Category: Nevin Manimala

Cancer Med. 2024 Mar;13(5). doi: 10.1002/cam4.6776.

ABSTRACT

Mivavotinib (TAK-659/CB-659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti-PD-1 therapy in cancer models. This dose-escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60-100 mg once-daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28-day cycles until disease progression or unacceptable toxicity. The dose-escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple-negative breast cancer (TNBC). During dose-escalation (n = 24), two dose-limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once-daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment-emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose-proportional (60-100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single-agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.

PMID:38501219 | DOI:10.1002/cam4.6776

JAMA. 2024 Mar 19. doi: 10.1001/jama.2024.2934. Online ahead of print.

ABSTRACT

IMPORTANCE: Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial.

OBJECTIVE: To assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU).

DESIGN, SETTING, AND PARTICIPANTS: Multicenter randomized clinical trial including 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023.

INTERVENTIONS: Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU.

MAIN OUTCOMES AND MEASURES: The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days.

RESULTS: Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adverse events or in number of days alive and out of hospital.

CONCLUSION AND RELEVANCE: In adult ICU patients with COVID-19 and severe hypoxemia, targeting a Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04425031.

PMID:38501214 | DOI:10.1001/jama.2024.2934

JAMA. 2024 Mar 19. doi: 10.1001/jama.2024.3376. Online ahead of print.

NO ABSTRACT

PMID:38501213 | DOI:10.1001/jama.2024.3376

J Sex Med. 2024 Mar 18:qdae019. doi: 10.1093/jsxmed/qdae019. Online ahead of print.

ABSTRACT

BACKGROUND: Genital self-image is among the factors affecting women’s sexual function.

AIM: The present study aimed to determine changes in the genital self-image and its relationship with women’s sexual function in the third trimester of pregnancy and postpartum.

METHODS: The participants of this prospective cohort study included 301 eligible pregnant women chosen through stratified random sampling with proportional allocation from comprehensive health centers in Gorgan, Iran. The Persian version of the 7-item Female Genital Self-Image Scale, the 6-item Female Sexual Function Index, and Depression Anxiety and Stress Scale 21 were filled in a self-report manner on 2 occasions: (1) 30 to 37 weeks of pregnancy and (2) 12 to 16 weeks (± 2 weeks) postpartum. Finally, the data were analyzed using SPSS 24 software.

OUTCOMES: Outcomes included Female Genital Self-Image Scale and Female Sexual Function Index changes from pregnancy to postpartum according to the childbirth mode.

RESULTS: The mean age of participants was 29.66 ± 5.27 years. These values for the genital self-image scores of women during pregnancy (19.18 ± 3.25) and postpartum (19.43 ± 3.57) were not significantly different (P = .30). Also, this difference was not statistically significant regarding the mode of delivery in 2 groups of women with vaginal birth (P = .62) and cesarean section (P = .14). The mean Female Sexual Function Index scores during pregnancy (15.15 ± 6.73) and postpartum (17.52 ± 6.46) were significantly different (P = .001). In addition, this difference was significant in women with vaginal birth (P = .004) and cesarean section (P = .001).

CLINICAL IMPLICATIONS: Clinicians should inform women/couples about changes in female sexual function and address genital self-image as a factor involved in female sexual function during pregnancy and postpartum.Strengths and Limitations: Because the participants of this study were women in the third trimester of pregnancy, the obtained results may not be generalized to pregnant women in the first and second trimesters of pregnancy or even to different postpartum periods (ie, midterm and long term).

CONCLUSION: The results showed that the female genital self-image is not significantly different during pregnancy and postpartum, or with the mode of delivery. However, the female sexual function score in postpartum is higher than in pregnancy, regardless of the mode of delivery.

PMID:38501193 | DOI:10.1093/jsxmed/qdae019

Nurs Manag (Harrow). 2024 Mar 19. doi: 10.7748/nm.2024.e2104. Online ahead of print.

ABSTRACT

BACKGROUND: There is increasing research interest in the relationship between ethical leadership and deviant workplace behaviour. Ethical leadership encompasses altruism, courage, ethical orientation, integrity and fairness. Examples of deviant workplace behaviours include theft, fraud, sabotage, assault, abuse, manipulation and bullying. It appears that when leaders are fair and emphasise ethical conduct, followers are less inclined to engage in deviant workplace behaviour.

AIM: To investigate the relationship between nurses’ self-rated levels of deviant workplace behaviour and perceived levels of ethical leadership in managers.

METHOD: For this descriptive correlational study, 355 nurses from one university hospital in Egypt responded to an online questionnaire comprising the Ethical Leadership Scale and the Workplace Deviance Behavior Scale. Descriptive and inferential statistics were used to explore results and examine the relationships between study variables.

RESULTS: There was a statistically significant negative relationship between respondents’ self-rated levels of deviant workplace behaviour and their perceptions of levels of ethical leadership in managers. The results appeared to confirm previous research. Nurses who feel that they are treated fairly by their managers tend to have positive attitudes towards work, colleagues and management.

CONCLUSION: Ethical leadership on the part of managers is a significant determinant of nurses’ behaviour in the workplace and should therefore be fostered by healthcare organisations.

PMID:38501169 | DOI:10.7748/nm.2024.e2104

Am J Hypertens. 2024 Mar 19:hpae033. doi: 10.1093/ajh/hpae033. Online ahead of print.

ABSTRACT

BACKGROUND: While Renin-Angiotensin System (RAS) inhibitors have a longstanding history in blood pressure control, their suitability as first-line in-patient treatment may be limited due to prolonged half-life and kidney failure concerns.

METHODS: Using a cohort design, we assessed the impact of RAS inhibitors, either alone or in combination with beta-blockers, on mortality, while exploring interactions, including those related to end-stage renal disease and serum creatinine levels. Eligible subjects were AIS patients aged 18 or older with specific subtypes who received in-patient antihypertensive treatment. The primary outcome was mortality rates. Statistical analyses included cross-sectional and longitudinal approaches, employing generalized linear models, G-computation, and discrete time survival analysis over a 20-day follow-up period.

RESULTS: In our study of 3058 AIS patients, those using RAS inhibitors had significantly lower in-hospital mortality (2.2%) compared to non-users (12.1%), resulting in a relative risk (RR) of 0.18 (95% CI 0.12-0.26). Further analysis using G-computation revealed a marked reduction in mortality risk associated with RAS inhibitors (0.0281 vs. 0.0913, Risk Difference (RD) of 6.31% or 0.0631, 95% CI 0.046-0.079). Subgroup analysis demonstrated notable benefits, with individuals having creatinine levels below and above 1.3 mg/dL exhibiting statistically significant RD (RD -0.0510 vs. -0.0895), and a significant difference in paired comparison (-0.0385 or 3.85%, CI 0.023-0.054). Additionally, longitudinal analysis confirmed a consistent daily reduction of 0.93% in mortality risk associated with the intake of RAS inhibitors.

CONCLUSION: RAS inhibitors are associated with a significant reduction in in-hospital mortality in AIS patients, suggesting potential clinical benefits in improving patient outcomes.

PMID:38501167 | DOI:10.1093/ajh/hpae033

J Biopharm Stat. 2024 Mar 19:1-28. doi: 10.1080/10543406.2024.2330213. Online ahead of print.

ABSTRACT

For the approval of a drug product, the United States Food and Drug Administration requires substantial evidence (SE) regarding effectiveness and safety of the test drug to be provided. In recent years, the use of real-world data in support of regulatory submission of pharmaceutical development has received much attention, and real-world evidence (RWE) is treated as complementary to SE by evaluating the real-world performance of the test treatment. In this article, we start by summarizing current regulatory perspectives on drug evaluation and some potential challenges in using RWE. To test for superiority in co-primary endpoints, a two-stage hybrid RCT/RWS adaptive design that combines randomized control trial for providing SE and real-world study for generating RWE is proposed. We use superiority in effectiveness and non-inferiority in safety as an example to illustrate how to implement this design. Numerical studies have shown that the proposed design has merits in reducing the required sample size compared with traditional co-primary endpoint tests while maintaining statistical power and controlling type I error inflation. The proposed design can be implemented in drug development considering co-primary endpoints, especially for oncology and rare disease drug development.

PMID:38501166 | DOI:10.1080/10543406.2024.2330213

Trauma Surg Acute Care Open. 2024 Mar 15;9(1):e001412. doi: 10.1136/tsaco-2024-001412. eCollection 2024.

NO ABSTRACT

PMID:38501133 | PMC:PMC10946341 | DOI:10.1136/tsaco-2024-001412

BMJ Neurol Open. 2024 Mar 13;6(1):e000544. doi: 10.1136/bmjno-2023-000544. eCollection 2024.

ABSTRACT

Background There are increasing reports of cases of Guillain-Barré syndrome (GBS), as an adverse event of an immune checkpoint inhibitor (ICI) but postmarket data on the incidence of this remains scarce. This study sought to conduct a comprehensive review of GBS events arising as a secondary outcome of ICI treatments in real-world patients, using the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods Data covering the period from the third quarter of 2003 to the second quarter of 2023 were extracted from the FAERS database. GBS cases (associated with the usage of avelumab, atezolizumab, ipilimumab, nivolumab and pembrolizumab) were subjected to disproportionality analysis to detect potential signals. Results A total of 2208 reports of GBS were identified within the FAERS database, with 242 of these cases (10.9%) being associated with ICIs. All five drugs exhibited a disproportionality in the reporting of adverse events, with the highest observed for avelumab (reporting OR, ROR: 29.8), followed by atezolizumab (ROR: 17.0), ipilimumab (ROR: 16.0), pembrolizumab (ROR: 11.9) and nivolumab (ROR: 8.2). Conclusion These checkpoint inhibitors are associated with a statistically significant disproportionate number of reports of GBS as an adverse event, with avelumab being the ICI with the highest association. The present pharmacovigilance study serves as a valuable tool, offering a more comprehensive and nuanced perspective on GBS associated with ICIs. This study contributes to a deeper comprehension of this rare adverse drug effect.

PMID:38501128 | PMC:PMC10946360 | DOI:10.1136/bmjno-2023-000544

Front Endocrinol (Lausanne). 2024 Mar 4;15:1334418. doi: 10.3389/fendo.2024.1334418. eCollection 2024.

ABSTRACT

BACKGROUND: Secretory leukocyte protease inhibitor (SLPI) is a multifunctional protein involved in the chronic inflammatory process, implicated in the pathogenesis of diabetic kidney disease (DKD). However, its potential as a diagnostic and prognostic biomarker of DKD has yet to be evaluated. This study explored the clinical utility of SLPI in the diagnosis and prognosis of renal endpoint events in patients with DKD.

METHODS: A multi-center cross-sectional study comprised of 266 patients with DKD and a predictive cohort study comprised of 120 patients with stage IV DKD conducted between December 2016 and January 2022. The clinical parameters were collected for statistical analysis, a multivariate Cox proportional hazards model was used to evaluate the independent risk factors for renal endpoints.

RESULTS: Serum SLPI levels gradually increased with DKD progression (p<0.01). A significant correlation was observed between serum SLPI levels and renal function in patients with DKD. The mean follow-up duration in this cohort study was 2.32 ± 1.30 years. Multivariate Cox regression analysis showed SLPI levels≥51.61ng/mL (HR=2.95, 95% CI[1.55, 5.60], p<0.01), 24h urinary protein levels≥3500 mg/24h (HR=3.02, 95% CI[1.66, 5.52], p<0.01), Alb levels<30g/l (HR=2.19, 95% CI[1.12, 4.28], p<0.05), HGB levels<13g/dl (HR=3.18, 95% CI[1.49, 6.80], p<0.01), and urea levels≥7.1 mmol/L (HR=8.27, 95% CI[1.96, 34.93], p<0.01) were the independent risk factors for renal endpoint events in DKD patients.

CONCLUSIONS: Serum SLPI levels increased with DKD progression and were associated with clinical parameters of DKD. Moreover, elevated SLPI levels showed potential prognostic value for renal endpoint events in individuals with DKD. These findings validate the results of previous studies on SLPI in patients with DKD and provide new insights into the role of SLPI as a biomarker for the diagnosis and prognosis of DKD that require validation.

PMID:38501106 | PMC:PMC10944902 | DOI:10.3389/fendo.2024.1334418