Category: Nevin Manimala

Optom Vis Sci. 2023 Jun 26. doi: 10.1097/OPX.0000000000002040. Online ahead of print.

ABSTRACT

SIGNIFICANCE: When worn for myopia control in children, soft multifocal contact lenses with a + 2.50 D add reduced the accommodative response over a three-year period, but wearing them for over four years did not affect accommodative amplitudes, lag, or facility.

PURPOSE: To compare the accommodative response to a 3 D stimulus between single vision, +1.50 D add, and + 2.50 D add multifocal contact lens wearers during three years of contact lens wear, then to compare accommodative amplitude, lag, and facility between the three groups after an average of 4.7 years of wear.

METHODS: Seven- to 11-year-old BLINK Study participants were randomly assigned to wear single vision, +1.50 D add, or + 2.50 D add soft contact lenses (CooperVision, Pleasanton, CA). The accommodative response to a 3 D stimulus was measured at baseline and annually for three years. After 4.7 years, we measured objective accommodative amplitudes, lead/lag, and binocular facility with ±2.00 D flippers. We compared the three accommodative measures using multivariate analysis of variance, adjusting for clinic site, sex, and age group (7-9 or 10-11 years).

RESULTS: The +2.50 D add contact lens wearers exhibited lower accommodative response than the single vision contact lens wearers for three years, but the +1.50 D add contact lens wearers only exhibited lower accommodative response than the single vision contact lens wearers for two years. After adjustment for clinic site, sex, and age group, there were no statistically significant or clinically meaningful differences between the three treatment groups for accommodative amplitude (MANOVA, P = .49), accommodative lag (MANOVA, P = .41), or accommodative facility (MANOVA, P = .87) after an average of 4.7 years of contact lens wear.

CONCLUSIONS: Almost five years of multifocal contact lens wear did not affect the accommodative amplitude, lag, or facility of children.

PMID:37369096 | DOI:10.1097/OPX.0000000000002040

J Clin Oncol. 2023 Jun 27:JCO2202887. doi: 10.1200/JCO.22.02887. Online ahead of print.

ABSTRACT

PURPOSE: Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting.

PATIENTS AND METHODS: In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms.

RESULTS: The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%).

CONCLUSION: EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.

PMID:37369081 | DOI:10.1200/JCO.22.02887

Menopause. 2023 Jun 27. doi: 10.1097/GME.0000000000002211. Online ahead of print.

ABSTRACT

IMPORTANCE: Ospemifene is a novel selective estrogen receptor modulator developed for the treatment of moderate to severe postmenopausal vulvovaginal atrophy (VVA).

OBJECTIVE: The aim of the study is to perform a systematic literature review (SLR) and network meta-analysis (NMA) to assess the efficacy and safety of ospemifene compared with other therapies used in the treatment of VVA in North America and Europe.

EVIDENCE REVIEW: Electronic database searches were conducted in November 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized or nonrandomized controlled trials targeting postmenopausal women with moderate to severe dyspareunia and/or vaginal dryness and involving ospemifene or at least one VVA local treatment were considered. Efficacy data included changes from baseline in superficial and parabasal cells, vaginal pH, and the most bothersome symptom of vaginal dryness or dyspareunia, as required for regulatory approval. Endometrial outcomes were endometrial thickness and histologic classifications, including endometrial polyp, hyperplasia, and cancer. For efficacy and safety outcomes, a Bayesian NMA was performed. Endometrial outcomes were compared in descriptive analyses.

FINDINGS: A total of 44 controlled trials met the eligibility criteria (N = 12,637 participants). Network meta-analysis results showed that ospemifene was not statistically different from other active therapies in most efficacy and safety results. For all treatments, including ospemifene, the posttreatment endometrial thickness values (up to 52 wk of treatment) were under the recognized clinical threshold value of 4 mm for significant risk of endometrial pathology. Specifically, for women treated with ospemifene, endometrial thickness ranged between 2.1 and 2.3 mm at baseline and 2.5 and 3.2 mm after treatment. No cases of endometrial carcinoma or hyperplasia were observed in ospemifene trials, nor polyps with atypical hyperplasia or cancer after up to 52 weeks of treatment.

CONCLUSIONS AND RELEVANCE: Ospemifene is an efficacious, well-tolerated, and safe therapeutic option for postmenopausal women with moderate to severe symptoms of VVA. Efficacy and safety outcomes with ospemifene are similar to other VVA therapies in North America and Europe.

PMID:37369079 | DOI:10.1097/GME.0000000000002211

J Phys Chem B. 2023 Jun 27. doi: 10.1021/acs.jpcb.3c01805. Online ahead of print.

ABSTRACT

The flow behavior of oil in nanochannels has attracted extensive attention for oil transport applications. In most, if not all, of the prior theoretical simulations, oil molecules were observed to flow steadily in nanochannels under pressure gradients. In this study, non-equilibrium molecular dynamics simulations are conducted to simulate the Poiseuille flow of oil with three different hydrocarbon chain lengths in graphene nanochannels. Contrary to the conventional perception of steady flows of oil in nanochannels, we find that oil molecules with the longest hydrocarbon chain (i.e., n-dodecane) exhibit notable stick-slip flow behavior. An alternation between the high average velocity of n-dodecane in the slip motion and the low average velocity in the stick motion is observed, with a drastic, abrupt velocity jolt of up to 40 times occurring at the transition in a stick-slip motion. Further statistical analyses show that the stick-slip flow behavior of n-dodecane molecules originates from the molecular alignment change of oil near the graphene wall. The molecular alignment of n-dodecane shows different statistical distributions under stick and slip motion states, leading to significant changes of friction forces and thus notable velocity fluctuations. This work provides new insights into the Poiseuille flow behavior of oil in graphene nanochannels and may offer useful guidelines for other mass transport applications.

PMID:37369077 | DOI:10.1021/acs.jpcb.3c01805

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