Category: Nevin Manimala

J Am Chem Soc. 2023 Jun 27. doi: 10.1021/jacs.3c01412. Online ahead of print.

ABSTRACT

Structural dynamics of water and its hydrogen-bonding networks play an important role in enzyme function via the transport of protons, ions, and substrates. To gain insights into these mechanisms in the water oxidation reaction in Photosystem II (PS II), we have performed crystalline molecular dynamics (MD) simulations of the dark-stable S₁ state. Our MD model consists of a full unit cell with 8 PS II monomers in explicit solvent (861 894 atoms), enabling us to compute the simulated crystalline electron density and to compare it directly with the experimental density from serial femtosecond X-ray crystallography under physiological temperature collected at X-ray free electron lasers (XFELs). The MD density reproduced the experimental density and water positions with high fidelity. The detailed dynamics in the simulations provided insights into the mobility of water molecules in the channels beyond what can be interpreted from experimental B-factors and electron densities alone. In particular, the simulations revealed fast, coordinated exchange of waters at sites where the density is strong, and water transport across the bottleneck region of the channels where the density is weak. By computing MD hydrogen and oxygen maps separately, we developed a novel Map-based Acceptor-Donor Identification (MADI) technique that yields information which helps to infer hydrogen-bond directionality and strength. The MADI analysis revealed a series of hydrogen-bond wires emanating from the Mn cluster through the Cl1 and O4 channels; such wires might provide pathways for proton transfer during the reaction cycle of PS II. Our simulations provide an atomistic picture of the dynamics of water and hydrogen-bonding networks in PS II, with implications for the specific role of each channel in the water oxidation reaction.

PMID:37369071 | DOI:10.1021/jacs.3c01412

Acad Med. 2023 Jun 27. doi: 10.1097/ACM.0000000000005308. Online ahead of print.

ABSTRACT

PURPOSE: This study examines how internal medicine clerkship faculty and leadership conceptualize professionalism and professional behaviors and attitudes, identifies whether and how faculty use metrics to assess professionalism and factor it into clerkship grades, and describes barriers that prevent faculty from feeling prepared to support the development of professional behaviors in students.

METHOD: The Clerkship Directors in Internal Medicine opened a call for thematic survey section proposals to its physician-faculty members, blind-reviewed all submissions, and selected 4 based on internal medicine clinical clerkship training experience relevance. The survey launched on October 5 and closed on December 7, 2021. Data were analyzed using descriptive statistics.

RESULTS: Of 137 core clerkship directors (CDs) at Liaison Committee on Medical Education-accredited medical schools, 103 (75.2%) responded to the survey. Of 102 respondents (1 nonrespondent), 84 (82.4%) identified professional behavior lapses in involvement and 60 (58.8%) identified introspection lapses. Of 103 respondents, 97 (94.2%) reported that their clerkships ask clinical faculty and residents to formally evaluate professionalism, and 64 (62.1%) reported that they factor professionalism assessments into final clerkship grades. CDs reported multiple barriers to addressing professionalism directly with students, including logistical barriers, professionalism assessment subjectivity concerns, and the possible adverse effect of an unprofessional label for students.

CONCLUSIONS: Professionalism assessment and remediation in medical education currently center on a deficit model that seeks to identify and remediate professionalism lapses, rather than a developmental model that seeks to nurture growth. This dichotomous characterization of behaviors as professional or unprofessional limits assessment and can adversely affect the learning environment. The authors propose a shift to a developmental model that considers professionalism as a continuous process parallel to the acquisition of clinical skills and medical knowledge.

PMID:37369066 | DOI:10.1097/ACM.0000000000005308

Hum Mol Genet. 2023 Jun 27:ddad097. doi: 10.1093/hmg/ddad097. Online ahead of print.

ABSTRACT

Recently a nonparametric method has been proposed to impute the genetic component of a trait for a large set of genotyped individuals based on a separate GWAS summary dataset of the same trait (from the same population). The imputed trait may contain linear, non-linear and epistatic effects of genetic variants, thus can be used for downstream linear or non-linear association analyses and machine learning tasks. Here we propose an extension of the method to impute both genetic and environmental components of a trait using both SNP-trait and omics-trait association summary data. We illustrate an application to a UK Biobank subset of individuals (n ≈ 80 K) with both body mass index (BMI) GWAS data and metabolomic data. We divided the whole dataset into two equally sized and non-overlapping training and test datasets; we used the training data to build SNP- and metabolite-BMI association summary data and impute BMI on the test data. We compared the performance of the original and new imputation methods. As by the original method, the imputed BMI values by the new method largely retained SNP-BMI association information; however, the latter retained more information about BMI-environment associations, and were more highly correlated with the original observed BMI values.

PMID:37369060 | DOI:10.1093/hmg/ddad097

Med Ultrason. 2023 Jun 26;25(2):161-167. doi: 10.11152/mu-3938.

ABSTRACT

AIMS: Charcot-Marie-Tooth disease type 1A (CMT1A) is characterized by enlargement and stiffness of peripheral nerves due to edema with large numbers of “onion bulbs” in the endoneurium. Ultrasound elastography seems to be an ideal method to detect this condition. The aim of this study was to analyze the shear wave elastography (SWE) features of peripheral nerves in patients with CMT1A.

MATERIAL AND METHODS: We included 24 CMT1A patients with a mean age of 28 years, along with 24 age- and gender-matched controls. All patients presented with mutations of the PMP22 gene and showed length-dependent polyneuropathy. The motor nerve conduction velocity (MNCV) of the median nerve ranged from 5.2 to 37.4 m/s. SWE and cross-sectional area (CSA) were used to evaluate the bilateral median nerves at predefined sites in both patients and con-trols.

RESULTS: The average elastography value (EV) of the median nerve was 73.5±11.7 kPa in patients with CMT1A and 37.5±6.1 kPa in control subjects. The difference between the two groups was statistically significant (P<0.05). In CMT1A pa-tients, the average EV at the proximal and distal parts of the median nerve were 81.4±9.4 kPa and 65.2±8.1 kPa, respectively. The average CSAs at the proximal and distal parts of the median nerve were 0.29±0.06 cm2 and 0.20±0.05 cm2, respectively. The EV on SWE was positively correlated with CSA (p< 0.01) and negatively correlated with MNCV in the median nerve (p< 0.01).

CONCLUSIONS: Peripheral nerve stiffness dramatically increases in CMT1A and is correlated with the severity of nerve involvement.

PMID:37369047 | DOI:10.11152/mu-3938

Med Ultrason. 2023 Jun 26;25(2):153-160. doi: 10.11152/mu-3877.

ABSTRACT

AIM: This study aimed to use high-frequency ultrasound guidance to compare the efficacy of percutaneous release combined with intra-tendon sheath injection (PR-ITSI) and percutaneous release only (PR-ONLY) in the treatment of adult trigger finger (TF) patients.

MATERIALS AND METHODS: A total of 48 patients were randomly divided into PR-ITSI group and PR-ONLY group. The thickness of the A1 pulley was measured prior to surgery and 1-year after surgery. Visual Analogue Scale (VAS) score and Patient Global Impression of Improvement (PGI-I) scale score of affected fingers were evaluated at 1 day, 1 month, and 1 year after surgery.

RESULTS: The overall difference of VAS score between the two groups after treatment was statistically significant (p<0.001), while the VAS scores gradually decreased in both groups at different time-points after treatment. The VAS scores in the PR-ITSI group at 1 day and 1 month after surgery were 1.475 and 0.904 (p<0.001), respectively, which were lower than those in the PR-ONLY group. Different treatment methods had no effect on the VAS score at 1 year after surgery (p=0.055). The thickness of the A1 pulley at 1 year after surgery was lower than that before surgery (p<0.001), whereas there was no significant difference in A1 pulley thickness between the two groups (p=0.095). The rate of PGI-I scale improvement by one grade at 1 day, 1 month, and 1 year after surgery in the PR-ITSI group was 15.322 times (95%CI: 4.466-52.573, p<0.001), 14.807 times (95%CI: 2.931-74.799, p=0.001), and 15.557 times (95%CI: 1.119-216.307, p=0.041), respectively, than that in the PR-ONLY group.

CONCLUSION: Ultrasound-guided PR-ITSI is superior to PR-ONLY in the VAS score and PGI-I scale for adult TF patients.

PMID:37369046 | DOI:10.11152/mu-3877

J Natl Cancer Inst. 2023 Jun 27:djad116. doi: 10.1093/jnci/djad116. Online ahead of print.

ABSTRACT

BACKGROUND: Radiation-induced secondary breast cancer may be a concern after radiotherapy for primary breast cancer (PBC), especially in young germline (g)BRCA-associated breast cancer patients with already high contralateral breast cancer (CBC) risk and potentially increased genetic susceptibility to radiation.

AIM: To investigate whether adjuvant radiotherapy for PBC increases the risk of CBC in gBRCA1/2-associated BC patients.

METHODS: gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between radiotherapy (yes versus no) and CBC risk. We further stratified for BRCA status and PBC age (<40 and >40 years). Statistical significance tests were two-sided.

RESULTS: Of 3,602 eligible patients, 2,297 (64%) received adjuvant radiotherapy. Median follow-up was 9.6 years. The radiotherapy group had more stage III PBC patients compared to the non-radiotherapy group (15% versus 3%, p < 0.001), received more often chemotherapy (81% vs. 70%, p < 0.001) and endocrine therapy (50% vs. 35%, p < 0.001). The radiotherapy group had an increased CBC risk compared to the non-radiotherapy group (adjusted HR: 1.44, 95% CI: 1.12-1.86). Statistical significance was observed in gBRCA2 (HR: 1.77, 95% CI: 1.13-2.77), but not in gBRCA1 pathogenic variant carriers (HR: 1.29, 95% CI: 0.93-1.77; p-value for interaction, 0.39). In the combined gBRCA1/2 group, patients irradiated below and above age 40 at PBC diagnosis showed similar risks (HR: 1.38, 95% CI: 0.93-2.04 and HR: 1.56, 95% CI: 1.11-2.19, respectively).

DISCUSSION/CONCLUSION: Radiotherapy regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers.

PMID:37369040 | DOI:10.1093/jnci/djad116

Med Ultrason. 2023 Jun 19. doi: 10.11152/mu-4007. Online ahead of print.

ABSTRACT

AIM: To investigate the feasibility of assessing the ecacy of non-surgical treatment for gastric lymphoma using oral contrast-enhanced ultrasound (OCEUS) and double contrast-enhanced ultrasound (DCEUS).

MATERIAL AND METHODS: A total of 27 patients with gastric lymphoma treated nonoperatively were included in this retrospective study. The ecacy was evaluated using OCEUS and CT, respectively, and the results were tested for kappa concordance. Sixteen of the 27 patients underwent multiple DCEUS examinations before and after treatment. Micro-perfusion of the lesion in DCEUS is represented by the Echo Intensity Ratio (EIR), (echo intensity of the lymphoma lesion/echo intensity of the normal gastric wall), and one-way ANOVA was used to compare the differences between groups in EIR values before and after treatment.

RESULTS: OCEUS and CT were highly consistent in assessing the efficacy of gastric lymphoma, with a Kappa value of 0.758. During a median follow-up of 8.8 months, there was no statistical difference between the complete remission rate obtained by OCEUS and that obtained by endoscopic and CT (25.93% vs. 44.44%, p=0.154; 25.93% vs. 33.33%, p=0.766). There was also no statistical difference in the time to achieve complete remission using OCEUS assessment and endoscopy and CT (4.71±1.03 months vs. 6.01±2.14 months, p=0.088; 4.47±1.84 months vs. 6.01±2.14 months p=0.143). The difference in EIR between the groups before treat-ment and after different numbers of treatments was statistically signifficant (p<0.05), and post hoc analysis revealed this dif-ference as early as after the second treatment (p<0.05).

CONCLUSIONS: Transabdominal OCEUS and CT are comparable in the assessment of gastric lymphoma treatment ecacy. DCEUS is a noninvasive, cost-effective, and widely available method for gastric lymphoma therapeutic effect evaluation. Therefore, transabdominal OCEUS and DCEUS have the potential to be used for the early assessment of the ecacy of the non-surgical treatment of gastric lymphoma.

PMID:37369032 | DOI:10.11152/mu-4007

JMIR Form Res. 2023 Jun 27;7:e44549. doi: 10.2196/44549.

ABSTRACT

BACKGROUND: During the COVID-19 pandemic, local health authorities were responsible for managing and reporting current cases in Germany. Since March 2020, employees had to contain the spread of COVID-19 by monitoring and contacting infected persons as well as tracing their contacts. In the EsteR project, we implemented existing and newly developed statistical models as decision support tools to assist in the work of the local health authorities.

OBJECTIVE: The main goal of this study was to validate the EsteR toolkit in two complementary ways: first, investigating the stability of the answers provided by our statistical tools regarding model parameters in the back end and, second, evaluating the usability and applicability of our web application in the front end by test users.

METHODS: For model stability assessment, a sensitivity analysis was carried out for all 5 developed statistical models. The default parameters of our models as well as the test ranges of the model parameters were based on a previous literature review on COVID-19 properties. The obtained answers resulting from different parameters were compared using dissimilarity metrics and visualized using contour plots. In addition, the parameter ranges of general model stability were identified. For the usability evaluation of the web application, cognitive walk-throughs and focus group interviews were conducted with 6 containment scouts located at 2 different local health authorities. They were first asked to complete small tasks with the tools and then express their general impressions of the web application.

RESULTS: The simulation results showed that some statistical models were more sensitive to changes in their parameters than others. For each of the single-person use cases, we determined an area where the respective model could be rated as stable. In contrast, the results of the group use cases highly depended on the user inputs, and thus, no area of parameters with general model stability could be identified. We have also provided a detailed simulation report of the sensitivity analysis. In the user evaluation, the cognitive walk-throughs and focus group interviews revealed that the user interface needed to be simplified and more information was necessary as guidance. In general, the testers rated the web application as helpful, especially for new employees.

CONCLUSIONS: This evaluation study allowed us to refine the EsteR toolkit. Using the sensitivity analysis, we identified suitable model parameters and analyzed how stable the statistical models were in terms of changes in their parameters. Furthermore, the front end of the web application was improved with the results of the conducted cognitive walk-throughs and focus group interviews regarding its user-friendliness.

PMID:37368487 | DOI:10.2196/44549

Worldviews Evid Based Nurs. 2023 Jun 27. doi: 10.1111/wvn.12665. Online ahead of print.

ABSTRACT

BACKGROUND: Weight management is an important part of disease management in patients with heart failure. However, the effectiveness of reported weight management interventions is inconclusive.

AIMS: The aim of this systematic review and meta-analysis was to assess the effects of weight management on functional status, heart failure-related hospitalizations, and all-cause mortality in patients with heart failure.

METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched on April 3, 2022. This study was registered with PROSPERO (CRD42021283817). Eligible studies assessed functional status, heart failure-related hospitalizations, and all-cause mortality in patients with heart failure. Two researchers independently screened the articles, extracted data, and evaluated the risk bias of each study. Dichotomous variables were presented as OR with a 95% confidence interval (CI). The data were analyzed using a fixed effect or random effect model, and heterogeneity was determined using I² statistics. All statistical analyses were conducted using RevMan 5.3.

RESULTS: Among 4279 studies screened, seven randomized controlled trials were included in this study. The results showed that weight management significantly improved functional status (OR = 0.15, 95% CI [0.07, 0.35], I² = 52%) and reduced the risk of all-cause mortality (OR = 0.54, 95% CI [0.34, 0.85], I² = 0%), but had no significant effect on heart failure-related hospitalizations (OR = 0.72, 95% CI [0.20, 2.66]).

LINKING EVIDENCE TO ACTION: Weight management has effects on improved functional status and reduced all-cause mortality in patients with heart failure. It is necessary to strengthen the weight management interventions of patients with heart failure to improve patients’ functional status and reduce all-cause mortality.

PMID:37368482 | DOI:10.1111/wvn.12665

JMIR Public Health Surveill. 2023 Jun 27;9:e42149. doi: 10.2196/42149.

ABSTRACT

BACKGROUND: Health advocates and the media often use the rankings of the leading causes of death (CODs) to draw attention to health issues with relatively high mortality burdens in a population. The National Center for Health Statistics (NCHS) publishes “Deaths: leading causes” annually. The ranking list used by the NCHS and statistical offices in several countries includes broad categories such as cancer, heart disease, and accidents. However, the list used by the World Health Organization (WHO) subdivides broad categories (17 for cancer, 8 for heart disease, and 6 for accidents) and classifies Alzheimer disease and related dementias and hypertensive diseases more comprehensively compared to the NCHS list. Regarding the data visualization of the rankings of leading CODs, the bar chart is the most commonly used graph; nevertheless, bar charts may not effectively reveal the changes in the rankings over time.

OBJECTIVE: The aim of this study is to use a dashboard with bump charts to visualize the changes in the rankings of the leading CODs in the United States by sex and age from 1999 to 2021, according to 2 lists (NCHS vs WHO).

METHODS: Data on the number of deaths in each category from each list for each year were obtained from the Wide-ranging Online Data for Epidemiologic Research system, maintained by the Center for Disease Control and Prevention. Rankings were based on the absolute number of deaths. The dashboard enables users to filter by list (NCHS or WHO) and demographic characteristics (sex and age) and highlight a particular COD.

RESULTS: Several CODs that were only on the WHO list, including brain, breast, colon, hematopoietic, lung, pancreas, prostate, and uterus cancer (all classified as cancer on the NCHS list); unintentional transport injury; poisoning; drowning; and falls (all classified as accidents on the NCHS list), were among the 10 leading CODs in several sex and age subgroups. In contrast, several CODs that appeared among the 10 leading CODs according to the NCHS list, such as pneumonia, kidney disease, cirrhosis, and sepsis, were excluded from the 10 leading CODs if the WHO list was used. The rank of Alzheimer disease and related dementias and hypertensive diseases according to the WHO list was higher than their ranks according to the NCHS list. A marked increase in the ranking of unintentional poisoning among men aged 45-64 years was noted from 2008 to 2021.

CONCLUSIONS: A dashboard with bump charts can be used to improve the visualization of the changes in the rankings of leading CODs according to the WHO and NCHS lists as well as demographic characteristics; the visualization can help users make informed decisions regarding the most appropriate ranking list for their needs.

PMID:37368475 | DOI:10.2196/42149