase chain reaction) proven COVID-19 infection and complete medical records were included in this study. A Novel 3-phase machine learning framework was developed to predict mortality in the inpatients setting. Phase 1 included variable selection that was done using univariate and multivariate Cox-regression analysis; all variables that failed the regression analysis were excluded from the machine learning phase of the study. Phase 2 involved new-variables creation and selection. Phase 3 and final phase applied deep neural networks and other traditional machine learning models like Decision Tree Model, k-nearest neighbor models, etc. The accuracy of these models were evaluated using test-set accuracy, sensitivity, specificity, positive predictive values, negative predictive values and area under the receiver-operating curves., Results: After application of inclusion and exclusion criteria (n=)1214 patients were selected from a total of 1228 admitted patients. We observed that several clinical and laboratory-based variables were statistically significant for both univariate and multivariate analyses while others were not. With most significant being septic shock (hazard ratio [HR], 4.30; 95% confidence interval [CI], 2.91-6.37), supportive treatment (HR, 3.51; 95% CI, 2.01-6.14), abnormal international normalized ratio (INR) (HR, 3.24; 95% CI, 2.28-4.63), admission to the intensive care unit (ICU) (HR, 3.24; 95% CI, 2.22-4.74), treatment with invasive ventilation (HR, 3.21; 95% CI, 2.15-4.79) and laboratory lymphocytic derangement (HR, 2.79; 95% CI, 1.6-4.86). Machine learning results showed our deep neural network (DNN) (Neo-V) model outperformed all conventional machine learning models with test set accuracy of 99.53%, sensitivity of 89.87%, and specificity of 95.63%; positive predictive value, 50.00%; negative predictive value, 91.05%; and area under the receiver-operator curve of 88.5., Conclusion: Our novel Deep-Neo-V model outperformed all other machine learning models. The model is easy to implement, user friendly and with high accuracy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Lymphoma-associated macrophages (LAMs) are key components in the lymphoma microenvironment, which may impact disease progression and response to therapy. There are two major subtypes of LAMs, CD68+ M1 and CD163+ M2. M2 LAMs can be transformed from M1 LAMs, particularly in certain diffuse large B-cell lymphomas (DLBCL). While mantle cell lymphoma (MCL) is well-known to contain frequent epithelioid macrophages, LAM characterization within MCL has not been fully described. Herein we evaluate the immunophenotypic subclassification, the expression of immune checkpoint molecule PD-L1, and the prognostic impact of LAMs in MCL., Materials and Methods: A total of 82 MCL cases were collected and a tissue microarray block was constructed. Immunohistochemical staining was performed using CD68 and CD163, and the positive cells were recorded manually in four representative 400× fields for each case. Multiplexed quantitative immunofluorescence assays were carried out to determine PD-L1 expression on CD68+ M1 LAMs and CD163+ M2 LAMs. In addition, we assessed Ki67 proliferation rate of MCL by an automated method using the QuPath digital imaging analysis. The cut-off points of optimal separation of overall survival (OS) were analyzed using the X-Tile software, the SPSS version 26 was used to construct survival curves, and the log-rank test was performed to calculate the p -values., Results: MCL had a much higher count of M1 LAMs than M2 LAMs with a CD68:CD163 ratio of 3:1. Both M1 and M2 LAMs were increased in MCL cases with high Ki67 proliferation rates (>30%), in contrast to those with low Ki67 (<30%). Increased number of M1 or M2 LAMs in MCL was associated with an inferior OS. Moreover, high expression of PD-L1 on M1 LAMs had a slightly better OS than the cases with low PD-L1 expression, whereas low expression of PD-L1 on M2 LAMs had a slightly improved OS, although both were not statistically significant., Conclusions: In contrast to DLBCL, MCL had a significantly lower rate of M1 to M2 polarization, and the high levels of M1 and M2 LAMs were associated with poor OS. Furthermore, differential PD-L1 expressions on LAMs may partially explain the different functions of tumor-suppressing or tumor-promoting of M1 and M2 LAMs, respectively., Competing Interests: MX has served in the Seattle Genetics lymphoma advisory board and as a Pure Marrow consultant. DR has served as a consultant, advisor or served on a Scientific Advisory Board for Amgen, Astra Zeneca, Agendia, Biocept, BMS, Cell Signaling Technology, Cepheid, Daiichi Sankyo, GSK, Merck, NanoString, Perkin Elmer, PAIGE, and Ultivue. He has received research funding from Astra Zeneca, Cepheid, Nanostring, Navigate/Novartis, NextCure, Lilly, Ultivue, and Perkin Elmer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Yuan, Ahmed, McHenry, Fu, Yu, Cheng, Xu, Rimm and Pan.)

Purpose: To study the association between gallbladder dimensions and acute cholecystitis and to define a sensitive cutoff for excluding the disease., Materials and Methods: 456 consecutive patients with an abdominal ultrasound performed for right upper quadrant pain, from 1/2019 to 4/2019, were retrospectively collected. Length and width of the gallbladder were measured by a blinded radiology fellow. Patient charts were examined for prospective sonographic findings, clinical data, and pathology from subsequent cholecystectomy or at least 1 month of follow-up with symptom resolution. Univariable and multivariable logistic regression analysis were conducted to define the association of gallbladder dimensions and other sonographic and clinical variables with acute cholecystitis. Optimal and sensitive cutoffs of gallbladder widths were defined. The determined sensitive cutoff was validated with a separate cohort of 501 consecutive patients., Results: 319 patients (median age 48 ± 19 years) including 11%, 19%, and 70% with acute, chronic, and no cholecystitis were included in the experimental cohort, respectively, and 298 patients (median age 50 ± 19 years) including 10%, 12%, and 79% with acute, chronic, and no cholecystitis were included in the validation cohort, respectively. Of all sonographic findings and clinical data, gallbladder width produced the best univariate ROC curve with an AUC of 0.91 (Odds ratio 5.1, 95% CI 3.1-8.5, p < 0.001). 2.2 cm was the gallbladder width cutoff below which there were no cases of acute cholecystitis in the experimental cohort. Multivariable logistic regression analysis using sonographic findings only produced an ROC curve with an AUC of 0.94. Applying the 2.2 cm cutoff in the validation cohort resulted in 100% sensitivity., Conclusion: Lack of gallbladder distention, defined as a width less than 2.2 cm, has potential to serve as a highly sensitive sign for exclusion of acute cholecystitis, regardless of additional sonographic findings and clinical data.

Purpose: We aimed to explore potential confounders of prognostic radiomics signature predicting survival outcomes in clear cell renal cell carcinoma (ccRCC) patients and demonstrate how to control for them., Materials and Methods: Preoperative contrast enhanced abdominal CT scan of ccRCC patients along with pathological grade/stage, gene mutation status, and survival outcomes were retrieved from The Cancer Imaging Archive (TCIA)/The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) database, a publicly available dataset. A semi-automatic segmentation method was applied to segment ccRCC tumors, and 1,160 radiomics features were extracted from each segmented tumor on the CT images. Non-parametric principal component decomposition (PCD) and unsupervised hierarchical clustering were applied to build the radiomics signature models. The factors confounding the radiomics signature were investigated and controlled sequentially. Kaplan-Meier curves and Cox regression analyses were performed to test the association between radiomics signatures and survival outcomes., Results: 183 patients of TCGA-KIRC cohort with available imaging, pathological, and clinical outcomes were included in this study. All 1,160 radiomics features were included in the first radiomics signature. Three additional radiomics signatures were then modelled in successive steps removing redundant radiomics features first, removing radiomics features biased by CT slice thickness second, and removing radiomics features dependent on tumor size third. The final radiomics signature model was the most parsimonious, unbiased by CT slice thickness, and independent of tumor size. This final radiomics signature stratified the cohort into radiomics phenotypes that are different by cancer-specific and recurrence-free survival; HR (95% CI) = 3.0 (1.5-5.7), p <0.05 and HR (95% CI) = 6.6 (3.1-14.1), p <0.05, respectively., Conclusion: Radiomics signature can be confounded by multiple factors, including feature redundancy, image acquisition parameters like slice thickness, and tumor size. Attention to and proper control for these potential confounders are necessary for a reliable and clinically valuable radiomics signature., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lu, Ahmed, Akin, Luk, Guo, Yang, Yoon, Hakimi, Schwartz and Zhao.)

Objectives: To compare tumor best overall response (BOR) by RECIST 1.1 and iRECIST, to explore the incidence of pseudoprogression in melanoma treated with pembrolizumab, and to assess the impact of pseudoprogression on overall survival (OS)., Methods: A total of 221 patients with locally advanced/unresectable melanoma who received pembrolizumab as part of KEYNOTE-002 trial were included in this study. Radiological assessment of imaging was centrally reviewed to assess tumor response. Incidence of discordance in BOR between RECIST 1.1 and iRECIST as well as rate of pseudoprogression were measured. OS of patients with pseudoprogression was compared with that of those with uncontrolled disease., Results: Of the 221 patients in this cohort, 136 patients developed PD as per RECIST v1.1 and 78 patients with PD continued treatment and imaging beyond initial RECIST 1.1-defined PD. Among the 78 patients who continued therapy and imaging post-progression, RECIST 1.1 and iRECIST were discordant in 10 patients (12.8%) and pseudoprogression was encountered in 14 patients (17.9%). OS of patients with pseudoprogression was longer than that of patients with uncontrolled disease/true progression (29.9 months versus 8.0 months, p value < 0.001)., Conclusions: Effectiveness of immunotherapy in clinical trials depends on the criterion used to assess tumor response (RECIST 1.1 vs iRECIST) with iRECIST being more appropriate to detect pseudoprogression and potentially prevent premature termination of effective therapy. Pseudoprogression was associated with improved OS in comparison with that of patients with uncontrolled disease., Key Points: • Discordance between iRECIST and RECIST 1.1 was found in 12.8% of unresectable melanoma patients on pembrolizumab who continued therapy beyond initial RECIST 1.1-defined progression. • Pseudoprogression, captured with iRECIST, occurred in 17.9% and was significantly associated with improved overall survival in comparison with uncontrolled disease.

The anaerobic bacterium Cutibacterium acnes has been increasingly linked to the development of degenerative disc disease (DDD), although causality is yet to be conclusively proven. To better study how this organism could contribute to the aetiology of DDD, improved animal models that are more reflective of human disc anatomy, biology and mechanical properties are required. Against this background, our proof-of concept study aimed to be the first demonstration that C. acnes could be safely administered percutaneously into sheep intervertebral discs (IVDs) for in vivo study. Following our protocol, two sheep were successfully injected with a strain of C. acnes (8.3 × 10 6 CFU/disc) previously recovered from a human degenerative disc. No adverse reactions were noted, and at one-month post inoculation all triplicate infected discs in our first animal grew C. acnes , albeit at a reduced load (5.12 × 10 4 to 6.67 × 10 4 CFU/disc). At six months, no growth was detected in discs from our second animal indicating bacterial clearance. This pilot study has demonstrated the feasibility of safe percutaneous injection of C. acnes into sheep IVDs under fluoroscopic guidance. The design of follow-up sheep studies to investigate the potential of C. acnes to drive pathological changes within infected discs should now be pursued.

Physiological impact of the intermittent or prolonged fasting is known from various studies on healthy subjects. However, data on impact of fasting on biochemical and biometric parameters in people with diabetes is building up. Safety of Ramadan fasting has always been assessed after Ramadan. This study looked into the immediate effect of fasting during the fasting days compared to time before and after the fasting month., Methods: This is an observational study. We looked into people with biometric and biochemical records before Ramadan, and we followed them up during and after Ramadan prospectively. We were aiming for assessing the biochemical and biometric changes for people with diabetes during Ramadan in comparison to pre-and post Ramadan. As well as the differences between these measures according to type and treatment of diabetes in those who fasted as well as in those who did not fast during Ramadan., Results: Total of 342 patients were recruited to the study. All were patients with diabetes at a mild to moderate risk of complications if fasted. Majority were males 52.3% (n = 180), while females were 47.7% (n = 162). Most of the results showed a U shape between Pre-Ramadan, During Ramadan and Post-Ramadan periods. there was a modest but significant reduction in weight but regained after Ramadan., Conclusions: Our study suggests that for many people with diabetes fasting is not associated with an increased risk to their glycemic control, their weight and/or their blood pressure. Indeed, what is seen is marginal benefit or no change in all parameters. This stratifies the ongoing recommendation that allows patients with categorized as low risk to fast Ramadan or non-Ramadan days whenever desired., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)