Recommendations to address key recruitment challenges of Alzheimer's disease clinical trials.

Clinical trials for Alzheimer's disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse volunteers to participate in clinical research studies remain among the key barriers to the successful completion of AD clinical trials. An advisory panel of experts from academia, patient-advocacy organizations, philanthropy, non-profit, government, and industry convened in 2020 to assess the critical challenges facing recruitment in Alzheimer's clinical trials and develop a set of recommendations to overcome them. This paper briefly reviews existing challenges in AD clinical research and discusses the feasibility and implications of the panel's recommendations for actionable and inclusive solutions to accelerate the development of novel therapies for AD.

Prevalence and clinical outcomes of pleural effusion in COVID-19 patients: A systematic review and meta-analysis.

Observational studies indicate that pleural effusion has an association with risk and the clinical prognosis of COVID-19 disease; however, the available literature on this area is inconsistent. The objective of this systematic review and meta-analysis is to evaluate the correlation between COVID-19 disease and pleural effusion. A rigorous literature search was conducted using multiple databases. All eligible observational studies were included from around the globe. The pooled prevalence and associated 95% confidence interval (CI) were calculated using the random effect model. Mantel-Haenszel odds ratios were produced to report overall effect size using random effect models for severity and mortality outcomes. Funnel plots, Egger regression tests, and Begg-Mazumdar's rank correlation test were used to appraise publication bias. Data from 23 studies including 6234 COVID-19 patients was obtained. The overall prevalence of pleural effusion in COVID-19 patients was 9.55% (95% CI, I2 = 92%). Our findings also indicated that the presence of pleural effusions associated with increased risk of severity of disease(OR = 5.08, 95% CI 3.14-8.22, I2 = 77.4%) and mortality due to illness(OR = 4.53, 95% CI 2.16-9.49, I2 = 66%) compared with patients without pleural effusion. Sensitivity analyses illustrated a similar effect size while decreasing the heterogeneity. No significant publication bias was evident in the meta-analysis. The presence of pleural effusion can assist as a prognostic factor to evaluate the risk of worse outcomes in COVID-19 patients hence, it is recommended that hospitalized COVID-19 patients with pleural effusion should be managed on an early basis.

Pre-medication protocols for the prevention of paclitaxel-induced infusion related reactions: a systematic review and meta-analysis.

BACKGROUND: Prophylaxis against infusion-related reactions (IRR) from paclitaxel with steroids and antihistamines is a standard of care due to high rates of IRR. This systematic review and meta-analysis aimed to comprehensively summarize the evidence behind various prophylaxis strategies. METHODS: EMBASE, MEDLINE, PubMed, and the Cochrane Register of Controlled Trials were searched (1946 to May 14, 2021). The primary outcomes were Grade 3/4 IRR and any-grade IRR. Secondary outcomes included treatment delay or discontinuation and adverse events secondary to pre-medications. RESULTS: Of the 1285 unique citations, 26 studies were selected: 11 studies for quantitative analysis and 15 studies for qualitative analysis. Studies included randomized controlled trials and observational studies (n = 25-281). There was a non-significant benefit in favour of oral steroids starting 12 h prior to paclitaxel administration versus intravenous steroids immediately prior to paclitaxel administration for grade 3/4 IRRs, with a risk difference (RD) of 2% [95%CI 0 to 5%], any-grade IRR with a RD of 4% [95%CI: -1% to 9%] and treatment discontinuation with a RD of 1% [95%CI -1% to 2%]. For de-escalation strategies, a point-estimate for any-grade IRR was 0.44% [95% CI, 0 to 0.02, p = 0.98] and for grade 3/4 IRR was 3.1% (95% CI, 0.02 to 0.07, p = 0.11). CONCLUSION: Although studies have high risk of bias and risk, differences between steroid routes of administration were small, there was a non-significant trend in favour of oral steroids. De-escalation strategies after two previous successful paclitaxel infusions have an overall low incidence rate of severe IRR and warrant further prospective clinical trials. Insufficient evidence remains to recommend for or against other interventions for the prevention of paclitaxel IRR.

Neoplastic nerve lesions.

Though metastasis and malignant infiltration of the peripheral nervous system is relatively rare, physicians should have a familiarity with their presentations to allow for prompt diagnosis and initiation of treatment. This article will review the clinical presentations, diagnostic evaluation, and treatment of neoplastic involvement of the cranial nerves, nerve roots, peripheral nerves, and muscle. Due to the proximity of the neural structure traversing the skull base, metastasis to this region results in distinctive syndromes, most often associated with breast, lung, and prostate cancer. Metastatic involvement of the nerve roots is uncommon, apart from leptomeningeal carcinomatosis and bony metastasis with resultant nerve root damage, and is characterized by significant pain, weakness, and numbness of an extremity. Neoplasms may metastasize or infiltrate the brachial and lumbosacral plexuses resulting in progressive and painful sensory and motor deficits. Differentiating neoplastic involvement from radiation-induced injury is of paramount importance as it dictates treatment and prognosis. Neurolymphomatosis, due to malignant lymphocytic infiltration of the cranial nerves, nerve roots, plexuses, and peripheral nerves, deserves special attention given its myriad presentations, often mimicking acquired demyelinating neuropathies.

Seeding metastases: The role and clinical utility of circulating tumour cells.

Peripheral human blood is a readily-accessible source of patient material in which circulating tumour cells (CTCs) can be found. Their isolation and characterization holds the potential to provide prognostic value for various solid cancers. Enumeration of CTCs from blood is becoming a common practice in informing prognosis and may guide therapy decisions. It is further recognized that enumeration alone does not capture perspective on the heterogeneity of tumours and varying functional abilities of the CTCs to interact with the secondary microenvironment. Characterizing the isolated CTCs further, in particular assessing their functional abilities, can track molecular changes in the disease progress. As a step towards identifying a suite of functional features of CTCs that could aid in clinical decisions, developing a CTC isolation technique based on extracellular matrix (ECM) interactions may provide a more solid foundation for isolating the cells of interest. Techniques based on size, charge, density, and single biomarkers are not sufficient as they underutilize other characteristics of cancer cells. The ability of cancer cells to interact with ECM proteins presents an opportunity to utilize their full character in capturing, and also allows assessment of the features that reveal how cells might behave at secondary sites during metastasis. This article will review some common techniques and recent advances in CTC capture technologies. It will further explore the heterogeneity of the CTC population, challenges they experience in their metastatic journey, and the advantages of utilizing an ECM-based platform for CTC capture. Lastly, we will discuss how tailored ECM approaches may present an optimal platform to capture an influential heterogeneous population of CTCs.

Crimean-Congo haemorrhagic fever-induced liver injury: A systematic review and meta-analysis.

BACKGROUND: Crimean-Congo haemorrhagic fever (CCHF) is a fatal acute tick-borne viral infection and substantial emerging global public health threat. This illness has a high case fatality rate of up to 40%. The liver is one of the important target organs of the CCHF virus. OBJECTIVE: The aim of this meta-analysis to evaluate the correlation between CCHF and liver injury and draw more generalised inferences about the abnormal serum markers of liver injury such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) in CCHF patients. METHODS: A literature search was accomplished for published eligible articles with MEDLINE/PubMed and Embase databases. All eligible observational studies and case series were included from around the world. The inclusion criteria were articles describing liver injury biomarkers amongst patients diagnosed with CCHF. RESULTS: Data from 18 studies, consisting of 1238 patients with CCHF were included in this meta-analysis. Overall pooled incidence of at least one raised liver injury biomarker was 77.95% (95% CI, I2  =  88.50%, P < .0001). Similarly, pooled incidence of elevated AST and ALT was 85.92% (95% CI, I2  = 85.27%, P < .0001) and 64.30% (95% CI, I2  =  88.32%, P < .0001), respectively. Both Egger and Begg-Mazumdar's tests detected no apparent publication bias in all three meta-analyses (P > .05). CONCLUSION: Our study shows that CCHF has a very detrimental effect on liver function. Abnormal liver function may lead to poor prognosis and increased morbidity and mortality in CCHF patients. Hence, Physicians must recognise and continuously monitor these biomarkers, since these markers may aid in early stratification of prognosis and the prevention of severe outcomes in infection with such a high case fatality rate.

Nodular fasciitis on the cheek of a child.

Nodular fasciitis is a benign proliferation of myofibroblastic cells affecting subcutaneous tissue, muscles, and fascia. This rare disorder is most commonly observed on the upper extremity of adults. We present a case of nodular fasciitis of the cheek of a 12-year-old girl.

Therapeutic alternatives and strategies for drug conservation in the intensive care unit during times of drug shortage: a report of the Ontario COVID-19 ICU Drug Task Force.

During the coronavirus disease (COVID-19) global pandemic, urgent strategies to alleviate shortages are required. Evaluation of the feasibility, practicality, and value of drug conservation strategies and therapeutic alternatives requires a collaborative approach at the provincial level. The Ontario COVID-19 ICU Drug Task Force was directed to create recommendations suggesting drug conservation strategies and therapeutic alternatives for essential drugs at risk of shortage in the intensive care unit during the COVID-19 pandemic. Recommendations were rapidly developed using a modified Delphi method and evaluated on their ease of implementation, feasibility, and supportive evidence. This article describes the recommendations for drug conservation strategies and therapeutic alternatives for drugs at risk of shortage that are commonly used in the care of critically ill patients. Recommendations are identified as preferred and secondary ones that might be less desirable. Although the impetus for generating this document was the COVID-19 pandemic, recommendations should also be applicable for mitigating drug shortages outside of a pandemic. Proposed provincial strategies for drug conservation and therapeutic alternatives may not all be appropriate for every institution. Local implementation will require consultation from end-users and hospital administrators. Competing equipment shortages and available resources should be considered when evaluating the appropriateness of each strategy.

RéSUMé: Pendant la pandémie mondiale du coronavirus (COVID-19), des stratégies urgentes pour réduire les pénuries sont nécessaires. L'évaluation de la faisabilité, de l'aspect pratique et du mérite des stratégies de préservation des médicaments et des alternatives thérapeutiques nécessite une approche collaborative au niveau provincial. Le Groupe de travail ontarien sur les médicaments à l'USI pendant la COVID-19 a reçu comme mandat d'élaborer des recommandations proposant des stratégies de préservation des médicaments et des alternatives thérapeutiques pour les médicaments essentiels utilisés dans les unités de soins intensifs courant un risque de pénurie pendant la pandémie de COVID-19. Des recommandations ont été rapidement élaborées en utilisant une méthode Delphi modifiée, puis évaluées selon leur facilité de mise en œuvre, leur faisabilité et les données probantes les préconisant. Cet article décrit les recommandations quant aux stratégies de préservation des médicaments et aux alternatives thérapeutiques aux médicaments possiblement à risque de pénurie fréquemment utilisés pour les soins des patients en état critique. Les recommandations sont identifiées comme 'à privilégier' ou 'secondaires' si moins souhaitables. Bien que la pandémie de la COVID-19 ait été l'impulsion incitant la création de ce document, ces recommandations devraient également être applicables pour réduire les pénuries de médicaments en contexte normal. Les stratégies provinciales proposées pour la préservation des médicaments et les alternatives thérapeutiques pourraient ne pas être adaptées pour toutes les institutions. La mise en œuvre locale nécessitera la consultation des utilisateurs et des administrateurs hospitaliers. Il faudrait tenir compte des pénuries de matériel concurrentes et des ressources disponibles lors de l'évaluation de la faisabilité de chaque stratégie.

Monitored Anesthesia Care versus General Anesthesia for Intrauterine Fetal Interventions: Analysis of Conversions and Complications for 480 Cases.

INTRODUCTION: Fetal intervention/surgery constitutes a relatively new field of maternal-fetal medicine in which monitored anesthesia care (MAC) or general anesthesia (GA) are utilized as anesthetic techniques when feasible. In this study, we sought to calculate the usage of MAC and GA in various fetal procedures as well as investigate any anesthetic complications and conversions from MAC to GA. METHODS: All intrauterine fetal intervention cases performed at the Texas Children's Hospital Pavilion for Women from 2012 to 2016 were retrospectively analyzed and categorized by mode of anesthesia. Anesthetic complications, conversions to GA, preoperative patient physical status, average number of intraoperative medications required, and average duration of procedure were compared between the MAC and GA groups. RESULTS: A total of 480 fetal interventions were performed with 432 under MAC (90%) and 37 under GA (7.7%). There were 11 conversions from MAC to GA (2.3%). These conversions were due to poor visualization with ultrasound and change of surgical approach to laparoscopic-assisted technique (n = 5), inability to lay flat due to back pain (n = 3), persistent vomiting (n = 2), and unresponsiveness after a spinal block (n = 1). One anesthetic complication occurred due to a medication administration error and did not require conversion to GA. The average preoperative American Society of Anesthesiologists (ASA) physical status classification was 1.97 for the MAC group and 1.87 for the GA group (p = 0.23). Duration of the interventions averaged 129 min under MAC and 138 min under GA (p = 0.23). An average of 7.8 different medications were administered during MAC cases compared to 13.1 during GA cases (p < 0.0001). DISCUSSION: This analysis suggests that MAC is the most commonly used anesthetic option for fetal interventions with a low complication rate and minimal conversion rates to GA. It is therefore preferable to use MAC when feasible due to the low complication rate and decreased drug exposure.

Polysomnography in children with obstructive sleep apnoea and neurocognitive disorders.

OBJECTIVE: The neurocognitive associations in paediatric obstructive sleep apnoea (OSA) are well known; however, whether polysomnographic features can predict these associations is unknown. Therefore, the primary objective of this study was to compare common polysomnographic parameters in children with OSA in the presence and absence of neurocognitive dysfunction. METHODS: Polysomnography data for children ages 3-6 years with mild-moderate OSA who as defined by AHI between 5 and 10 were analysed from a single sleep centre at a tertiary paediatric hospital from January 2016 to December 2018. The following parameters were identified: arousals per hour, percentage of time asleep, apnoea-hypopnoea index (AHI), oxygen desaturation nadir during sleeps, baseline oxygen saturation during sleep, time spent with SpO2 less than 90%, maximum transcutaneous CO2, per cent of the total sleep time spent with TcCO2 greater than 50 mmHg, age, body mass index (BMI), gender and type of disability in the neurocognitive dysfunction group. Neurocognitive diagnoses were recorded. Those with syndromic comorbidities were excluded. The study cohort was then compared to a cohort of 200 subjects with OSA and no neurocognitive disorders matched for age, gender and BMI. A paired column analysis by chi-squared analysis was then undertaken between the two groups. RESULTS: A total of 200 children were identified (126 males and 74 females) in the neurocognitive dysfunction group (OSA with neurocognitive dysfunction) and compared with 200 children in the control group (OSA without neurocognitive dysfunction) (113 males and 87 females). There were no statistical differences between groups. CONCLUSION: Commonly used polysomnographic indices are not predictive of neurocognitive dysfunction in paediatric OSA.

Serotonin levels and 1-year mortality in patients with neuroendocrine tumors: a systematic review and meta-analysis.

Aim: Elevated serotonin in patients with neuroendocrine tumors (NETs) may impact heart failure incidence but a quantitative relationship has not been established. Materials & methods: Systematic review and meta-analysis of studies assessing 24-h urinary 5-hydroxyindoleacetic acid (u5-HIAA) and mortality in patients with NETs (2007-2017) with a primary outcome of 1-year mortality risk and 24-h u5-HIAA. Results: We identified 1715 records of which 12 studies including 755 patients (3442 person-years with 376 deaths) were eligible for meta-analysis. Mean u5-HIAA was 149.2 mg/24 h (standard deviation: 96.6) and mortality was 13.0%. The meta-regression equation showed an 11.8% (95% CI: 8.9-17.0%; I2  = 93.0%) increase in 1-year mortality for every ten-unit increase in u5-HIAA. Conclusion: Serotonin measured by its metabolite u5-HIAA is predictive of 1-year all-cause mortality in patients with NETs.

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model.

Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2weeks. 48h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocyte count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1ß, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers.

Identifying contributing factors and locations of pedestrian severe crashes using hazard-based duration model.

Pedestrian safety remains a significant concern, with the growing number of severe pedestrian crashes resulting in substantial human and economic costs. Previous research into pedestrian crashes has extensively analyzed the influences of weather, lighting, and pedestrian demographics. However, these studies often overlook the critical spatial variables that contribute to pedestrian crashes. Our study aims to explore these overlooked spatial variables by examining the distance pedestrians travel before encountering a severe crash. This approach provides a supplementary perspective in safety analysis, emphasizing the importance of pedestrian movement patterns. The model considers various factors that may influence pedestrian traveled distance before being involved in a severe crash, such as weather conditions, lighting conditions, and pedestrian demographics. Ohio's pedestrian-involved crashes were gathered and analyzed as a case study. The results indicated that 50 % of fatal pedestrian crashes occurred within 0.84 miles of the pedestrians' residences. Moreover, it was shown that factors including lighting condition, pedestrian age, drug toxication, and the location at impact significantly influence the pedestrians traveled distance. These findings provide valuable insights into the spatial distribution of pedestrian crashes and shed light on the factors contributing to their severity. By understanding these relationships, policymakers and urban planners can design targeted interventions such as improving street lighting, implementing traffic calming measures, and developing safety awareness campaigns for specific age groups, to enhance pedestrian safety and reduce the incidence of severe crashes.

Left atrial myxoma with cardiogenic shock following a myocardial infarction: a case report.

BACKGROUND: Myxomas are the most common primary cardiac tumor and typically originate in the left atrium. Atrial myxomas may present following complications of obstruction and emboli. If an atrial myxoma goes untreated, complications such as congestive heart failure, embolic stroke, and sudden death can occur. CASE PRESENTATION: A 58-year-old Caucasian male presented following a cardiac arrest. He was taken emergently to the cardiac catheterization lab and received two drug eluting stents. Following the procedure, he was found to have a left atrial mass that was intermittently obstructing the mitral valve on echocardiography. After leaving the cardiac catheterization lab, he was hypotensive and placed on multiple intravenous medications for hemodynamic support as well as an Impella device. Following medical optimization, he underwent one vessel coronary artery bypass graft as well as surgical excision of the left atrial mass, which pathology had shown to be an atrial myxoma. CONCLUSION: This patient's case of cardiogenic shock following revascularization was complicated by the identification of an atrial myxoma, which, when large enough, can obstruct blood flow through the mitral valve leading to acute mitral dynamic stenosis. This condition results in circulatory collapse due to obstruction of the left ventricle in diastole as the myxoma occludes the mitral valve.

Corrigendum: Regulatory T cells targeting a pathogenic MHC class II: insulin peptide epitope postpone spontaneous autoimmune diabetes.

[This corrects the article DOI: 10.3389/fimmu.2023.1207108.].

A framework for proactive safety evaluation of intersection using surrogate safety measures and non-compliance behavior.

In recent years, identifying road users' behavior and conflicts at intersections have become an essential data source for evaluating traffic safety. According to the Federal Highway Administration (FHWA), in 2020, more than 50% of fatal and injury crashes occurred at or near intersections, necessitating further investigation. This study developed an innovative artificial intelligence (AI)-based video analytic tool to assess intersection safety using surrogate safety measures and non-compliance behavior. To extract the trajectory data, a real-time AI detection model - YOLO-v5 with a tracking framework based on the DeepSORT algorithm was deployed. 54 h of high-resolution video data were collected at six signalized intersections (including three 3-leg and three 4-leg intersections) in Glassboro, New Jersey. Non-compliance behaviors, such as redlight running and pedestrian crossing outside the crosswalk, are captured to better understand the risky behaviors at these locations. The proposed approach achieved an accuracy of 92% to 98% for detecting and tracking road users' trajectories. Additionally, the developed tool also provided directional traffic volumes, pedestrian volumes, vehicles running a red light, pedestrian crossing outside the crosswalk events, and PET and TTC for crossing conflicts between vehicles. Furthermore, an extreme value theory (EVT) was used to estimate the number of crashes at each intersection utilizing the frequency of PETs and TTCs. Finally, the intersections were ranked based on the calculated score considering the severity of crashes. Overall, the developed tool and the crash estimation, as well as the model and ranking method, can provide valuable information for engineers and policymakers to assess the safety of intersections and implement effective countermeasures to mitigate intersection-involved crashes.