Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia.

BACKGROUND: Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear. METHODS: We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28. RESULTS: A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P = 0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, -5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.).

Intrastromal keratopigmentation: a boon for unsightly corneal scars.

PURPOSE: The aim of this study was to improve cosmesis in patients with corneal opacity (CO) using newer organic micronized pigments. METHODS: Settings: Tertiary Care eye center, Design: Retrospective study. INCLUSION CRITERIA: Patients with unsightly corneal scars not suitable for keratoplasty, eccentric corneal opacity not requiring keratoplasty, or lenticular opacity/anterior or posterior capsular opacities in non-seeing eyes. Micronized organic pigment was used for keratopigmentation by the intrastromal pocket technique (ISPT) in deep corneal opacities and lenticular opacities, whereas the intrastromal needle puncture technique (ISNT) was used in superficial opacities or corneoiridic scars. The records of 463 patients were reviewed and analyzed for the duration of the past 7 years. RESULTS: Two hundred and ninety-three (63.2%) patients underwent ISNT, eight underwent combined technique, and the rest underwent ISPT. The postoperative follow-up period showed more watering and redness in the needle puncture technique (p > 0.001), which resolved in 70.4% of patients by the end of 4 weeks. Repeat procedures were required in 5.3% of the patients with ISNT. The patient's satisfaction grading showed excellent levels in 375 (80.9%) patients, 45 (9.7%) had good satisfaction levels, and the rest had average satisfaction levels. CONCLUSION: Intrastromal keratopigmentation is a boon for unsightly corneal scars and gives respite to the patients from the social stigma.

Treatment patterns in US patients hospitalized with COVID-19 and pulmonary involvement.

This study describes the baseline characteristics and treatment patterns of US patients hospitalized with a diagnosis of coronavirus disease 2019 (COVID-19) and pulmonary involvement. Patients hospitalized with pulmonary involvement due to COVID-19 (first hospitalization) were identified in the IBM Explorys® electronic health records database. Demographics, baseline clinical characteristics, and in-hospital medications were assessed. For evaluation of in-hospital medications, results were stratified by race, geographic region, age, and month of admission. Of 6564 hospitalized patients with COVID-19-related pulmonary involvement, 50.4% were male, and mean (SD) age was 62.6 (16.4) years; 75.2% and 23.6% of patients were from the South and Midwest, respectively, and 50.2% of patients were African American. Compared with African American patients, a numerically higher proportion of White patients received dexamethasone (19.7% vs. 31.8%, respectively), nonsteroidal anti-inflammatory drugs (NSAIDs; 27.1% vs. 34.9%), bronchodilators (19.8% vs. 29.5%), and remdesivir (9.3% vs. 21.0%). Numerically higher proportions of White patients than African American patients received select medications in the South but not in the Midwest. Compared with patients in the South, a numerically higher proportion of patients in the Midwest received dexamethasone (20.1% vs. 34.5%, respectively), NSAIDs (19.6% vs. 55.7%), bronchodilators (15.9% vs. 41.3%), and remdesivir (10.6% vs. 23.1%). Inpatient use of hydroxychloroquine decreased over time, whereas the use of dexamethasone and remdesivir increased over time. Among US patients predominantly from the South and Midwest hospitalized with COVID-19 and pulmonary involvement, differences were seen in medication use between different races, geographic regions, and months of hospitalization.

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.

Evaluation of ethyl gallate for its antioxidant and anticancer properties against chemical-induced tongue carcinogenesis in mice.

Cancer arising in the oral cavity is one of the major causes of mortality worldwide and demands immediate attention. Regardless of the use of advanced treatment for oral cancer, successful treatment resulting in cancer survival is low. Currently available drugs are ineffective and are toxic. Therefore, successful treatment without toxic effects remains essential. This is quite challenging, leading to the identification of natural bioactive compounds for oral cancer treatment. Thus, a plant extract rich in phenolics is preferred for studying the cellular, biochemical and molecular changes associated with oral carcinogenesis.The present study aims to deal with the above need using Acacia nilotica (L.) leaf extract (AN) and ethyl gallate (EG), a phenolic compound present in AN against oral carcinogenesis. Extension of a tumor cell line to a mouse model was investigated with 4-nitroquinoline 1-oxide (4-NQO) as carcinogen, a surrogate for tobacco. The progression of squamous cell carcinoma (SCC) was achieved through hyperplasia and dysplasia after 4-NQO induction in Swiss albino mice. Administration of AN and EG to animals undergoing dysplasia led to the inhibition of SCC, thereby reducing the tumor burden. The antioxidant capacity of AN and EG was also brought out via biochemical analysis. Further investigation of biomarkers in tongue tissues revealed the involvement of apoptosis in vivo Moreover, no adverse or toxic effect was observed earlier in rats upon oral administration of AN and EG. Thus, AN and EG shows strong hope as drugs against oral cancer progression.

Alleviation of 4-nitroquinoline 1-oxide induced oxidative stress by Oroxylum indicum (L.) leaf extract in albino Wistar rats.

BACKGROUND: 4-nitroquinoline 1-oxide (4-NQO) is a mutagen known to be responsible for causing cancer by generating oxidative stress in humans. Oroxylum indicum (L.) possesses various bioactive compounds with antioxidant properties. In this connection, the present study aims to analyze the alleviation of 4-NQO induced oxidative stress in albino Wistar rats using O. indicum (L.) leaf extract. METHODS: O. indicum (L.) belonging to the family Bignoniaceae, has anticancer and anti-inflammatory properties. In this study, we observed severe oxidative stress in 4-NQO induced albino Wistar rats when compared to untreated control. Alleviation of this condition was seen after the oral administration of O. indicum (L.) leaf extract at 50, 100, and 200 mg/kg body weight. RESULTS: 4-NQO (50 ppm) administration in drinking water resulted in the generation of reactive oxygen species (ROS) leading to cellular damage, lipid peroxidation and imbalance in antioxidant status. Administration of O. indicum (L.) leaf extract has alleviated the level of 4-NQO induced oxidative stress by increasing the antioxidant status and decreasing the elevation of liver markers in serum. CONCLUSIONS: Results clearly suggest that O. indicum (L.) leaf extract when administered orally in a dose dependent manner has the ability to overcome the oxidative stress induced by 4-NQO with hepatoprotective and lipid protective properties.

Higher serum testosterone and dihydrotestosterone, but not oestradiol, are independently associated with favourable indices of lung function in community-dwelling men.

OBJECTIVES: Lower circulating androgens and poorer lung function are associated with increased cardiovascular risk and mortality in men. The association between androgens and lung function is unclear. We tested the hypothesis that circulating testosterone (T) and its metabolites dihydrotestosterone (DHT) and oestradiol (E2) are differentially associated with lung function in men. METHODS: Early-morning serum T, DHT and E2 were assayed using mass spectrometry in 1768 community-dwelling men from Busselton, Western Australia. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured using spirometry. Linear regression models adjusting for age, height, smoking, exercise, body mass index, respiratory conditions and cardiovascular risk factors were used. RESULTS: Mean age was 50.1 ± 16·8 years. 16·0% were current smokers, 14·1% reported a history of asthma and 2·7% reported chronic obstructive pulmonary disease. Current smokers had higher T compared with never smokers (age-adjusted mean 14·5 vs 13·5 nmol/l, P = 0·002) and higher E2 (65·3 vs 60·1 pmol/l, P = 0·017). In fully adjusted analyses, T was associated with FEV1 (51 ml per 1 SD increase, P < 0·001) as was DHT (62 ml, P < 0·001), E2 was not (P = 0·926). Similar results were seen for FVC (T: 76 ml, P < 0·001; DHT: 65 ml, P < 0·001; E2 P = 0·664). Higher DHT was marginally associated with the ratio FEV1/FVC (0·3% per 1 SD increase, P = 0·047). CONCLUSIONS: Both T and DHT were independently associated with higher FEV1 and FVC in predominantly middle-aged community-dwelling men. Androgens may contribute to, or be biomarkers for, better lung function in men. Further research is needed to clarify whether androgens preserve lung function in ageing men.

The interaction surface of a bacterial transcription elongation factor required for complex formation with an antiterminator during transcription antitermination.

The bacterial transcription elongation factor, NusA, functions as an antiterminator when it is bound to the lambdoid phage derived antiterminator protein, N. The mode of N-NusA interaction is unknown, knowledge of which is essential to understand the antitermination process. It was reported earlier that in the absence of the transcription elongation complex (EC), N interacts with the C-terminal AR1 domain of NusA. However, the functional significance of this interaction is obscure. Here we identified mutations in NusA N terminus (NTD) specifically defective for N-mediated antitermination. These are located at a convex surface of the NusA-NTD, situated opposite its concave RNA polymerase (RNAP) binding surface. These NusA mutants disrupt the N-nut site interactions on the nascent RNA emerging out of a stalled EC. In the N/NusA-modified EC, a Cys-53 (S53C) from the convex surface of the NusA-NTD forms a specific disulfide (S-S) bridge with a Cys-39 (S39C) of the NusA binding region of the N protein. We conclude that when bound to the EC, the N interaction surface of NusA shifts from the AR1 domain to its NTD domain. This occurred due to a massive away-movement of the adjacent AR2 domain of NusA upon binding to the EC. We propose that the close proximity of this altered N-interaction site of NusA to its RNAP binding surface, enables N to influence the NusA-RNAP interaction during transcription antitermination that in turn facilitates the conversion of NusA into an antiterminator.

Precision medicine and precision therapeutics: hedgehog signaling pathway, basal cell carcinoma and beyond.

Precision medicine and precision therapeutics is currently in its infancy with tremendous potential to improve patient care by better identifying individuals at risk for skin cancer and predict tumor responses to treatment. This review focuses on the Hedgehog signaling pathway, its critical role in the pathogenesis of basal cell carcinoma, and the emergence of targeted treatments for advanced basal cell carcinoma. Opportunities to utilize precision medicine are outlined, such as molecular profiling to predict basal cell carcinoma response to targeted therapy and to inform therapeutic decisions.

In vitro protection of biological macromolecules against oxidative stress and in vivo toxicity evaluation of Acacia nilotica (L.) and ethyl gallate in rats.

BACKGROUND: Recently, enormous research has been focused on natural bioactive compounds possessing potential antioxidant and anticancer properties using cell lines and animal models. Acacia nilotica (L.) is widely distributed in Asia, Africa, Australia and Kenya. The plant is traditionally used to treat mouth, ear and bone cancer. However, reports on Acacia nilotica (L.) Wild. Ex. Delile subsp. indica (Benth.) Brenan regarding its toxicity profile is limited. Hence in this study, we investigated the antioxidant capacity and acute toxicity of ethyl gallate, a phenolic antioxidant present in the A. nilotica (L.) leaf extract. METHODS: The antioxidant activity of ethyl gallate against Fenton's system (Fe3+/H2O2/ascorbic acid) generated oxidative damage to pBR322 DNA and BSA was investigated. We also studied the interaction of ethyl gallate to CT-DNA by wave scan and FTIR analysis. The amount of ethyl gallate present in the A. nilotica (L.) leaf extract was calculated using HPLC and represented in gram equivalence of ethyl gallate. The acute toxicity profile of ethyl gallate in the A. nilotica (L.) leaf extract was analyzed in albino Wistar rats. Measurement of liver and kidney function markers, total proteins and glucose were determined in the serum. Statistical analysis was done using statistical package for social sciences (SPSS) tool version 16.0. RESULTS: Ethyl gallate was found to be effective at 100 µg/mL concentration by inhibiting the free radical mediated damage to BSA and pBR322 DNA. We also found that the interaction of ethyl gallate and A. nilotica (L.) leaf extract to CT-DNA occurs through intercalation. One gram of A. nilotica (L.) leaf extract was found to be equivalent to 20 mg of ethyl gallate through HPLC analysis. Based on the acute toxicity results, A. nilotica (L.) leaf extract and ethyl gallate as well was found to be non-toxic and safe. CONCLUSIONS: Results revealed no mortality or abnormal biochemical changes in vivo and the protective effect of A. nilotica (L.) leaf extract and ethyl gallate on DNA and protein against oxidative stress in vitro. Hence, A. nilotica (L.) leaf extract or ethyl gallate could be used as potential antioxidants with safe therapeutic application in cancer chemotherapy.

A questionnaire-based survey of dry eye disease among leather tannery workers in Kanpur, India: a case-control study.

CONTEXT: Kanpur is a major leather processing center in India, where a large number of tanneries are situated. During tanning process, workers are constantly exposed to heat, leather dust produced in buffering operations and a wide range of chemicals. All these factors are known to cause dry eye. Being ophthalmologists of a tertiary health care center in Kanpur, we used to notice over a period of time that a considerable number of patients with dry eye symptoms, attending our out-patient department, were related to leather tanning industries. But, no published data is available on the prevalence of and risk factors for dry eye disorders among tannery worker. OBJECTIVE: To estimate the prevalence of dry eye problem and its severity among the workers of leather tanneries in the industrial belt of Kanpur and to evaluate various risk factors related to it. METHODS: In this cross-sectional case-control study, Ocular Surface Disease Index (OSDI) Questionnaire was presented to randomly selected tannery workers and control group. OSDI score was calculated based on subjects' response, and was evaluated with OSDI chart to assess the magnitude of dry eye symptoms and to grade its severity. RESULTS were analyzed statistically to evaluate the significance level. RESULTS: A total of 800 workers were selected by simple random sampling, out of which 72 workers were excluded from the study. Thus the questionnaire was presented to a total of 728 workers, while control group included 260 individuals. All the workers as well as controls were male with age ranging from 20 to 59 years. The mean age for tannery workers was 34.05 ± 8.96 years and that for control group was 32.97 ± 10.59 years (p = 0.14). The tannery workers had mean duration of work at tanneries for 6.99 ± 4.86 years. The prevalence of dry eye symptoms among tannery workers was 33.79% (95% CI: 30.35-37.24), while that in control group was 15.77% (95% CI: 11.31-20.23) (p < 0.0001). Among symptomatic workers, 47.96% (95% CI: 41.68-54.26) workers had mild, 36.99% (95% CI: 30.91-43.07) workers had moderate and 15.04% (95% CI: 10.54-19.54) workers had severe dry eye symptoms. Severe symptoms were more prevalent among symptomatic workers of age ≥ 40 years in comparison to those <40 years (34.72% versus 6.90%, p < 0.0001). With increase in duration of work (1-5, 6-15 and 16-25 years), both prevalence and severity of dry eye symptoms increased significantly (p = 0.036 and <0.0001, respectively). CONCLUSION: Dry eye is a significantly prevalent occupational hazard among tannery workers, severity of which increases with the age and the duration of work in tannery. Chemical exposure in hot and dusty working environment of a tannery may have a causative role. Tannery workers should be motivated to use various preventive measures to reduce chemical and dust exposure such as wearing protective glasses, and their ocular health should be monitored periodically for adequate and timely treatment, if required.

Role of multilayered amniotic membrane transplantation for the treatment of resistant corneal ulcers in North India.

To study the role of multilayer amniotic membrane transplantation (AMT) in the treatment of non-healing corneal ulcers. This study included 28 patients with non-healing bacterial corneal ulcers. AMT was performed using the 'overlay on-inlay' technique'. The outcome was assessed in terms of best corrected visual acuity (BCVA), corneal re-epithelization, graft/tissue edema and vascularity, graft melting, graft retraction, infection of graft and surface necrosis. The success rate of ulcer healing was 82.1 % (23 patients) 1 month after surgery, 78.5 % (22 patients) after 3 months and 75 % (21 patients) after 6 months. In the early post-operative period, BCVA deteriorated in all patients (perception of light to hand movement) but improved later. In 26 of the 28 patients (92.8 %) graft retraction occurred after 1 month and neovascularization was seen in 17 of the 28 patients (60.7 %). Multilayer AMT using an overlay on-inlay graft in non-healing bacterial corneal ulcers is a good option in terms of ulcer healing and symptomatic improvement.

Evaluation of the inhibitory potential of bioactive compounds against SARS-CoV-2 by in silico approach.

CONTEXT: The COVID-19 (coronavirus disease 19) pandemic brought on by the SARS-CoV-2 outbreak (severe acute respiratory syndrome coronavirus 2) has stimulated the exploration of various available chemical compounds that could be used to treat the infection. This has driven numerous researchers to investigate the antiviral potential of several bioactive compounds from medicinal plants due to their reduced adverse effects compared to chemicals. Some of the bioactive compounds used in folklore treatment strategies are reported as effective inhibitors against the proliferative and infective cycles of SARS-CoV-2. The secondary metabolites from plants are generally used to treat various diseases due to their intact medicinal properties. The present study analyzes the inhibitory potential of phytochemicals from medicinal plants like Sphaeranthus indicus, Lantana camara, and Nelumbo nucifera against SARS-CoV-2 by molecular docking. METHODS: Ten druggable protein targets from SARS-CoV-2 are docked against the phytochemicals from the selected medicinal plants. The phytocompounds astragalin, isoquercetin, and 5-hydroxy-7-methoxy-6-c-glycosy flavone were found to have lower binding energy depicting their inhibitive potential compared with the reported inhibitors that are used in the treatment of SARS-CoV-2 infection. The phytocompounds found to have the least binding energy were selected for further analyses. To assess the compounds' potential as drugs, their ADMET characteristics were also examined. Sphaeranthus indicus, Lantana camara, and Nelumbo nucifera six possible compounds were separately screened for ADME and toxicity characteristics; then, the results were analyzed. To assess the impact of the phytocompound binding on the dynamics of SARS-CoV-2 ribonuclease protein NSP15, microsecond-level all atomistic molecular dynamics simulations were performed, and their dynamics were analyzed. Microsecond-level molecular dynamics simulations of both the ligands complexed with NSP15 revealed that the ligand induces allosteric effects on NSP15, which could lead to destabilization of NSP15 hexameric interface and loss of RNA binding. The low binding energy exhibited by the phytochemicals from Lantana camera, Sphaeranthus indicus, and Nelumbo nucifera against the protein targets of SARS-CoV-2 showed inhibitory potential by the selected molecules. Their predicted interference of the enzymes involved in the molecular mechanisms aiding the proliferation of SARS-CoV-2 indicated the inhibitive ability of the phytochemicals.

Microplastics in water: types, detection, and removal strategies.

Microplastics are one of the most concerning groups of contaminants that pollute most of the surroundings of the Earth. The abundance of plastic materials available in the environment moved the scientific community in defining a new historical era known as Plasticene. Regardless of their minuscule size, microplastics have posed severe threats to the life forms like animals, plants, and other species present in the ecosystem. Ingestion of microplastics could lead to harmful health effects like teratogenic and mutagenic abnormalities. The source of microplastics could be either primary or secondary in which the components of microplastics are directly released into the atmosphere and the breakdown of larger units to generate the smaller molecules. Though numerous physical and chemical techniques are reported for the removal of microplastics, their increased cost prevents the large-scale applicability of the process. Coagulation, flocculation, sedimentation, and ultrafiltration are some of the methods used for the removal of microplastics. Certain species of microalgae are known to remove microplastics by their inherent nature. One of the biological treatment strategies for microplastic removal is the activated sludge strategy that is used for the separation of microplastic. The overall microplastic removal efficiency is significantly high compared to conventional techniques. Thus, the reported biological avenues like the bio-flocculant for microplastic removal are discussed in this review article.

A Review of the Evolving Landscape of Inclusive Research and Improved Clinical Trial Access.

Current clinical research does not reflect the diversity of patient populations, despite continued recommendations to increase enrollment of under-represented racial and ethnic groups. The ramifications of this lack of trial diversity are important because of potential differences between races and ethnicities in response to therapies, which have been observed for drugs across indications. Nonrepresentative research populations limit the generalizability of study results, which may lead to questions about safety and efficacy in certain subgroups of patients and hinder regulators, healthcare providers, and patients in their ability to adequately consider the benefits and risks of a therapeutic treatment across all populations. Renewed efforts to address healthcare disparities and increase diversity in clinical trials have demonstrated that inclusive trials are achievable and can provide scientifically rigorous results, and, thus, should stimulate greater action across all stakeholders. Ensuring that studies throughout the clinical development process include representative populations is a scientific imperative to advance health equity, racial justice, and trust in the safety and efficacy of medical therapies. This article reviews the long-standing lack of diversity and barriers to enrollment of diverse and representative populations in clinical trials, outlines the current evolving trial landscape and the efforts of stakeholders, and provides examples from scientifically rigorous inclusive trials. The goal is to share learnings in a wider context of opportunities to enhance diversity, equity, and inclusion in clinical development while ensuring the safety and efficacy of medical therapies in all populations of patients, and in doing so, provide wider patient access to therapeutic treatments.

Listeria monocytogenes Cerebritis and Infective Endocarditis in an Immunocompetent Adult: A Rare Clinical Manifestation.

Cerebritis and infective endocarditis caused by Listeria monocytogenes are very rare. A 56-year-old man presented with slurring of speech and generalized body weakness of 1 week duration. He did not have any past medical history. On systemic examination, he had mild slurring of speech and facial asymmetry and was initially treated for multifocal chronic cerebral infarcts. Listeria monocytogenes was isolated from blood culture on day 5 of admission. A diagnosis of neurolisteriosis was made as contrast-enhanced-computed tomography (CECT) of the brain showed right frontal cerebritis. He was treated with intravenous benzyl penicillin. His general condition was improving until day 13 of hospitalization whereby he developed haemoptysis and severe Type 1 respiratory failure requiring reintubation. An urgent transthoracic echocardiogram revealed a large vegetation at the anterior mitral valve leaflet measuring 2.01 cm. No active arterial bleeding was seen on computed tomography angiography (CTA) of the thorax. Magnetic resonance imaging (MRI) of the brain showed evidence of right frontal cerebritis. He continued to deteriorate and succumbed to his illness after 3 weeks of hospitalization. Clinicians should be aware of such an occurrence and prompt recognition and adequate treatment are necessary in cases of Listeria monocytogenes cerebritis and infective endocarditis as both are deadly entities.

Mechanical ventilation for COVID-19: Outcomes following discharge from inpatient treatment.

Though mechanical ventilation (MV) is used to treat patients with severe coronavirus disease 2019 (COVID-19), little is known about the long-term health implications of this treatment. Our objective was to determine the association between MV for treatment of COVID-19 and likelihood of hospital readmission, all-cause mortality, and reason for readmission. This study was a longitudinal observational design with electronic health record (EHR) data collected between 3/1/2020 and 1/31/2021. Participants included 17,652 patients hospitalized for COVID-19 during this period who were followed through 6/30/2021. The primary outcome was readmission to inpatient care following discharge. Secondary outcomes included all-cause mortality and reason for readmission. Rates of readmission and mortality were compared between ventilated and non-ventilated patients using Cox proportional hazards regression models. Differences in reasons for readmission by MV status were compared using multinomial logistic regression. Patient characteristics and measures of illness severity were balanced between those who were mechanically ventilated and those who were not utilizing 1-to-1 propensity score matching. The sample had a median age of 63 and was 47.1% female. There were 1,131 (6.4%) patients who required MV during their initial hospitalization. Rates (32.1% versus 9.9%) and hazard of readmission were greater for patients requiring MV in the propensity score-matched samples [hazard ratio (95% confidence interval) = 3.34 (2.72-4.10)]. Rates (15.3% versus 3.4%) and hazard [hazard ratio (95% confidence interval) = 3.12 (2.32-4.20)] of all-cause mortality were also associated with MV status. Ventilated patients were more likely to be readmitted for reasons which were classified as COVID-19, infectious diseases, and respiratory diagnoses compared to non-ventilated patients. Mechanical ventilation is a necessary treatment for severely ill patients. However, it may be associated with adverse outcomes including hospital readmission and death. More intense post-discharge monitoring may be warranted to decrease this associational finding.

Considerations for Embedding Inclusive Research Principles in the Design and Execution of Clinical Trials.

There is a growing recognition that the clinical research enterprise has a diversity problem, given that many clinical trials recruit historically marginalized individuals or patients reflective of real-world data at a rate that is far below the incidence and prevalence of the disease for which the investigational therapy or device is targeting. This lack of diversity in clinical research participation can obscure the safety and efficacy of drug therapies and limits our collective ability to develop effective treatments for all patients, leading to even wider health disparities. This review article provides an in-depth analysis of the impact of this bias on public health, along with a description of some of the barriers that prevent historically marginalized populations from participating in clinical research. Some practical solutions that can be employed to increase diversity in clinical trial participation are also discussed, including the crucial role clinical trial sponsors, research organizations, patients, and caregivers need to play in supporting the industry to achieve this ambitious but necessary goal.

Outcomes during and after long-term tocilizumab treatment in patients with giant cell arteritis.

OBJECTIVE: To assess outcomes in giant cell arteritis (GCA) patients during and after long-term tocilizumab (TCZ) treatment. METHODS: Retrospective analysis of GCA patients treated with TCZ at a single centre (2010-2022). Time to relapse and annualised relapse rate during and after TCZ treatment, prednisone use, and safety were assessed. Relapse was defined as reappearance of any GCA clinical manifestation that required treatment intensification, regardless of C reactive protein levels and erythrocyte sedimentation rate. RESULTS: Sixty-five GCA patients were followed for a mean (SD) of 3.1 (1.6) years. The mean duration of the initial TCZ course was 1.9 (1.1) years. The Kaplan-Meier (KM)-estimated relapse rate at 18 months on TCZ was 15.5%. The first TCZ course was discontinued due to satisfactory remission achievement in 45 (69.2%) patients and adverse events in 6 (9.2%) patients. KM-estimated relapse rate at 18 months after TCZ discontinuation was 47.3%. Compared with patients stopping TCZ at or before 12 months of treatment, the multivariable adjusted HR (95% CI) for relapse in patients on TCZ beyond 12 months was 0.01 (0.00 to 0.28; p=0.005). Thirteen patients received >1 TCZ course. Multivariable adjusted annualised relapse rates (95% CI) in all periods on and off TCZ aggregated were 0.1 (0.1 to 0.2) and 0.4 (0.3 to 0.7), respectively (p=0.0004). Prednisone was discontinued in 76.9% of patients. During the study, 13 serious adverse events occurred in 11 (16.9%) patients. CONCLUSION: Long-term TCZ treatment was associated with remission maintenance in most patients with GCA. The estimated relapse rate by 18 months after TCZ discontinuation was 47.3%.