Development of Clinical Algorithm Utilizing Vibration-Controlled Transient Elastography to Detect Advanced Hepatic Fibrosis in Liver Transplant Recipients.

INTRODUCTION: Vibration-controlled transient elastography (VCTE) based liver stiffness measurement (LSM) is an excellent 'rule-out' test for advanced hepatic fibrosis in liver transplant (LT) recipients, however, its ability to 'rule-in' the disease is suboptimal. The study aimed to improve diagnostic performance of LSM in LT recipients. METHODS: Adult LT recipients with a liver biopsy and VCTE were included (N = 150). Sequential covering analysis was performed to create rules to identify patients at low or high risk for advanced fibrosis (stage 3-4). RESULTS: Advanced hepatic fibrosis was excluded in patients with either LSM < 7.45 kPa (n = 72) or 7.45 ≤ LSM < 12.1 kPa and time from LT < 5.6 years (n = 25). Conversely, likelihood of advanced fibrosis was 95% if patients had LSM > 14.1 and controlled attenuation parameter > 279 dB/m (n = 21). Thus, 118 (79%) were correctly identified and 32 (21%) would have required a biopsy to establish the diagnosis. Compared to previously established LSM based cutoff values of 10.5 kPa (Youden index) and 13.3 kPa (maximized specificity), the false positive rates of sequential covering analysis was 1% compared to 16.5% with LSM ≥ 10.5 kPa and 8.3% with LSM ≥ 13.3 kPa. The true positive rates were comparable at 87% for sequential covering analysis, 93% for LSM ≥ 10.5 kPa and 83% for LSM ≥ 13.3 kPa. CONCLUSION: The proposed clinical sequential covering analysis allows for better risk stratification when evaluating for advanced fibrosis in LT recipients compared to LSM alone. Additional efforts are necessary to further reduce the number of patients with indeterminate results in whom a liver biopsy may be required.

TrkB-BDNF Signalling and Arc/Arg3.1 Immediate Early Genes in the Anterior Cingulate Cortex and Hippocampus: Insights into Novel Memory Milestones Through Behavioural Tagging.

In recent years, there has been a surge in interest in investigating the mechanisms underlying memory consolidation. However, our understanding of the behavioural tagging (BT) model and its establishment in diverse brain regions remains limited. This study elucidates the contributions of the anterior cingulate cortex (ACC) and hippocampus in the formation of long-term memory (LTM) employing behaviour tagging as a model for studying the underlying mechanism of LTM formation in rats. Existing knowledge highlights a protein synthesis-dependent phase as imperative for LTM. Brain-derived neurotrophic factor (BDNF) stands as a pivotal plasticity-related protein (PRP) in mediating molecular alterations crucial for long-term synaptic plasticity and memory consolidation. Our study offers evidence suggesting that tropomyosin receptor kinase B (TrkB), the receptor of BDNF, may act as a combined "behavioural tag/PRP". Interfering with the expression of these molecules resulted in impaired LTM after 24 h. Furthermore, augmenting BDNF expression led to an elevation in Arc protein levels in both the ACC and hippocampus regions. Introducing novelty around weak inhibitory avoidance (IA) training resulted in heightened step-down latencies and expression of these molecules, respectively. We also demonstrate that the increase in Arc expression relies on BDNF synthesis, which is vital for the memory consolidation process. Additionally, inhibiting BDNF using an anti-BDNF function-blocking antibody impacted Arc expression in both the ACC and hippocampus regions, disrupting the transformations from labile to robust memory. These findings mark the initial identification of a "behavioural tag/PRP" combination and underscore the involvement of the TrkB-BDNF-Arc cascade in the behavioural tagging model of learning and memory.

Lymph node stromal cells vary in susceptibility to infection but can support the intracellular growth of Listeria monocytogenes.

Lymph node stromal cells (LNSC) are an often overlooked component of the immune system, but play a crucial role in maintaining tissue homeostasis and orchestrating immune responses. Our understanding of the functions these cells serve in the context of bacterial infections remains limited. We previously showed that Listeria monocytogenes, a facultative intracellular foodborne bacterial pathogen, must replicate within an as-yet-unidentified cell type in the mesenteric lymph node (MLN) to spread systemically. Here, we show that L. monocytogenes could invade, escape from the vacuole, replicate exponentially, and induce a type I IFN response in the cytosol of two LNSC populations infected in vitro, fibroblastic reticular cells (FRC) and blood endothelial cells (BEC). Infected FRC and BEC also produced a significant chemokine and pro-inflammatory cytokine response after in vitro infection. Flow cytometric analysis confirmed that GFP+  L. monocytogenes were associated with a small percentage of MLN stromal cells in vivo following foodborne infection of mice. Using fluorescent microscopy, we showed that these cell-associated bacteria were intracellular L. monocytogenes and the number of infected FRC and BEC changed over the course of a three-day infection in mice. Ex vivo culturing of these infected LNSC populations revealed viable, replicating bacteria that grew on agar plates. These results highlight the unexplored potential of FRC and BEC to serve as suitable growth niches for L. monocytogenes during foodborne infection and to contribute to the pro-inflammatory environment within the MLN that promotes clearance of listeriosis.

Water striders are impervious to raindrop collision forces and submerged by collapsing craters.

Water striders are abundant in areas with high humidity and rainfall. Raindrops can weigh more than 40 times the adult water strider and some pelagic species spend their entire lives at sea, never contacting ground. Until now, researchers have not systematically investigated the survival of water striders when impacted by raindrops. In this experimental study, we use high-speed videography to film drop impacts on water striders. Drops force the insects subsurface upon direct contact. As the ensuing crater rebounds upward, the water strider is propelled airborne by a Worthington jet, herein called the first jet. We show the water strider's locomotive responses, low density, resistance to wetting when briefly submerged, and ability to regain a super-surface rest state, rendering it impervious to the initial impact. When pulled subsurface during a second crater formation caused by the collapsing first jet, water striders face the possibility of ejection above the surface or submersion below the surface, a fate determined by their position in the second crater. We identify a critical crater collapse acceleration threshold ∼ 5.7 gravities for the collapsing second crater which determines the ejection and submersion of passive water striders. Entrapment by submersion makes the water strider poised to penetrate the air-water interface from below, which appears impossible without the aid of a plastron and proper locomotive techniques. Our study is likely the first to consider second crater dynamics and our results translate to the submersion dynamics of other passively floating particles such as millimetric microplastics atop the world's oceans.

Paediatric femoral shaft fractures: an instructional review for the FRCS examination.

This review presents the principal features of paediatric femoral shaft fractures including the contemporary management strategies and relevant supporting evidence. The article is an overview of information relevant to clinical practice, in addition to preparation for the FRCS (Orth) examination.

Codeveloping an Adolescent Health Program in India During the COVID-19 Pandemic: A Case Study of a Community-Partnered Responsive Feedback Approach.

We describe the responsive feedback (RF) approach experience of a nongovernmental organization, Girls Health Champions (now known as Adolescent Health Champions [AHC]), that undertakes peer education interventions in Mumbai, India, schools to improve gender equality and health outcomes for adolescents aged 13-19 years. AHC used the RF approach at the onset of the COVID-19 pandemic in light of uncertainties stemming from school closures and the negative impact of the lockdown on adolescents' physical and mental health. Using an RF approach, AHC was able to: (1) understand pandemic-specific challenges faced by adolescents; (2) overhaul its theory of change; (3) pilot new modes of intervention delivery; (4) design a curriculum for parents/guardians and a COVID-19 module; (5) design an AHC mobile app; (6) develop a new, more gender-inclusive name and visual identity; (7) change the overall structure, adolescent-friendly nature, and agility of the organization; (8) and help clarify future directions taken by the organization. Overall, use of the RF approach had significant positive impacts on AHC as an organization, such as changes in organizational culture, deeper stakeholder engagement, and innovation, and was instrumental in AHC's growth, development, and pandemic response. This article outlines the steps of the process, from initial informal stakeholder consultations to the eventual formalization of the RF approach into the everyday working of AHC through the creation of a youth advisory board. We discuss challenges, such as time and resource constraints encountered; strategies for dealing with such challenges; and general key findings and learnings from this experience that could be beneficial to other youth- and community-serving organizations.

Efficacy of pharmacological and mechanical cervical priming methods for induction of labour and their applicability for outpatient management: A systematic review of randomised controlled trials.

BACKGROUND: A systematic review to determine the efficacy and safety of prostaglandins (PG) and Foley catheter (FC) for cervical priming in the outpatient setting. Various methods are available to achieve cervical ripening prior to induction of labour (IOL). In this systematic review, we will report the literature to date, and investigate the efficacy and safety of using the Foley catheter balloon or prostaglandins for cervical ripening, comparing both methods with each other, and discuss the implications of these findings for midwifery led units. METHODS: English peer-reviewed journals were systematically searched in the databases PubMed, MEDLINE, EMCARE, EMBASE and CINAHL, for studies investigating cervical ripening using the FC or PGs. Additional randomised controlled trials (RCTs) and non-RCTs were identified by a manual search. Search terms included: cervix dilatation effacement, cervix ripening, outpatient, ambulatory care, obstetric patients, pharmacological preparations, and Foley catheter. Only RCTs of FC versus PG or either intervention versus placebo or intervention in the in-patient Vs. outpatient setting were included. 15 RCTs were included. RESULTS: The results of this review show that both FC and PG analogues are equally effective cervical ripening agents. When compared to FC, PGs lead to a reduced requirement for oxytocin augmentation and a shorter intervention to delivery interval. However, PG use is also associated with an increased risk of hyperstimulation, cardiotocographic monitoring abnormalities and negative neonatal outcomes. CONCLUSIONS: FC cervical ripening is an effective method of outpatient cervical priming, which is safe, acceptable, and cost-effective and thus has a potential role in both resource-rich and resource-poor countries. With appropriate dosing, some PG analogues also appear to offer similar outcomes.

Financial Toxicity in Cancer Care: Implications for Clinical Care and Potential Practice Solutions.

Patients with cancer face an array of financial consequences as a result of their diagnosis and treatment, collectively referred to as financial toxicity (FT). In the past 10 years, the body of literature on this subject has grown tremendously, with a recent focus on interventions and mitigation strategies. In this review, we will briefly summarize the FT literature, focusing on the contributing factors and downstream consequences on patient outcomes. In addition, we will put FT into context with our emerging understanding of the role of social determinants of health and provide a framework for understanding FT across the cancer care continuum. We will then discuss the role of the oncology community in addressing FT and outline potential strategies that oncologists and health systems can implement to reduce this undue burden on patients with cancer and their families.

Procalcitonin Testing With Secondary Coinfection in Patients With COVID-19.

Background The coronavirus disease (COVID-19) virus has caused millions of deaths. It is difficult to differentiate between pure viral COVID-19 pneumonia and secondary infection. Clinicians often use procalcitonin (PCT) to decide on empiric antibiotic therapy. Methodology We performed a retrospective study of patients admitted with COVID-19 between January 1st, 2020, and June 30th, 2020. Patient demographics, clinical findings, and laboratory findings with a focus on PCT levels were recorded. Coinfection was considered if clinicians ordered a septic workup (urine, blood, and respiratory cultures) or if the physicians started or escalated antimicrobial therapy. PCT levels on the day of culture and daily for the next three days were recorded. Significant PCT change was defined as a decrease in PCT levels of >50% from the initial elevated PCT level. Results In total, 143 (59.8%) patients had one secondary infection. These included pulmonary infections (118, 49.4%), blood infections (99, 41.4%), and urine infections (64, 26.8%). Many patients had more than one documented positive culture: respiratory system and blood together in 80 (33.4%) patients, sputum and urine in 55 (23.1%) patients, and urine and blood in 46 (19.2%) patients. Out of the 143 patients with a positive culture, PCT was abnormal on the day of positive culture in 93 (65.5%), while PCT was abnormal in 64 out of 96 on the day of negative culture (66.7%) (p = 0.89). Individual analysis for PCT levels of respiratory cultures showed out of 118 positive sputum cultures, 86 (72%) had abnormal PCT on the day of culture. PCT in positive versus negative cultures was not significantly different, with median PCT (interquartile range, IQR) of 1.66 (6.61) versus 1.03 (2.23) (p = 0.172). For blood cultures, out of 99 positive blood cultures, 73 (73%) had abnormal PCT levels on the day of the culture. PCT in positive versus negative cultures was significantly elevated, with a median of 1.61 (5.97) vs. 0.65 (1.77) (p < 0.001). For urine, out of 64 positive cultures, 41 (64.1%) had abnormal PCT levels on the day of the culture. PCT in positive versus negative cultures was not significantly different, with a median of 0.71 (2.92) vs. 0.93 (4.71) (p = 0.551). To observe the change in PCT after culture, PCT values for the next three days after culture were analyzed. We found that patients with positive cultures had higher PCT levels than those with negative cultures. There was no significant improvement over the following three days. Patients with abnormal PCT on the day of the suspected infection had a longer length of stay in the hospital, with a median (IQR) of 23.9 days (3.16) vs. 16.9 days (2.18) (p = 0.021). Conclusions Secondary coinfections in patients with COVID-19 infections are not associated with PCT elevation on the day of suspected secondary infection. However, most patients with bacteremia had a significant elevation of PCT on the day of bacteremia before collection and reporting of positive culture. Patients with abnormal PCT levels on the day of suspected infection had a longer hospital stay than patients with normal PCT levels. Subsequent testing of PCT in patients showed no significant improvement in PCT.

Zolpidem use and risk of suicide: A systematic review and meta-analysis.

INTRODUCTION: Zolpidem is one of the most commonly prescribed nonbenzodiazepine hypnotic drugs for insomnia. Published epidemiological studies linked zolpidem with the risk of suicide. However, to date, no meta-analysis investigated this association. Hence, we systematically reviewed and meta-analysed the current evidence from real-world studies reporting the risk of suicide with the use of zolpidem. METHODS: Medline (Ovid), Embase (Ovid), and PsycINFO databases were searched from inception till June 2021 for real-world evidence studies reporting the risk of suicide with the use of zolpidem. The quality assessment of included studies was assessed using the New-Castle Ottawa Scale (NOS). Random-effect meta-analysis was performed using a generic inverse variance method. RESULTS: This meta-analysis was based on four studies with 344,753 participants, of which 42,279 were zolpidem users. The methodological quality of all the included studies was of high quality. A significantly increased risk of suicide or suicide attempt was found in zolpidem users compared to non-users, with a pooled relative risk of 1.88 (95% CI: 1.54 - 2.30). Furthermore, an increased risk of suicidal death was observed in zolpidem users compared to non-users, with a pooled relative risk of 1.82 (95% CI: 1.43 - 2.30). Dose-response analysis also revealed a significantly increased risk of suicide in patients receiving ≥ 180cDDD (cumulative defined daily doses) of zolpidem (124 times), followed by 90-179cDDD (113 times) and <90cDDD (93 times) of zolpidem compared to non-users. CONCLUSION: In conclusion, zolpidem use was associated with an increased risk of suicide or suicide attempt and suicidal death. Therefore, careful prescribing practices must be followed by considering the risk-benefit profile.

Germline genetics of prostate cancer.

BACKGROUND: An important fraction (>/~10%) of men with high-risk, localized prostate cancer and metastatic prostate cancer carry germline (heritable) pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes. These can represent known or suspected autosomal dominant cancer predisposition syndromes. Growing evidence suggests that pathogenic variants in key genes involved in homologous recombination and mismatch DNA repair are important in prostate cancer initiation and/or the development of metastases. AIMS: Here we provide a comprehensive review regarding individual genes and available literature regarding risks for developing prostate cancer, and discuss current national guidelines for germline genetic testing in the prostate cancer population and treatment implications. RESULTS: The association with prostate cancer risk and treatment implications is best understood for those with germline mutations of BRCA2, with emerging data supporting associations with ATM, CHEK2, BRCA1, HOXB13, MSH2, MSH6, PALB2, TP53 and NBN. Treatment implications in the metastatic castration resistant prostate cancer setting include rucaparib and olaparib, and pembrolizumab with potential clinical trial opportunities in earlier disease settings. DISCUSSION: The data summarized in this review has led to the expansion of national guidelines for germline genetic testing in prostate cancer. We review these guidelines, and discuss the importance of cascade genetic testing of relatives, diverse populations with attention to inclusion, as well as prostate cancer screening updates and clinical trial opportunities for men who carry genetic risk factors for prostate cancer.

COVID-19 outcomes in patients with Dermatomyositis: A registry-based cohort analysis.

BACKGROUND: Patients with rheumatic diseases (RDs) like DM are known to be vulnerable towards various types of infections due to aggressive disease activity mandating high dose immunosuppressive therapy. The severity of COVID-19 in RDs is limited in literature due to the heterogeneous nature of the condition. Therefore, specific details on mortality is essential to navigate any precautions required in the treatment. OBJECTIVES: To determine outcomes of COVID-19 in DM as compared to controls, and identify the risk association of gender, race, interstitial lung disease, neoplasms, and use of immunosuppressant. METHODS: Retrospective data of individuals with DM and COVID-19 and the general population with COVID-19 between January 2020 to August 2021 was retrieved from the TriNetX database. 1:1 Propensity Score matching was used to adjust for confounders. We assessed COVID-19 outcomes such as mortality, hospitalisation, ICU admission, severe COVID-19, mechanical ventilation (MV), acute kidney injury (AKI), venous thromboembolism (VTE), ischemic stroke, acute respiratory distress syndrome (ARDS), renal replacement therapy (RRT) and sepsis. Subgroup analyses included gender, race, ILD, cancer patients, disease-modifying rheumatic drugs (DMARDs) use, and glucocorticoids (GC) use. RESULTS: We identified 5,574 DM patients with COVID-19, and 5,574 general population with COVID-19 (controls). DM with COVID-19 had a lower risk of mortality in comparison to controls [RR 0.76], hospitalisation [RR 0.8], severe COVID-19 [RR 0.76], AKI [RR 0.83], and sepsis [RR 0.73]. Males and African Americans were more likely to develop AKI [RR 1.35, 1.65], while African Americans had higher odds for severe COVID-19 [RR 1.62] and VTE [RR 1.54]. DM with ILD group also experienced higher odds for severe COVID-19 infection [RR 1.64], and VTE [RR 2.06]. DM patients receiving DMARDs and glucocorticoids had higher odds for hospitalisation [RR 1.46, 2.12], and sepsis [RR 3.25, 2.4] Subgroup analysis of 5-year neoplasm history amongst DM patients with COVID-19 was inadequate for meaningful comparison. CONCLUSION: Dermatomyositis patients without comorbities have reasonable COVID-19 outcomes including mortality and hospitalisation. Black race, male gender, ILD, DMARDS and glucocorticoid users, are associated with poor outcomes.

Bibliometric and Altmetric Analysis of Retracted Articles on COVID-19.

BACKGROUND: With greater use of social media platforms for promotions of research articles, retracted articles tend to receive approximately the same attention. We systematically analyzed retracted articles from retractionwatch.com to look at the Altmetric Attention Scores (AAS) garnered over a period of time in order to highlight the role of social media and other platforms in advertising retracted articles and its effect on the spread of misinformation. METHODS: Retractionwatch.com was searched for coronavirus disease 2019 related retracted papers on November 6th, 2021. Articles were excluded based on lack of digital object identifier (DOI), if they were preprint articles, absent AAS, and incomplete AAS of pre retraction, post retraction, or both scores. RESULTS: A total of 196 articles were found on the Retraction Watch website of which 189 were retracted papers and 7 were expression of concern (EOC). We then identified 175 articles after excluding those that did not have a DOI and 30 preprint articles were also excluded giving 145 articles. Further exclusion of articles with absent AAS and incomplete AAS resulted in a total of 22 articles. CONCLUSION: Retracted articles receive significant online attention. Twitter and Mendeley were the most popular medium for publicizing retracted articles, therefore more focus should be given by journals and their Twitter accounts to discredit all their retracted articles. Preprints should be reconsidered as a whole by journals due to the huge risk they carry in disseminating false information.

Emotional responses and coping strategies of medical students during the COVID-19 pandemic.

OBJECTIVES: To assess the emotional responses and coping strategies of medical students during the lockdown and social distancing measures implemented during the coronavirus disease -19 (COVID-19) pandemic. METHODS: This cross­sectional study is based on data collected from undergraduate medical students at the College of Medicine, Alfaisal University Riyadh, Saudi Arabia, during the fall semester of academic year 2020-2021. All the participants completed a self-administered online questionnaire consisting of 3 parts: demographic information, emotional response scale, and 14-item, adapted brief coping orientation to problems experienced inventory to determine the use of avoidant or approach coping strategies. Coping and emotional response scores were compared using t-test. Linear regression analysis was also performed. RESULTS: A total of 261 students from all years were included. Overall scores were higher for avoidant coping strategies. The use of avoidant coping strategies was significantly higher in females (p=0.03) and in preclinical students (p<0.001). Preclinical students had a higher mean score for anger (p=0.002). Conversely, students in the clinical phase had higher scores for anxiety (p=0.005) and sadness (p=0.027). The regression analysis of emotional responses and coping strategies suggests that avoidant coping is a predictor of anger (p=0.003) and sadness (p=0.005). CONCLUSION: Interventions to train medical students in the use of more productive and effective coping strategies may reduce negative emotional responses linked to the present COVID-19 pandemic and in the future.

Foreign workers in the Middle East during COVID-19.

The COVID-19 pandemic is having an unprecedented and consequential impact on global economies, businesses, and workforces. Foreign nationals account for the majority of the population in the Middle East. Throughout this article, the authors address the negative ramifications the COVID-19 pandemic has had on the migrant workforce in the Middle East. This pandemic has intensified various socio-economic and public health crises such as unemployment, income cuts, depletion of savings, repatriation difficulties, inadequate living conditions, and associated burden on healthcare facilities by the COVID-19 infection.

The effect of time to surgery in neck of femur fracture patients with ASA Grade of 3 and above.

INTRODUCTION: Hip fractures are an important cause of morbidity and mortality. Early surgery has been shown to reduce mortality rates and surgical complications. The American Society of Anesthesiologists (ASA) grade is a widely used tool to assess preoperative health of patients. This study aims to assess is whether delay in surgical time has a greater impact on the mortality rates for high risk patients. METHOD: Retrospective study using the National Hip Fracture Database (NHFD) of 4883 neck of femur fracture patients. Time of surgery, ASA grade, reason for delay and mortality at 120 days was analysed, using statistical analysis software. RESULTS: There was a significant increase in mortality (p < 0.001) with increasing ASA grade. Surgical delays of more than 36 hours increased mortality by 2.9%. The impact of delaying surgery became more pronounced as the ASA grade increased. ASA 3 and above had an optimum time to surgery of between 12 and 24 hours giving the statistically significant lowest mortality rate (p = 0.004). DISCUSSION: Surgical delay beyond the 36-hour target for surgery has a greater impact on mortality for patients with higher ASA grades. The effect is most profound in the high-risk ASA grade 5 patients with delayed patients showing a 37.5% increase in mortality in this group. This would imply that by prioritising this higher risk group and operating on it within a specific time frame there would be a subsequent fall in mortality associated with neck of femur fractures.