Nevin Manimala

J Phys Chem Lett. 2024 Aug 19:8697-8705. doi: 10.1021/acs.jpclett.4c01954. Online ahead of print.

ABSTRACT

In this work, we study the synthesis of glycine, the simplest amino acid, using ab initio molecular dynamics and enhanced sampling techniques to explore and quantify novel potential pathways. Our protocol integrates state-of-the-art machine learning approaches, allowing us to sample relevant chemical spaces more efficiently. We discover a novel “oxyglycolate path”, distinct from the “standard” Strecker mechanism, identify new intermediates, and provide a full thermodynamic characterization of all reaction steps. This alternative pathway aligns better with meteoritic and experimental observations, paving the way for further investigations. Integrating quantum accuracy and machine learning in prebiotic chemistry represents a methodological milestone advancing the exploration of life’s prebiotic origins.

PMID:39159425 | DOI:10.1021/acs.jpclett.4c01954

JCO Clin Cancer Inform. 2024 Aug;8:e2400094. doi: 10.1200/CCI.24.00094.

ABSTRACT

PURPOSE: No consensus about the effectiveness of prostate-specific antigen (PSA) screening exists among clinical guidelines, especially for the elderly. Randomized trials of PSA screening have yielded different results, partly because of variations in adherence, and it is unlikely that new trials will be conducted. Our objective was to estimate the effect of annual PSA screening on prostate cancer (PC) mortality in Medicare beneficiaries age 67-84 years.

METHODS: This is a large-scale, population-based, observational study of two screening strategies: annual PSA screening and no screening. We used data from 537,599 US Medicare (2001-2008) beneficiaries age 67-84 years who had a good life expectancy, no previous PC, and no PSA test in the 2 years before baseline. We estimated the 8-year PC mortality and incidence, treatments for PC, and treatment complications of PSA screening.

RESULTS: In men age 67-74 years, the estimated difference in 8-year risk of PC death between PSA screening and no screening was -2.3 (95% CI, -4.1 to -1.1) deaths per 1,000 men (a negative risk difference favors screening). Treatment complications were more frequent under PSA screening than under no screening. In men age 75-84 years, risk difference estimates were closer to zero.

CONCLUSION: Our estimates suggest that under conventional statistical criteria, annual PSA screening for 8 years is highly compatible with reductions of PC mortality from four to one fewer PC deaths per 1,000 screened men age 67-74 years. As with any study using real-world data, the estimates could be affected by residual confounding.

PMID:39159422 | DOI:10.1200/CCI.24.00094

J Clin Oncol. 2024 Aug 19:JCO2400427. doi: 10.1200/JCO.24.00427. Online ahead of print.

ABSTRACT

PURPOSE: The US Food and Drug Administration (FDA) approved capivasertib in combination with fulvestrant for adult patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced, or metastatic breast cancer (MBC) who have received at least one previous endocrine therapy and whose tumors harbor one or more phosphatidylinositol 3-kinase (PIK3CA)/AKT Serine/Threonine Kinase 1 (AKT1)/phosphatase and tensin homolog (PTEN) alterations, as detected by an FDA-approved test.

PATIENTS AND METHODS: Approval was based on CAPItello-291, a randomized, double-blind, multicenter trial of 708 patients with hormone receptor-positive, HER2-negative advanced or MBC, including 289 patients with PIK3CA/AKT1/PTEN tumor alterations. Patients were randomly assigned 1:1 to receive capivasertib 400 mg twice daily for 4 days per week with fulvestrant versus placebo with fulvestrant. Random assignment was stratified by presence of liver metastases, previous treatment with CDK4/6i, cyclin-dependent kinase four and six (CDK4/6) inhibitors, and geographical region.

RESULTS: A statistically significant progression-free survival (PFS) benefit was demonstrated in the overall population (hazard ratio [HR], 0.6 [95% CI, 0.51 to 0.71]); this result was driven by 289 patients in the biomarker-positive population (HR, 0.5 [95% CI, 0.37 to 0.68]). An exploratory analysis of investigator-assessed PFS in the 313 (44%) patients in the biomarker-negative population showed uncertain benefit (HR, 0.78 [95% CI, 0.60 to 1.01]). With capivasertib, more patients had Grade ≥3 toxicities. Key concerns included hyperglycemia (18% all-grade, 2.8% Grade ≥3), cutaneous toxicity (58% all-grade, 17% Grade ≥3), and diarrhea (72% all-grade, 9% Grade ≥3).

CONCLUSION: Capivasertib with fulvestrant was approved for patients whose tumors harbored PIK3CA/AKT1/PTEN alterations. Benefit-risk assessment in this subgroup was favorable based on a statistically significant and clinically meaningful improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in overall survival. By contrast, the benefit-risk was unfavorable in the biomarker-negative population.

PMID:39159418 | DOI:10.1200/JCO.24.00427

Neurology. 2024 Sep 10;103(5):e209746. doi: 10.1212/WNL.0000000000209746. Epub 2024 Aug 19.

ABSTRACT

BACKGROUND AND OBJECTIVES: Gender disparities have been demonstrated across several medical specialties, including neurology. Although women have comprised most of the child neurology trainees since 2007, it is not apparent whether this demographic shift is reflected in the Child Neurology Society (CNS) awards and leadership. This study aimed to evaluate the differences in gender representation among leadership positions and award recipients within the CNS. The primary outcome measure was the total number of board of director (BOD) positions or awards given by gender each year.

METHODS: A retrospective review of publicly available data was conducted on CNS members, post-training award recipients, and BOD positions, including nomination records, from 1972 to 2023. Data abstracted were restricted to gender to preserve member and nominee anonymity. Gender identification and consensus were determined through a combination of strategies and study members. Data analysis included descriptive statistics, Pearson χ² test, and the exact binomial test to compare gender proportions and the probability of being underrepresented in awards, leadership, and nominations over time. Data are presented according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.

RESULTS: From 1972 to 2023, women represented 29% (44/152) of the BOD positions and 26% (61/236) of post-training award recipients presented by the CNS. Despite the increase in the proportion of women in child neurology, the overall gap in gender representation in leadership positions remains broadly stable. Only 13% (4/32) of CNS presidents have been women, a significant underrepresentation (95% CI 2.3%-52%, p < 0.004), although the representation of women in nonpresidential positions increased from 2003 to 2023. Women are also underrepresented as overall awardees (95% CI 12%-38%, p < 0.00001) except for the Philip R. Dodge Young Investigator Award, which is an investigator-initiated application.

DISCUSSION: Women remain underrepresented at the highest levels of recognition in child neurology despite representing most of the field. Reasons for disparities are known to be multifactorial and likely include gender bias and structural sexism. We present several discussion topics that seek to rationalize this disparity and provide suggestions for improving diversity, equity, and inclusion for leadership roles and awards.

PMID:39159414 | DOI:10.1212/WNL.0000000000209746

JCO Glob Oncol. 2024 Aug;10:e2400141. doi: 10.1200/GO.24.00141.

ABSTRACT

PURPOSE: Standard-dose immune checkpoint inhibitors (SD-ICIs) are the standard of care as initial therapy in microsatellite instable-high (MSI-H) advanced/metastatic colorectal adenocarcinomas (mCRC), but there are preclinical data to suggest that low-dose ICIs (LD-ICI) might also have similar efficacy.

MATERIALS AND METHODS: A retrospective study of patients with MSI-H mCRC receiving ICIs between June 2017 and January 2023 was conducted. The primary end point of the study was 12-month progression-free survival (PFS), which was computed using the Kaplan-Meier method.

RESULTS: A total of 65 patients were available for analysis during the study period. Sixty patients (92%) received nivolumab, whereas the remaining received pembrolizumab. First-line ICIs were received by 18 patients (28%), whereas 47 patients (72%) received ICIs during later lines. Thirty patients (47%) received LD-ICIs (all received nivolumab), with the remaining receiving SD-ICIs (53%). At a median follow-up of 16.5 (95% CI, 11.8 to 21.2) months, median PFS was not reached in the entire cohort. The 12-month PFS rate in the LD-ICI cohort was 90%, whereas it was 75.8% in the SD-ICI cohort. There were no statistical differences in patients receiving ICIs as first-line therapy (12 months PFS-94.4%) or during later lines of therapy (12-month PFS-77.9%; P = .56).

CONCLUSION: ICIs in the current study show survivals which are similar to those seen in seminal trials in patients with MSI-H mCRC. Low-dose ICIs appear to work in MSI-H mCRC and should be explored prospectively in clinical trials. Patients with MSI-H status should be exposed to ICIs, whether initially or later during treatment, whenever feasible.

PMID:39159410 | DOI:10.1200/GO.24.00141

Proc Natl Acad Sci U S A. 2024 Aug 27;121(35):e2405351121. doi: 10.1073/pnas.2405351121. Epub 2024 Aug 19.

ABSTRACT

Matter entanglement is a common chaotic structure found in both quantum and classical systems. For classical turbulence, viscous vortices are like sinews in fluid flows, storing and dissipating energy and accommodating strain and stress throughout a complex vortex network. However, to explain how the statistical properties of turbulence arise from elemental vortical structures remains challenging. Here, we use the quantum vortex tangle as a skeleton to generate an instantaneous classical turbulent field with intertwined vortex tubes. Combining the quantum skeleton and tunable vortex thickness makes the synthetic turbulence satisfy key statistical laws, offering valuable insights for elucidating energy cascade and extreme events. By manipulating the elemental structures, we customize turbulence with desired statistical features. This bottom-up approach of designing turbulence provides a testbed for analyzing and modeling turbulence.

PMID:39159373 | DOI:10.1073/pnas.2405351121

Invest Radiol. 2024 Aug 20. doi: 10.1097/RLI.0000000000001117. Online ahead of print.

ABSTRACT

OBJECTIVES: The aim of this study was to compare the performances of photon-counting detector computed tomography (PCD-CT) and energy-integrating detector computed tomography (EID-CT) for visualizing nodules and airways in human cadaveric lungs.

MATERIALS AND METHODS: Previously obtained 20 cadaveric lungs were scanned, and images were prospectively acquired by EID-CT and PCD-CT at a radiation dose with a noise level equivalent to the diagnostic reference level. PCD-CT was scanned with ultra-high-resolution mode. The EID-CT images were reconstructed with a 512 matrix, 0.6-mm thickness, and a 350-mm field of view (FOV). The PCD-CT images were reconstructed at 3 settings: PCD-512: same as EID-CT; PCD-1024-FOV350: 1024 matrix, 0.2-mm thickness, 350-mm FOV; and PCD-1024-FOV50: 1024 matrix, 0.2-mm thickness, 50-mm FOV. Two specimens per lung were examined after hematoxylin and eosin staining. The CT images were evaluated for nodules on a 5-point scale and for airways on a 4-point scale to compare the histology. The Wilcoxon signed rank test with Bonferroni correction was performed for statistical analyses.

RESULTS: Sixty-seven nodules (1321 μm; interquartile range [IQR], 758-3105 μm) and 92 airways (851 μm; IQR, 514-1337 μm) were evaluated. For nodules and airways, scores decreased in order of PCD-1024-FOV50, PCD-1024-FOV350, PCD-512, and EID-CT. Significant differences were observed between series other than PCD-1024-FOV350 versus PCD-1024-FOV50 for nodules (PCD-1024-FOV350 vs PCD-1024-FOV50, P = 0.063; others P < 0.001) and between series other than EID-CT versus PCD-512 for airways (EID-CT vs PCD-512, P = 0.549; others P < 0.005). On PCD-1024-FOV50, the median size of barely detectable nodules was 604 μm (IQR, 469-756 μm) and that of barely detectable airways was 601 μm (IQR, 489-929 μm). On EID-CT, that of barely detectable nodules was 837 μm (IQR, 678-914 μm) and that of barely detectable airways was 1210 μm (IQR, 674-1435 μm).

CONCLUSIONS: PCD-CT visualized small nodules and airways better than EID-CT and improved with high spatial resolution and potentially can detect submillimeter nodules and airways.

PMID:39159364 | DOI:10.1097/RLI.0000000000001117

Cutis. 2024 Jul;114(1):12-14. doi: 10.12788/cutis.1053.

NO ABSTRACT

PMID:39159339 | DOI:10.12788/cutis.1053

Clin Nurse Spec. 2024 Sep-Oct 01;38(5):229-236. doi: 10.1097/NUR.0000000000000839.

ABSTRACT

AIM: The aim of this study was to examine the effect of laughter yoga applied to intensive care nurses on perceived stress, job motivation, and mental well-being.

DESIGN: This study was a randomized controlled trial.

METHODS: The study was conducted with nurses working at the university hospital’s surgical intensive care and anesthesia intensive care units of the third-level intensive care unit in Turkey. Data obtained from 30 participants in the intervention group and 33 participants in the control group were analyzed. The Nurse Introduction Form, Nurse Job Motivation Scale, Perceived Stress Scale, and Warwick-Edinburgh Mental Well-being Scale were used to collect data. Data obtained from the study were evaluated using the SPSS 22.0 package.

RESULTS: It was determined that there was no statistically significant difference in the average scores of the pretest/posttest 1/posttest 2 of the Perceived Stress Scale (13.70 ± 3.33 to 14.57 ± 4.57, P > .05; 13.50 ± 3.15 to 13.48 ± 4.59, P > .05; and 13.56 ± 3.15 to 13.15 ± 3.49, P > .05, respectively) and Work Motivation Scale (59.70 ± 7.58 to 59.69 ± 7.98, P > .05; 60.30 ± 8.07 to 58.48 ± 8.94, P > .05; and 60.56 ± 7.86 to 57.93 ± 9.54, P > .05, respectively) for both the intervention and control groups of nurses. A statistically significant difference was found in the average scores of the Warwick-Edinburgh Mental Well-Being Scale pretest/posttest 1/posttest 2 for the intervention group of nurses (50.90 ± 7.60, 51.50 ± 7.80, and 53.70 ± 7.08, respectively; F = 3.330, P = .043). However, the difference was found to be insignificant in pairwise comparisons in the further analysis (a = b = c). It was determined that there was no statistically significant difference in the average scores of the Warwick-Edinburgh Mental Well-Being Scale pretest/posttest 1/posttest 2 for the control group of nurses (52.21 ± 9.89, 51.93 ± 10.45, and 51.03 ± 9.63, respectively; P > .05).

CONCLUSIONS: The application of laughter yoga on intensive care nurses did not result in a significant change in perceived stress levels and work motivation. However, statistically significant differences were observed in the average mental well-being scores among the intervention group.

PMID:39159324 | DOI:10.1097/NUR.0000000000000839

Urogynecology (Phila). 2024 Aug 12. doi: 10.1097/SPV.0000000000001541. Online ahead of print.

ABSTRACT

IMPORTANCE: Up to 50% of patients report not readily seeking treatment for pelvic floor disorders (PFDs). The increase in phone applications (apps) for health care information is an opportunity to increase access to care.

OBJECTIVE: The aim of the study was to systematically evaluate content and function of apps for patients with PFDs.

STUDY DESIGN: Apps were screened using PFD-related search terms. Included apps were on the Apple store, in English, and targeted patients with PFDs. The primary outcome was app quality based on the APPLICATIONS scoring system (scored 0-16). Secondary outcomes included professional medical involvement, iTunes rating details, the presence of a voiding/bowel diary, tracking of diet, pain/symptoms, exercise, and medication, graphing or social functions, reminders, disease information, and decision support. Data was reported with descriptive statistics (medians (ranges) and n (percentages).

RESULTS: Eight hundred forty apps were identified and 83 were analyzed. The top 3 PFD categories represented were defecatory dysfunction (29), overactive bladder (28), and stress incontinence (27). The median APPLICATIONS score was 7 (3-12). Most apps (78%) were developed without professional medical involvement. Most apps were free, while the remainder ranged from $1.99 to $4.99. No app had all features. Twenty-five apps (30%) included a voiding diary, 33 (40%) had a bowel diary, 27 (33%) included exercise tracking, and 44 (53%) had reminder systems.

CONCLUSIONS: Most apps had reasonable, but not high, functionality. Current apps provide varying degrees of overall utility, with limited disease information and decision support. Further collaboration with medical providers in app development would support better integration of clinician and patient needs.

PMID:39159315 | DOI:10.1097/SPV.0000000000001541