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The BioFire® FilmArray® meningitis/encephalitis (FA/ME) panel provides rapid testing for common cerebrospinal fluid pathogens. We compared empiric antibiotic utilization between patients with suspected community-acquired meningitis with and without an FA/ME panel ordered. No significant differences in antibiotic use were found.

Background: Although the association between acute kidney injury and heart failure has recently become understood, the patient’s recognition of this relationship is still deficient. The least impact of heart failure on kidney functioning may attributed to promoted patient perception and self-care. Aims: To identify the impact of heart failure nurse-led education on the perception and self-care behaviours of heart failure patients suffering from acute kidney injury. Methods: A pre-test-post-test intervention design was implemented. Perception of cardio-renal disease and self-care behaviours were assessed before and after conducting a brief nurse-led educational program focusing on self-care management for heart failure and its association with renal disease using the “Visual Learners” learning model. Results: A total of fifty patients completed the study. The mean age of the patients was 51.16 years, and 58.0 % were males. The pre-test assessment revealed a moderate deficit in perception and self-care behaviours. However, education improved patients’ perception (t: 3.65, df: 49, SE: 0.34, p

While mentors can learn general strategies for effective mentoring, existing mentorship curricula do not comprehensively address how to support marginalized mentees, including LGBTQIA+ mentees. After identifying best mentoring practices and existing evidence-based curricula, we adapted these to create the Harvard Sexual and Gender Minority Health Mentoring Program. The primary goal was to address the needs of underrepresented health professionals in two overlapping groups: (1) LGBTQIA+ mentees and (2) any mentees focused on LGBTQIA+ health. An inaugural cohort (N = 12) of early-, mid-, and late-career faculty piloted this curriculum in spring 2022 during six 90-minute sessions. We evaluated the program using confidential surveys after each session and at the program’s conclusion as well as with focus groups. Faculty were highly satisfied with the program and reported skill gains and behavioral changes. Our findings suggest this novel curriculum can effectively prepare mentors to support mentees with identities different from their own; the whole curriculum, or parts, could be integrated into other trainings to enhance inclusive mentoring. Our adaptations are also a model for how mentorship curricula can be tailored to a particular focus (i.e., LGBTQIA+ health). Ideally, such mentor trainings can help create more inclusive environments throughout academic medicine.

ABSTRACT Early COVID-19 convalescent plasma (CCP) transfusion to outpatients with COVID-19 decreases progression to hospitalization, but the mechanism of how CCP reduces severity is unknown. Among 882 COVID-19 participants transfused with CCP or control plasma in a randomized controlled trial, 21 cytokines and chemokines were measured using electrochemiluminescence assays. Wilcoxon rank sum tests were used to evaluate the difference between early (transfused within 5 days of symptom onset) CCP vs early control plasma and late (transfused 6–9 days after symptom onset) CCP vs late control plasma at each visit. Linear mixed-effect models were used to assess the difference in the slope of cytokine change. Median cytokine and chemokine levels were similar between the early CCP and early control groups pre-transfusion. At the day 14 visit, only the median IL-6 (P = 0.014) and IL-16 (P = 0.036) levels were lower in the early CCP group compared to the early control group, but these differences were not statistically significant after correcting for multiple comparisons (requiring P < 0.0024). IL-6 levels decreased significantly faster in the early CCP group from screening to the day 14 visit compared to the early control group (P < 0.001). No difference was observed in the slope of cytokine change from screening to day 90 between early CCP and early control groups. Late control and late CCP arms showed similar cytokine and chemokine levels through study follow-up. One mechanism by which early CCP transfusion reduces hospitalization may be by decreasing IL-6 levels, as the reduction is associated with better recovery from COVID-19. IMPORTANCE This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Introduction: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are cardioprotective, and canagliflozin (CANA), an SGLT2i, has been shown to improve perfusion, AMPK signaling, and oxidative stress in chronically ischemic myocardium. The aim of this study is to determine the effects of CANA in nonischemic myocardium on coronary collateralization, oxidative stress, and other molecular pathways determined by proteomic profiling. Methods: Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery. Two weeks later, pigs received no drug (CON, n = 8) or 300 mg CANA daily (n = 8). Treatment continued for five weeks, followed by tissue harvest of nonischemic myocardium. Results: CANA was associated with decreased capillary density (p = 0.05) compared to CON, without changes in arteriolar density. Reduced capillary density did not correlate with reduced perfusion. Oxidative stress was reduced with CANA (22 % decrease). In the CANA group, there was a trend towards increased p-eNOS and eNOS, without a change in p-eNOS/eNOS ratio, p-Akt, Akt, and p-Akt/Akt ratio. There was no change in p-ERK1/2, but a decrease in total ERK1/2 and increase in p-ERK1/2/ERK1/2 ratio. There were no changes in expression of p-AMPK, AMPK, with a trend towards increased ratio of p-AMPK/AMPK. Proteomics analysis identified 2819 common proteins, of which 120 were upregulated and 425 were downregulated with CANA. Pathway analysis demonstrated wide regulation of metabolic proteins. Conclusions: The effects of CANA on myocardial perfusion and AMPK signaling in chronically ischemic myocardium are not found in nonischemic territory, despite attenuation of oxidative stress. Metabolic proteins are widely regulated in nonischemic myocardium with CANA.

We consider Melvin-like cosmological and static solutions for the theories of N=2, D=4 supergravity coupled to vector multiplets. We analyze the equations of motion and give some explicit solutions with one scalar and two gauge fields. Generalized Melvin solutions with four charges are also constructed for an embedding of a truncated N=8 supergravity theory. Our results are then extended to supergravity theories with the scalar manifolds SL(N,R)/SO(N,R). It is shown that solutions with N charges only exist for N=8, 6 and 5 corresponding to theories with space-time dimensions D=4, 5 and 7.

Background: Contribution of host factors in mediating susceptibility to extrapulmonary tuberculosis is not well understood. Objective: To examine the influence of patient sex on anatomical localization of extrapulmonary tuberculosis. Methods: We conducted a retrospective cross-sectional study in Mali, West Africa. Hospital records of 1,304 suspected cases of extrapulmonary tuberculosis, available in TB Registry of a tertiary tuberculosis referral center from 2019 to 2021, were examined. Results: A total of 1,012 (77.6%) were confirmed to have extrapulmonary tuberculosis with a male to female ratio of 1.59:1. Four clinical forms of EPTB predominated, namely pleural (40.4%), osteoarticular (29.8%), lymph node (12.5%), and abdominal TB (10.3%). We found sex-based differences in anatomical localization of extrapulmonary tuberculosis, with males more likely than females to have pleural TB (OR: 1.51; 95% CI [1.16 to 1.98]). Conversely, being male was associated with 43% and 41% lower odds of having lymph node and abdominal TB, respectively (OR: 0.57 and 0.59). Conclusion: Anatomical sites of extrapulmonary tuberculosis differ by sex with pleural TB being associated with male sex while lymph node and abdominal TB are predominately associated with female sex. Future studies are warranted to understand the role of sex in mediating anatomical site preference of tuberculosis.

The escalating environmental alterations have precipitated a transition towards renewable energy sources. Concurrently, recent technological advancements, such as big data and artificial intelligence, have fundamentally altered the landscape of decision-making processes. Consequently, this research endeavors to assess the impact of integrating big data and AI on the economic feasibility of solar microgrids in the rural context of Jordan. Furthermore, the study investigates several mediating factors, including adoption rates, costs, economic benefits, decision-making processes, investments, and community acceptance. The data were gathered from 250 professionals involved in solar microgrid initiatives, utilizing a quantitative deductive approach and employing questionnaires as the primary data collection tool. Subsequently, the collected data underwent statistical analysis through SPSS and PLS-SEM. The findings of the study indicate a positive and significant influence of big data and AI integration on adoption rates, costs, economic benefits, decision-making processes, investments, and community acceptance. Moreover, the results suggest that economic benefits are influenced by adoption rates, costs, economic benefits, decision-making processes, investments, and community acceptance. Importantly, all identified mediation paths were found to be statistically significant. These outcomes underscore the potential of big data and AI integration to enhance decision-making processes in favour of adopting solar microgrids by providing crucial insights into their benefits. The study concludes with a discussion on research limitations and outlines potential directions for future investigations.

Introduction Cognitive dysfunction, a leading cause of mortality and morbidity in the USA and globally, has been shown to disproportionately affect the socioeconomically disadvantaged and those who identify as black or Hispanic/Latinx. Poor sleep is strongly associated with the development of vascular and metabolic diseases, which correlate with cognitive dysfunction. Therefore, sleep may contribute to observed disparities in cognitive disorders. The Epidemiologic Study of Disparities in Sleep and Cognition in Older Adults (DISCO) is a longitudinal, observational cohort study that focuses on gathering data to better understand racial/ethnic sleep disparities and illuminate the relationship among sleep, race and ethnicity and changes in cognitive function. This investigation may help inform targeted interventions to minimise disparities in cognitive health among ageing adults.Methods and analysis The DISCO study will examine up to 495 individuals aged 55 and older at two time points over 24 months. An equal number of black, white and Hispanic/Latinx individuals will be recruited using methods aimed for adults traditionally under-represented in research. Study procedures at each time point will include cognitive tests, gait speed measurement, wrist actigraphy, a type 2 home polysomnography and a clinical examination. Participants will also complete self-identified assessments and questionnaires on cognitive ability, sleep, medication use, quality of life, sociodemographic characteristics, diet, substance use, and psychological and social health.Ethics and dissemination This study was approved by the Northwestern University Feinberg School of Medicine Institutional Review Board. Deidentified datasets will be shared via the BioLINCC repository following the completion of the project. Biospecimen samples from the study that are not being analysed can be made available to qualified investigators on review and approval by study investigators. Requests that do not lead to participant burden or that conflict with the primary aims of the study will be reviewed by the study investigators.

Abstract Background There is an urgent need for active safety surveillance to monitor vaccine exposure during pregnancy in low- and middle-income countries (LMICs). Existing maternal, newborn, and child health (MNCH) data collection systems could serve as platforms for post-marketing active surveillance of maternal immunization safety. To identify sites using existing systems, a thorough assessment should be conducted. Therefore, this study had the objectives to first develop an assessment tool and then to pilot this tool in sites using MNCH data collection systems through virtual informant interviews. Methods We conducted a rapid review of the literature to identify frameworks on population health or post-marketing drug surveillance. Four frameworks that met the eligibility criteria were identified and served to develop an assessment tool capable of evaluating sites that could support active monitoring of vaccine safety during pregnancy. We conducted semi-structured interviews in six geographical sites using MNCH data collection systems (DHIS2, INDEPTH, and GNMNHR) to pilot domains included in the assessment tool. Results We developed and piloted the “VPASS (Vaccines during Pregnancy – sites supporting Active Safety Surveillance) assessment tool” through interviews with nine stakeholders, including central-level systems key informants and site-level managers from DHIS2 and GNMNHR; DHIS2 in Kampala (Uganda) and Kigali (Rwanda); GNMNHR from Belagavi (India) and Lusaka (Zambia); and INDEPTH from Nanoro (Burkina Faso) and Manhica (Mozambique). The tool includes different domains such as the system’s purpose, the scale of implementation, data capture and confidentiality, type of data collected, the capability of integration with other platforms, data management policies and data quality monitoring. Similarities among sites were found regarding some domains, such as data confidentiality, data management policies, and data quality monitoring. Four of the six sites met some domains to be eligible as potential sites for active surveillance of vaccinations during pregnancy, such as a routine collection of MNCH individual data and the capability of electronically integrating individual MNCH outcomes with information related to vaccine exposure during pregnancy. Those sites were: Rwanda (DHIS2), Manhica (IN-DEPTH), Lusaka (GNMNHR), and Belagavi (GNMNHR). Conclusion This study's findings should inform the successful implementation of active safety surveillance of vaccines during pregnancy by identifying and using active individual MNCH data collection systems in LMICs.

Abstract Background Stroke is the most common acquired neurological disease in the adult population worldwide with an incidence of 16 million new cases every year responsible for about 6.1 million deaths and 130.6 million disability-adjusted life-years (DALYs). The objectives of this work were to study the level of stroke awareness and the proper response for suspected stroke patients in urban and rural areas of Tanta City, Egypt. The study was conducted on 1869 Egyptian Citizens; 908 and 961 reside in urban and rural areas, respectively, who were submitted to a face-to-face interview using the stroke awareness questionnaire (Arabic version). Results Rural participants showed a significant reduction in acute cerebrovascular stroke (CVS) awareness and knowledge including the most affected organ by CVS, what are the risk factors, what are the early stroke symptoms, is there specific treatment for acute ischemic stroke, and what is the proper reaction when confronted with a case of acute CVS? Conclusion Urban populations have better recognition of stroke risk factors, early stroke symptoms, and the proper response when confronted with a case of acute CVS when compared with rural people possibly due to better socioeconomic status and higher educational levels.

Abstract Background Poisoning is a major health problem especially in developing countries and leads to high morbidity and mortality. Aim To identify the profile of acute poisoning in the Toxicology Unit at Tanta University Hospital, Egypt (2017-2021). Methods A cross-sectional study using data extracted from medical records from beginning of January 2017 to end of December 2021. Data including demographic data, Glasgow coma scale, type of poisons, manner of poisoning, time of admission and discharge and state at discharge. Results This study included 9713 cases. Rodenticides represented the most frequent cause of poisoning among both males (30%) and females (27%). Pharmaceutical drugs, CNS abused pharmaceutical drugs, and chemicals represent the most common categories (24%, 22%, and 21%, respectively) among children (up to 12 years). Rodenticides and pharmaceutical drugs represent the highest categories among other age groups. Evening admissions represented 52% of cases. Glasgow coma scale was 15 among 86.3% of cases. Intentional poisoning was more common than accidental poisoning (58.6% and 34.7%, respectively). One half (52.2%) of the admitted cases were discharged within 24 hours of admission and 44.4% of them were discharged after 48-72 hours. Family request was the main reason of discharge of cases (70.3%), 15.7% were improved, 4% died. Mortality by rodenticide was 12.5%. Conclusion Rodenticides, pharmaceutical and CNS abused pharmaceutical drugs were the most common categories of poisoning. Intentional poisoning was more common than accidental poisoning. Rodenticides were responsible for most deaths.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic that has infected over 36 million and killed over 1 million people. Informed implementation of government public health policies depends on accurate data on SARS-CoV-2 immunity at a population scale. We hypothesized that detection of SARS-CoV-2 salivary antibodies could serve as a noninvasive alternative to serological testing for monitoring of SARS-CoV-2 infection and seropositivity at a population scale. We developed a multiplex SARS-CoV-2 antibody immunoassay based on Luminex technology that comprised 12 CoV antigens, mostly derived from SARS-CoV-2 nucleocapsid (N) and spike (S). Saliva and sera collected from confirmed coronavirus disease 2019 (COVID-19) cases and from the pre-COVID-19 era were tested for IgG, IgA, and IgM to the antigen panel. Matched saliva and serum IgG responses (n = 28) were significantly correlated. The salivary anti-N IgG response resulted in the highest sensitivity (100%), exhibiting a positive response in 24/24 reverse transcription-PCR (RT-PCR)-confirmed COVID-19 cases sampled at >14 days post-symptom onset (DPSO), whereas the salivary anti-receptor binding domain (RBD) IgG response yielded 100% specificity. Temporal kinetics of IgG in saliva were consistent with those observed in blood and indicated that most individuals seroconvert at around 10 DPSO. Algorithms employing a combination of the IgG responses to N and S antigens result in high diagnostic accuracy (100%) by as early as 10 DPSO. These results support the use of saliva-based antibody testing as a noninvasive and scalable alternative to blood-based antibody testing.

Changes to the DSM-5's conceptualization of posttraumatic stress disorder (PTSD) highlight the importance of impulsivity within the context of PTSD-related arousal dysregulation. While the relationship between PTSD and threat sensitivity is well defined, how they relate to impulsivity remains understudied. We examined the relationship between PTSD symptom severity, threat sensitivity, and impulsivity. 124 participants completed the PTSD Checklist (PCL-C) and the Barratt Impulsiveness Scale 11th ed (BIS-11). BIS-11 items were separated to define cognitive and behavioral impulsivity subdomains. A trauma-exposed subsample of 39 participants were also exposed to no, ambiguous, and high threat conditions in a threat-enhanced acoustic startle paradigm with psychophysiological response as the outcome variable. PTSD severity was significantly associated with greater overall impulsivity and behavioral impulsivity. Greater overall impulsivity and both cognitive and behavioral impulsivity subdomains were significantly associated with psychophysiological magnitudes across threat conditions in the traumatized subsample. Our results suggest PTSD severity may linked to behavioral impulsivity and both cognitive and behavioral impulsivity are associated with threat sensitivity and hyperarousal. Assessing impulsivity within the context of PTSD, particularly in terms of its cognitive and behavioral subdomains, may provide important, clinically relevant information.

Epstein–Barr virus (EBV), a Herpesviridae family member, is associated with an increased risk of autoimmune disease development in the host. We previously demonstrated that EBV DNA elevates levels of the pro-inflammatory cytokine IL-17A and that inhibiting Toll-like receptor (TLR) 3, 7, or 9 reduces its levels. Moreover, this DNA exacerbated colitis in a mouse model of inflammatory bowel disease (IBD). In the study at hand, we examined whether inhibition of TLR3, 7, or 9 alleviates this exacerbation. Mice were fed 1.5% dextran sulfate sodium (DSS) water and administered EBV DNA. Then, they were treated with a TLR3, 7, or 9 inhibitor or left untreated. We also assessed the additive impact of combined inhibition of all three receptors. Mice that received DSS, EBV DNA, and each inhibitor alone, or a combination of inhibitors, showed significant improvement. They also had a decrease in the numbers of the pathogenic colonic IL-17A+IFN-γ+ foci. Inhibition of all three endosomal TLR receptors offered no additive benefit over administering a single inhibitor. Therefore, inhibition of endosomal TLRs reduces EBV DNA exacerbation of mouse colitis, offering a potential approach for managing IBD patients infected with EBV.

Cancers and neurological disorders are two major types of diseases in humans. We developed the concept called the “Aberrant Cell Cycle Disease (ACCD)” due to the accumulating evidence that shows that two different diseases share the common mechanism of aberrant cell cycle re-entry. The aberrant cell cycle re-entry is manifested as kinase/oncoprotein activation and tumor suppressor (TS) inactivation, which are associated with both tumor growth in cancers and neuronal death in neurological disorders. Therefore, some cancer therapies (e.g., kinase/oncogene inhibition and TS elevation) can be leveraged for neurological treatments. MicroRNA (miR/miRNA) provides a new style of drug-target binding. For example, a single tumor suppressor miRNA (TS-miR/miRNA) can bind to and decrease tens of target kinases/oncogenes, producing much more robust efficacy to block cell cycle re-entry than inhibiting a single kinase/oncogene. In this review, we summarize the miRNAs that are altered in both cancers and neurological disorders, with an emphasis on miRNA drugs that have entered into clinical trials for neurological treatment.

SARS-CoV-2 infection during pregnancy is associated with severe COVID-19 and adverse fetal outcomes, but the underlying mechanisms remain poorly understood. Moreover, clinical studies assessing therapeutics against SARS-CoV-2 in pregnancy are limited. To address these gaps, we developed a mouse model of SARS-CoV-2 infection during pregnancy. Outbred CD1 mice were infected at E6, E10, or E16 with a mouse-adapted SARS-CoV-2 (maSCV2) virus. Outcomes were gestational age–dependent, with greater morbidity, reduced antiviral immunity, greater viral titers, and impaired fetal growth and neurodevelopment occurring with infection at E16 (third trimester equivalent) than with infection at either E6 (first trimester equivalent) or E10 (second trimester equivalent). To assess the efficacy of ritonavir-boosted nirmatrelvir, which is recommended for individuals who are pregnant with COVID-19, we treated E16-infected dams with mouse-equivalent doses of nirmatrelvir and ritonavir. Treatment reduced pulmonary viral titers, decreased maternal morbidity, and prevented offspring growth restriction and neurodevelopmental impairments. Our results highlight that severe COVID-19 during pregnancy and fetal growth restriction is associated with heightened virus replication in maternal lungs. Ritonavir-boosted nirmatrelvir mitigated maternal morbidity along with fetal growth and neurodevelopment restriction after SARS-CoV-2 infection. These findings prompt the need for further consideration of pregnancy in preclinical and clinical studies of therapeutics against viral infections.

Post-COVID conditions (PCCs) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about treatment, inflammation, and PCC. Among 882 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of COVID-19 convalescent plasma (CCP) vs control plasma with available biospecimens and symptom data, the association between early CCP treatment, cytokine levels, and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14, and day 90 using a multiplexed sandwich immunoassay (Meso Scale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. Associations between CCP treatment, cytokine levels, and PCC were examined using multivariate logistic regression models. One third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and anosmia (14.5%) being most common. Cytokine levels decreased from baseline to day 90. In a multivariable analysis, female sex (adjusted odds ratio [AOR] = 2.69 [1.93–3.81]), older age (AOR = 1.32 [1.17–1.50]), and elevated baseline levels of IL-6 (AOR = 1.59 [1.02–2.47]) were independently associated with development of PCC. Those who received early CCP treatment (≤5 days after symptom onset) compared to late CCP treatment had statistically significant lower odds of PCC. IMPORTANCE Approximately 20% of individuals infected with SARS-CoV-2 experienced long-term health effects, as defined PCC. However, it is unknown if there are any early biomarkers associated with PCC or whether early intervention treatments may decrease the risk of PCC. In a secondary analysis of a randomized clinical trial, this study demonstrates that among outpatients with SARS-CoV-2, increased IL-6 at time of infection is associated with increased odds of PCC. In addition, among individuals treated early, within 5 days of symptom onset, with COVID-19 convalescent plasma, there was a trend for decreased odds of PCC after adjusting for other demographic and clinical characteristics. Future treatment studies should be considered to evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.

Objective: To identify the tobacco effect on flexural properties and the microhardness of three acrylic resins. Material and Methods: Three resins were tested: two thermo-polymerizable acrylic resins (RMB 20 and BMS 014) and one autopolymerized acrylic resin. The 3-point bending and microhardness tests were carried out with a universal tensile-compression machine and a micro-Vickers hardness tester. The acrylic resin specimens have been exposed for 21 days to cigarette smoke in a smoking room. Their mechanical strength was compared to unexposed samples. Statistical analysis was performed using the data processing software SPSS Statistics 21.0. Results: The flexural properties of the resins were affected by cigarette smoke only in the case of Major Base 20® (drop in strength with p= 0.02; 0.6; 0.7 and in elastic modulus with p= 0.86; 0.74 and 0.85 for Major Base 20®, BMS 014® and Major Repair®). The cigarette smoke affected significantly microhardness for all groups (p

Patients with inflammatory arthritis (IA) are at increased risk of severe COVID-19 due to medication-induced immunosuppression that impairs host defenses. The aim of this study was to assess antibody and B cell responses to COVID-19 mRNA vaccination in IA patients receiving immunomodulatory therapies. Adults with IA were enrolled through the Johns Hopkins Arthritis Center and compared with healthy controls (HC). Paired plasma and peripheral blood mononuclear cell (PBMC) samples were collected prior to and 30 days or 6 months following the first two doses of mRNA vaccines (D2; HC=77 and IA=31 patients), or 30 days following a third dose of mRNA vaccines (D3; HC=11 and IA=96 patients). Neutralizing antibody titers, total binding antibody titers, and B cell responses to vaccine and Omicron variants were analyzed. Anti-Spike (S) IgG and S-specific B cells developed appropriately in most IA patients following D3, with reduced responses to Omicron variants, and negligible effects of medication type or drug withholding. Neutralizing antibody responses were lower compared to healthy controls after both D2 and D3, with a small number of individuals demonstrating persistently undetectable neutralizing antibody levels. Most IA patients respond as well to mRNA COVID-19 vaccines as immunocompetent individuals by the third dose, with no evidence of improved responses following medication withholding. These data suggest that IA-associated immune impairment may not hinder immunity to COVID-19 mRNA vaccines in most individuals.

Summary: Bacillus Calmette-Guérin (BCG) confers heterologous immune protection against viral infections and has been proposed as vaccine against SARS-CoV-2 (SCV2). Here, we tested intravenous BCG vaccination against COVID-19 using the golden Syrian hamster model. BCG vaccination conferred a modest reduction on lung SCV2 viral load, bronchopneumonia scores, and weight loss, accompanied by a reversal of SCV2-mediated T cell lymphopenia, and reduced lung granulocytes. BCG uniquely recruited immunoglobulin-producing plasma cells to the lung suggesting accelerated local antibody production. BCG vaccination also recruited elevated levels of Th1, Th17, Treg, CTLs, and Tmem cells, with a transcriptional shift away from exhaustion markers and toward antigen presentation and repair. Similarly, BCG enhanced recruitment of alveolar macrophages and reduced key interstitial macrophage subsets, that show reduced IFN-associated gene expression. Our observations indicate that BCG vaccination protects against SCV2 immunopathology by promoting early lung immunoglobulin production and immunotolerizing transcriptional patterns among key myeloid and lymphoid populations.

Patients with triple-negative breast cancer remain at risk for metastatic disease despite treatment. The acquisition of chemoresistance is a major cause of tumor relapse and death, but the mechanisms are far from understood. We have demonstrated that breast cancer cells (BCCs) can engulf mesenchymal stem/stromal cells (MSCs), leading to enhanced dissemination. Here, we show that clinical samples of primary invasive carcinoma and chemoresistant breast cancer metastasis contain a unique hybrid cancer cell population coexpressing pancytokeratin and the MSC marker fibroblast activation protein-α. We show that hybrid cells form in primary tumors and that they promote breast cancer metastasis and chemoresistance. Using single-cell microfluidics and in vivo models, we found that there are polyploid senescent cells within the hybrid cell population that contribute to metastatic dissemination. Our data reveal that Wnt Family Member 5A (WNT5A) plays a crucial role in supporting the chemoresistance properties of hybrid cells. Furthermore, we identified that WNT5A mediates hybrid cell formation through a phagocytosis-like mechanism that requires BCC-derived IL-6 and MSC-derived C-C Motif Chemokine Ligand 2. These findings reveal hybrid cell formation as a mechanism of chemoresistance and suggest that interrupting this mechanism may be a strategy in overcoming breast cancer drug resistance.

B. anthracis is one of the most often weaponized pathogens. States had it in their bioweapons programs and criminals and terrorists have used or attempted to use it. This study is motivated by the narrative that emerging and developing technologies today contribute to the amplification of danger through greater easiness, accessibility and affordability of steps in the making of an anthrax weapon. As states would have way better preconditions if they would decide for an offensive bioweapons program, we focus on bioterrorism. This paper analyzes and assesses the possible bioterrorism threat arising from advances in synthetic biology, genome editing, information availability, and other emerging, and converging sciences and enabling technologies. Methodologically we apply foresight methods to encourage the analysis of contemporary technological advances. We have developed a conceptual six-step foresight science framework approach. It represents a synthesis of various foresight methodologies including literature review, elements of horizon scanning, trend impact analysis, red team exercise, and free flow open-ended discussions. Our results show a significant shift in the threat landscape. Increasing affordability, widespread distribution, efficiency, as well as ease of use of DNA synthesis, and rapid advances in genome-editing and synthetic genomic technologies lead to an ever-growing number and types of actors who could potentially weaponize B. anthracis. Understanding the current and future capabilities of these technologies and their potential for misuse critically shapes the current and future threat landscape and underlines the necessary adaptation of biosecurity measures in the spheres of multi-level political decision making and in the science community.

Hypnotic medications can adversely affect behavior during unanticipated awakenings during the night. Animals treated with the hypocretin (Hcrt) receptor antagonist almorexant (ALM) have less acute cognitive impairment compared to the GABAA receptor modulator zolpidem (ZOL). This study aimed to determine whether ALM produces less acute cognitive impairment than ZOL in human subjects. Healthy, young adult, unmedicated male and female subjects participated in a controlled trial of a single dose of ALM 100 mg (N = 48), ALM 200 mg (N = 53), ZOL 10 mg (N = 49), and placebo (PBO, N = 52). ZOL and both doses of ALM produced similar levels of subjective sleepiness and impaired the ability of subjects to remain awake in a dark, low-stimulus setting relative to PBO. For most cognitive measures, performance under ZOL was significantly worse than ALM or PBO. For tasks involving verbal memory or visual-motor coordination, ZOL impaired performance, whereas the two doses of ALM were no different than PBO. For tasks involving higher-order executive function, ZOL produced impairment in processing speed and inhibitory control, whereas the two doses of ALM were no different than PBO. Performance decrements for ALM were less than ZOL but greater than PBO for some reaction time measures. The data provide support for the hypothesis that Hcrt receptor antagonists produce less functional impairment than a benzodiazepine receptor agonist (BzRA). These observations are particularly relevant to patients treated with sedative-hypnotics who are at elevated risk for falls and other untoward events during the intended hours for sleep.

Severe outcomes and death from the novel coronavirus disease 2019 (COVID-19) appear to be characterized by an exaggerated immune response with hypercytokinemia leading to inflammatory infiltration of the lungs and acute respiratory distress syndrome. Risk of severe COVID-19 outcomes is consistently lower in women than men worldwide, suggesting that female biological sex is instrumental in protection. This mini-review discusses the immunomodulatory and anti-inflammatory actions of high physiological concentrations of the steroids 17β-estradiol (E2) and progesterone (P4). We review how E2 and P4 favor a state of decreased innate immune inflammatory response while enhancing immune tolerance and antibody production. We discuss how the combination of E2 and P4 may improve the immune dysregulation that leads to the COVID-19 cytokine storm. It is intended to stimulate novel consideration of the biological forces that are protective in women compared to men, and to therapeutically harness these factors to mitigate COVID-19 morbidity and mortality.

Study objectivesOur objective was to examine the ability of a consumer-grade wearable device (Basis B1) with accelerometer and heart rate technology to assess sleep patterns compared with polysomnography (PSG) and research-grade actigraphy in healthy adults.MethodsEighteen adults underwent consecutive nights of sleep monitoring using Basis B1, actigraphy, and PSG; 40 nights were used in analyses. Discrepancies in gross sleep parameters and epoch-by-epoch agreements in sleep/wake classification were assessed.ResultsBasis B1 accuracy was 54.20 ± 8.20%, sensitivity was 98.90 ± 2.70%, and specificity was 8.10 ± 15.00%. Accuracy, sensitivity, and specificity for distinguishing between the different sleep stages were 60-72%, 48-62%, and 57-86%, respectively. Pearson correlations demonstrated strong associations between Basis B1 and PSG estimates of sleep onset latency and total sleep time; moderate associations for sleep efficiency, duration of light sleep, and duration of rapid eye movement sleep; and a weak association for duration of deep sleep. Basis B1 significantly overestimates total sleep time, sleep efficiency, and duration of light sleep and significantly underestimates wake after sleep onset and duration of deep sleep.ConclusionsBasis B1 demonstrated utility for estimates of gross sleep parameters and performed similarly to actigraphy for estimates of total sleep time. Basis B1 specificity was poor, and Basis B1 is not useful for the assessment of wake. Basis B1 accuracy for sleep stages was better than chance but is not a suitable replacement for PSG assessment. Despite low cost, ease of use, and attractiveness for patients, consumer devices are not yet accurate or reliable enough to guide treatment decision making in clinical settings.

After exposure to a traumatic event, a subset of people develop post-traumatic stress disorder (PTSD). One of the key deficits in PTSD is regulation of fear, and impaired inhibition of fear-potentiated startle (FPS) has been identified as a potential physiological biomarker specific to PTSD. As part of a larger clinical trial, this study investigated the effects of a CRF receptor 1 antagonist, GSK561679, on inhibition of fear-potentiated startle during a conditional discrimination fear-conditioning paradigm, termed AX+/BX-. Prior research using this paradigm has demonstrated deficits in inhibition of conditioned fear in several PTSD populations. The randomized, double-blind, placebo-controlled clinical trial compared fear inhibition between female PTSD participants taking 350 mg/day GSK561679 (n = 47 pre- and 29 post-treatment) and patients taking a placebo pill (n = 52 pre- and 30 post-treatment) daily for 6 weeks. There was no significant difference between the two groups in their acquisition of fear or discrimination between threat and safety cues, and no pre-post-treatment effect on these measures. However, there was a significant effect of treatment on inhibition of FPS during the AB trials in the AX+/BX- transfer test (p

Background: To determine KRAS gene in circulating tumor DNA in comparison with histological grading through liquid biopsy in colorectal cancer patients. Methods: This dual-centered cross-sectional study included 73 diagnosed patients of colorectal cancer at different grading levels [Grade I, well differentiated (n = 7, 9.5%); Grade II, moderately differentiated (n = 14,18.9%); and Grade III, poorly differentiated (n = 52, 70%)]. Blood was collected, and plasma was separated. ctDNA was extracted, using magnetic bead-based technique (MagMAX Cell-Free DNA kit). KRAS gene was quantified through qPCR. STRING database was used to find KRAS interactomes. Results: Mean threshold cycle (CT value) of KRAS gene in Grade III samples showed significantly higher (P = 0.001) levels of ctDNA (2.7 ± 1.14) compared with Grade II and Grade I (3.1 ± 0.68, 2.3 ± 0.60), respectively. Grading characterization showed that rectal cancer (n = 22, 42.3%) with Grade III (68.8%) was more prevalent than colon and sigmoid cancer (n = 19, 36.5%, n = 11, 21%, respectively). STRING database showed 10 functional genes interacting with KRAS expressed as gene/proteins. Conclusion: Liquid biopsy can be used to detect ctDNA in plasma of CRC patients and enabled to detect the KRAS gene by qPCR. The technique being less invasive and cost-effective is convenient for multiple biopsies in different cancers.

Background: Periodontitis causes the destruction of soft and hard tissues. Stem cells have immense potential in regenerative cellular therapy. This clinical trial aimed to evaluate clinically and radiographically the effectiveness of the local application of Edelweiss stem cells as a nonsurgical treatment for stage III periodontitis. Materials and Methods: The trial included 40 periodontal pockets in participants who have stage III periodontitis with probing pocket depth (PPD) ≥5 mm and clinical attachment loss (CAL) ≥5 mm. Pockets were randomly divided into two groups Group 1: was given oral hygiene instruction, scaling, root planing, and subgingival application of plant stem cells on gel foam carrier after that a periodontal dressing was applied. The procedures were repeated after 2 weeks. Group 2: was treated only by scaling and root planing. Gingival index, CAL, and PPD were measured at baseline and 3 months' posttherapy. The radiographical evaluation was done by digital long-cone parallel periapical radiographs at baseline and 6 months posttherapy. Results: Clinical parameters for both groups showed a statistically significant improvement. Regarding radiographic evaluation, there was a significant increase in bone density in favor of the study group. Conclusions: Locally applied Edelweiss stem cells can be considered a promising nonsurgical treatment modality for periodontal regeneration.

Validation measurements for the Future Railway Communication System in railway environments is a very challenging task and should be reduced to a minimum for cost and time efficiency. “Zero-on-site testing” consists of using simulation/emulation tools and testing procedures to allow validation and verification activities in the laboratory to avoid complex and expensive trials with trains on real-world sites. A solution to test a communication network in a laboratory under realistic conditions consists of injecting perturbations at the IP level (such as additional delay, packet losses, or jitters). It is essential to correlate the IP impairments with the radio environment, their effects on end-to-end transmission, and how the network and its elements react. To do so, IP impairments (or the conditions that lead to them) should be generated in such a way that allows assessing their impact on the performance of transmissions. This paper presents the results of an experimental research based on an original emulation platform (Emulradio4Rail platform), able to emulate and test wireless systems taking into account both physical layer as well as IP traffic in realistic railway environments. Different types of IP traffics are injected at the application layer and go through the platform. The work aimed at extracting various statistical distributions of classical IP metrics (delay, packet loss, jitter, throughput) versus time, as a function of radio channel conditions for Wi-Fi and LTE transmissions in typical railway environments. Then, the modeled IP impairments statistical distributions can be considered at the IP level to test very easily wireless system modems. The results and methodology can be considered for the evaluation of the Future Railway Mobile Communication System modems.

Abstract The light-slowing effect near band endpoints is frequently exploited in photonic crystals to enhance the optical transmittance. In a one-dimensional binary photonic crystal (1DPC) made of hyperbolic metamaterials (HMMs), we theoretically examined the angle-dependent omnidirectional photonic bandgap (PBG) for TM polarization. Using the transfer matrix approach, the optical characteristics of the 1DPC structure having dielectric and HMM layers were examined at the infrared range (IR). As such, we observed the existing of numerous PBGs in this operating wavelength range (IR). Meanwhile, the HMM layer is engineered by the subwavelength dielectric- nanocomposite multilayers. The filling fraction of nanoparticles have been explored to show how they affect the effective permittivity of the HMM layer. Furthermore, the transmittance properties of the suggested structure are investigated at various incident angles for transverse magnetic (TM) and transverse electric polarizations. Other parameters such as, the permittivity of the host material, the filling fraction of nanoparticles, and the thickness of the second layer (HMM) are also taken into account. Finally, we investigated the effect of these parameters on the number and the width of the (PBGs). With the optimum values of the optical parameters of the nanocomposite (NC) layer, this research could open the way for better multi-channel filter photonic crystals.

Abstract Background One of the commonest pediatric surgeries is hydrocele. There are suggestions to wait for spontaneous resolution than to operate these cases without harmful adverse events. Herein, we evaluated the outcome of the watchfulness of these cases over 18 months. Methods The study included 93 infants with communicating hydrocele for the Pediatric Surgery Department, Faculty of Medicine (Assiut, Egypt). They were planned to be followed up for 18 months, and indications for intervention included hernia, increasing in size, being tense, and completion of 18 months of follow-up without improvement. Results The gestational age of the included patients was 38.5 ± 2.2 weeks and the age at the time of presentation was 50 (7, 495) days. Most cases were bilateral, reducible, and had an intermittent course. After 18 months of follow-up, 60.2% of the patients resolved spontaneously and 39.8% were surgically treated. Age at the time of presentation was higher among operated patients. Patients with reducibility criteria on clinical examination and lack of intermittent course had higher frequency among operated patients (89.2%). Conclusions It is safe to wait and not to operate on infants with hydrocele up to 18 months as long as there was no hernia. Higher age at presentation and reducibility on examination are indicators that favor the need for surgery.

Abstract We have theoretically demonstrated and explored the transmittance characteristics of a one-dimensional binary photonic crystal composed of metamaterial (MM) and nanocomposite (NC) layers. The NC layer was designed from silver nanoparticles (Ag-NPs) in a host material as Yttrium oxide (Y2O3). Using the transfer matrix approach (TMM), the optical properties of a one-dimensional binary periodic structure having MM and NC layers in the Giga Hertz (GHz) range were examined. The filling fractions of nanoparticles have been explored to see their effect on the effective permittivity of NC materials. Furthermore, the transmittance properties of the suggested structure were investigated at various incident angles for the transverse electric (TE) polarization. In addition to that, different parameters, such as the thickness of the MM layer, the permittivity of the host dielectric material, the filling fraction, and the thickness of the NC layer are also taken into account. We also discussed the effect of these parameters on the width of the photonic bandgap (PBG). With the optimum values of the optical parameters of NC layer, this research could open the way for better photonic crystal circuits, splitters, switches and others.

This article aims to detect empirically, the nexus dynamic interrelationships between health expenditure, totally and disaggregated, economic growth, fertility rate, life expectancy and CO2 emissions in selected middle-income MENA countries. Article results show a significant and robust positive association between health expenditure and economic growth, in one hand, and negative associations between economic growth and all which of, fertility rate, life expectancy and CO2 emissions, on the other hand. Moreover, a negative nexus between fertility rate and life expectancy has been detected. Public, private and external health expenditure affect economic growth positively and significantly, meanwhile affect fertility rate negatively, except health public expenditure, which seems to encourage fertility rate. This indicates that disaggregated health expenditure matters for examination. Furthermore, negative impact of CO2 emissions on growth and life expectancy can crowd out health expenditure positive impacts on both growth and life expectancy. A series of recommendations have been introduced such as increasing health share in public spending, and for more effective government health expenditure and control pollution and CO2 emissions. Furthermore, health spending, policies and system has to function as well to mitigate impacts of high fertility, in marginalized, rural and fungible population and areas.

As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition, and reoccur. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic KrasG12D, develops breast tumors. Upon inactivation of KrasG12D, tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of KrasG12D expression and return. KrasG12D‐independent tumor cells show a strong mesenchymal profile with active RAS‐RAF‐MEK‐ERK (MAPK/ERK) signaling. Both KrasG12D‐dependent and KrasG12D‐independent tumors display a high level of genomic instability, and KrasG12D‐independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelial‐mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic KrasG12D withdrawal in a novel Trp53−/− breast cancer mouse model. To achieve long‐lasting responses in the clinic to RAS‐fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition.