Nevin Manimala

J Clin Pharmacol. 2024 Aug 14. doi: 10.1002/jcph.6113. Online ahead of print.

ABSTRACT

This parallel-group, open-label Phase I study evaluated the effect of mild to moderate hepatic impairment on pharmacokinetics (PK), pharmacodynamics (PD), and safety of a single oral dose of SHR4640. Participants with mild or moderate hepatic impairment were enrolled, with each cohort consisting of eight individuals, alongside eight well-matched controls with normal hepatic function. The participants were administered 10 mg SHR4640, and blood samples were collected for PK evaluation over 72 h. Additionally, serum uric acid (sUA) levels were measured to assess PD changes. Safety was evaluated through adverse events, laboratory tests, vital signs, and electrocardiograms. The C_max of SHR4640 decreased by 15.0% in the mild hepatic impairment group (geometric least squares means of the ratios [GMR] = 0.850, 90% CI: 0.701-1.03) and by 17.5% in the moderate hepatic impairment group (GMR = 0.825, 90% CI: 0.681-1.00). These reductions were not statistically significant compared to the normal hepatic function group. AUC_0-t and AUC_0-inf were similar across all groups, indicating that overall exposure to the drug was not clinical significantly affected by hepatic impairment. Apparent clearance and volume of distribution of SHR4640 showed no association with the severity of hepatic impairment as measured by the Child-Pugh score. There were no significant differences in the changes in sUA levels from baseline across different levels of hepatic function. SHR4640 is well tolerated in participants with mild or moderate hepatic impairment. Mild and moderate hepatic impairment did not have a clinically relevant impact on PK, PD, and safety of SHR4640. SHR4640 can be used in patients with mild to moderate hepatic impairment without the need for dose adjustment.

PMID:39141421 | DOI:10.1002/jcph.6113

Skin Res Technol. 2024 Aug;30(8):e13908. doi: 10.1111/srt.13908.

ABSTRACT

BACKGROUND: Classifying diverse skin types is crucial for promoting skin health. However, efficiently identifying and analyzing relevant biomarkers from a vast array of available genetic data is challenging. Therefore, this study aimed to develop a precise and efficient platform for analyzing specific skin biomarkers using quantitative real-time PCR (qRT-PCR) with the minimal invasive skin sampling method (MISSM).

MATERIALS AND METHODS: MISSM was used for RNA extraction from skin samples, followed by qRT-PCR analysis to quantify the expression of 20 biomarkers associated with skin characteristics (four biomarkers each for five skin characteristics). Noninvasive measurements from 299 Korean participants were utilized to correlate biomarker expression with skin parameters. Statistical analyses were conducted between biomarker expression levels and noninvasive skin measurements to select the relatively best-performing biomarker for each skin characteristic.

RESULTS: Collagen type 1 alpha 1 (COL1A1) and moesin (MSN) were identified as skin aging biomarkers. Krüppel-like factor 4 (KLF4) and serine peptidase inhibitor Kazal type 5 (SPINK5) were identified as skin dryness biomarkers, whereas melan-A (MLANA) was selected as a biomarker for understanding pigmentation dynamics. Myelin protein zero like 3 (MPZL3) and high mobility group box 2 (HMGB2) were identified as markers of oily skin and skin sensitivity, respectively. Statistically significant correlations were found between the biomarker expression levels and noninvasive skin characteristic measurements.

CONCLUSION: This study successfully developed a platform for the precise evaluation of individual skin characteristics using MISSM and qRT-PCR biomarker analysis. By selecting biomarkers that correlate with noninvasive measurements of skin characteristics, we demonstrated the platform’s efficacy in assessing diverse skin conditions.

PMID:39141418 | DOI:10.1111/srt.13908

Mil Med. 2024 Aug 14:usae391. doi: 10.1093/milmed/usae391. Online ahead of print.

ABSTRACT

INTRODUCTION: After mild traumatic brain injury, service members may experience difficulty with executive functions, which could interfere with return to duty and life roles. Because performance-based multitasking assessments are sensitive to executive dysfunction, a team of military and civilian rehabilitation researchers developed the Charge of Quarters Duty Test (CQDT) to help inform duty readiness after concussion; it is a multitasking test based on a military task scenario that challenges executive functions, such as foresight and planning, set shifting, and prospective memory. Although previous study indicates that CQDT has reliability and known-groups validity, like other multitasking tests, it should not be readministered after rehabilitative care because of learning effects. The purpose of this study was to develop an alternate form of the CQDT and evaluate its equivalence to the CQDT.

MATERIALS AND METHODS: A measurement development study was conducted in which subject matter experts on the study team used an iterative approach to create an alternate form. To evaluate equivalence, a repeated measures design was employed in which each participant performed one or both test versions twice and acted as their own control.

RESULTS: The study team created the Maintenance Office Duty Test (MODT), the alternate form of the CQDT. A convenience sample of 40 adults performed both the MODT and CQDT approximately 2 weeks apart; 4 had a history of military service and 16 had a history of acquired brain injury. We compared mean scores and standard deviations of each test’s 4 subscores using matched-pair t-tests and found that scores were not statistically different, suggesting that the 2 tests are equivalent. In addition, matched-pair t-tests were used to compare Time 1 and Time 2 subscores when (1) participants performed the 2 test versions (CQDT and MODT) and (2) participants performed the same test twice. None of the differences in Time 1 and Time 2 subscores were statistically significant when participants performed the 2 test versions. However, when participants performed the same test twice, three of the four Time 1 and Time 2 scores were significantly different, with Time 2 reflecting improved performance and possible learning effects (performance accuracy P = .013; total number of rule breaks P = .015; performance time P = .002).

CONCLUSIONS: The MODT appears to be an equivalent form of the CQDT that mitigates learning effects that often accompany performance of multitasking assessments. Having developed and validated the equivalence of the CDQT’s alternate form, military rehabilitation clinicians have an expanded set of clinical tools by which to identify possible executive dysfunction and evaluate service members’ response to rehabilitative care via pre- and post-rehabilitation testing after mild traumatic brain injury.

PMID:39141414 | DOI:10.1093/milmed/usae391

Epilepsia Open. 2024 Aug 14. doi: 10.1002/epi4.13028. Online ahead of print.

ABSTRACT

OBJECTIVE: To summarize the clinical features and genetic mutation characteristics of Chinese children with KCNQ2-related epilepsy.

METHODS: A cohort of children with genetically caused epilepsy was evaluated at Linyi People’s Hospital from January 2017 to December 2023. After next-generation sequencing and pathogenicity analysis, we summarized the medical records and genetic testing data of the children who had KCNQ2 gene mutations.

RESULTS: We identified 23 KCNQ2 gene mutations. 73.9% (n = 17) of the mutation sites were located in S5-S6 segments and the C-terminal region. In addition to the common phenotypes, 2 new phenotypes were identified: infantile convulsion with paroxysmal choreoathetosis (ICCA) and febrile seizure plus (FS+). Of all the cases with abnormal video-electro-encephalography, three cases with self-limited familial infantile epilepsy (SeLNE) exhibited a small number of multifocal discharges. Of the patients who have taken a particular antiepileptic drug, the statistics on the number of patients who have responded to the drug are as follows: oxcarbazepine (8/9, 88.9%), levetiracetam (5/7, 71.4%), phenobarbital (9/16, 56.3%), and topiramate (2/5, 40.0%). However, the efficacy of phenobarbital varied widely in treating SeLNE and KCNQ2-DEE. At the final follow-up, 1 case with SeLNE had a transient developmental regression and 7 cases with KCNQ2-DEE had mild to severe developmental backwardness.

SIGNIFICANCE: Although clinically rare, we report 10 new KCNQ2 mutations and two new phenotypes: ICCA and FS+. This further expands genetic and phenotypic spectrum of KCNQ2-related epilepsy. The gene mutation sites are mostly located in S5-S6 segments and the C-terminal region, and the former is usually associated with KCNQ2-DEE. Sodium channel blockers (including oxcarbazepine and topiramate) and levetiracetam should be prioritized over phenobarbital for KCNQ2-DEE. Some cases with KCNQ2-related epilepsy may have transient developmental regression during periods of frequent seizures. Early treatment and early seizure control may be beneficial for willing outcomes in children with KCNQ2-DEE.

PLAIN LANGUAGE SUMMARY: This article reports 23 cases of children with KCNQ2-related epilepsy, including 10 new mutation sites and 2 new phenotypes. It further expands the genetic and phenotypic spectrum of KCNQ2-related epilepsy. In addition, the article summarizes the gene mutation characteristics and clinical manifestations of children with KCNQ2-related epilepsy, with the expectation of providing a certain theoretical basis for the diagnosis and treatment of such patients.

PMID:39141400 | DOI:10.1002/epi4.13028

JAMA Surg. 2024 Aug 14. doi: 10.1001/jamasurg.2024.2977. Online ahead of print.

ABSTRACT

IMPORTANCE: While nipple-sparing mastectomy (NSM) for breast cancer was only performed using the open method in the past, its frequency using endoscopic and robotic surgical instruments has been increasing rapidly. However, there are limited studies regarding postoperative complications and the benefits and drawbacks of minimal access NSM (M-NSM) compared with conventional NSM (C-NSM).

OBJECTIVE: To examine the differences in postoperative complications between C-NSM and M-NSM.

DESIGN, SETTING, PARTICIPANTS: This was a retrospective multicenter cohort study enrolling 1583 female patients aged 19 years and older with breast cancer who underwent NSM at 21 university hospitals in Korea between January 2018 and December 2020. Those with mastectomy without preserving the nipple-areolar complex (NAC), clinical or pathological malignancy in the NAC, inflammatory breast cancer, breast cancer infiltrating the chest wall or skin, metastatic breast cancer, or insufficient medical records were excluded. Data were analyzed from November 2021 to March 2024.

EXPOSURES: M-NSM or C-NSM.

MAIN OUTCOMES AND MEASURES: Clinicopathological factors and postoperative complications within 3 months of surgery were assessed. Statistical analyses, including logistic regression, were used to identify the factors associated with complications.

RESULTS: There were 1356 individuals (mean [SD] age, 45.47 [8.56] years) undergoing C-NSM and 227 (mean [SD] age, 45.41 [7.99] years) undergoing M-NSM (35 endoscopy assisted and 192 robot assisted). There was no significant difference between the 2 groups regarding short- and long-term postoperative complications (<30 days: C-NSM, 465 of 1356 [34.29%] vs M-NSM, 73 of 227 [32.16%]; P = .53; <90 days: C-NSM, 525 of 1356 [38.72%] vs M-NSM, 73 of 227 [32.16%]; P = .06). Nipple-areolar complex necrosis was more common in the long term after C-NSM than M-NSM (C-NSM, 91 of 1356 [6.71%] vs M-NSM, 5 of 227 [2.20%]; P = .04). Wound infection occurred more frequently after M-NSM (C-NSM, 58 of 1356 [4.28%] vs M-NSM, 18 of 227 [7.93%]; P = .03). Postoperative seroma occurred more frequently after C-NSM (C-NSM, 193 of 1356 [14.23%] vs M-NSM, 21 of 227 [9.25%]; P = .04). Mild or severe breast ptosis was a significant risk factor for nipple or areolar necrosis (odds ratio [OR], 4.75; 95% CI, 1.66-13.60; P = .004 and OR, 8.78; 95% CI, 1.88-41.02; P = .006, respectively). Conversely, use of a midaxillary, anterior axillary, or axillary incision was associated with a lower risk of necrosis (OR for other incisions, 32.72; 95% CI, 2.11-508.36; P = .01). Necrosis occurred significantly less often in direct-to-implant breast reconstruction compared to other breast reconstructions (OR, 2.85; 95% CI, 1.11-7.34; P = .03).

CONCLUSIONS AND RELEVANCE: The similar complication rates between C-NSM and M-NSM demonstrates that both methods were equally safe, allowing the choice to be guided by patient preferences and specific needs.

PMID:39141399 | DOI:10.1001/jamasurg.2024.2977

JAMA Netw Open. 2024 Aug 1;7(8):e2426826. doi: 10.1001/jamanetworkopen.2024.26826.

NO ABSTRACT

PMID:39141390 | DOI:10.1001/jamanetworkopen.2024.26826

JAMA Netw Open. 2024 Aug 1;7(8):e2425280. doi: 10.1001/jamanetworkopen.2024.25280.

ABSTRACT

IMPORTANCE: Many insulin users ration doses due to high out-of-pocket costs. Starting January 2020 with Colorado, 25 states and the District of Columbia enacted laws that cap insulin copayments.

OBJECTIVE: To estimate the association of Colorado’s $100 copayment cap with out-of-pocket spending, medication adherence, and health care services utilization for diabetes-related complications.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study using Colorado’s All-Payer Claims Database, nonelderly insulin users with type 1 diabetes were analyzed from January 2019 to December 2020. Outcome changes were compared in the prepolicy and postpolicy period among individuals continuously enrolled in state-regulated and non-state-regulated plans using difference-in-differences regressions. Subgroup analyses were conducted based on individuals’ prepolicy spending (low: never ≥$100 out-of-pocket vs high: ≥$100 out-of-pocket cost at least once). Data were analyzed from June 2023 to May 2024.

EXPOSURE: Enrollment in state-regulated health insurance plans subject to the copayment cap legislation.

MAIN OUTCOMES AND MEASURES: Adherence to basal and bolus insulin treatment was evaluated using the proportion of days covered measure, out-of-pocket spending reflected prescription cost for a 30-day supply, and health care utilization for diabetes-related complications was identified using primary diagnosis codes from medical claims data.

RESULTS: The panel included 1629 individuals with type 1 diabetes (39 096 person-months), of which 924 were male (56.7%), 540 (33.1%) had 1 or more comorbidities, and the mean (SD) age was 40.6 (15.9) years. Overall, the copayment cap was associated with out-of-pocket spending declines of $17.3 (95% CI, -$27.3 to -$7.3) for basal and $11.5 (95% CI, -$24.7 to $1.7) for bolus insulins and increases in adherence of 3.2 (95% CI, 0.0 to 6.5) percentage points for basal and 3.3 (95% CI, 0.3 to 6.4) percentage points for bolus insulins. Changes in adherence were associated with increases within the prepolicy high-spending group (basal, 9.9; 95% CI, 2.4 to 17.4 percentage points; bolus, 13.0; 95% CI, 5.1 to 20.9 percentage points). The policy was also associated with a mean reduction of -0.09 (95% CI, -0.16 to -0.02) medical claims for diabetes-related complications per person per month among high spenders, a 30% decrease.

CONCLUSIONS AND RELEVANCE: In this cohort study of Colorado’s insulin copayment cap among individuals with type 1 diabetes, the policy was associated with an overall decline in out-of-pocket spending, an increase in medication adherence, and a decline in claims for diabetes-related complications only among insulin users who spent more than $100 in the prepolicy period at least once.

PMID:39141389 | DOI:10.1001/jamanetworkopen.2024.25280

JAMA Netw Open. 2024 Aug 1;7(8):e2426847. doi: 10.1001/jamanetworkopen.2024.26847.

ABSTRACT

IMPORTANCE: Seventeen states introduced COVID-19 vaccine mandates for health care workers (HCWs) in mid-2021. Prior research on the effect of these mandates was centered on the nursing home sector, and more evidence is needed for their effect on the entire HCW population.

OBJECTIVE: To examine the association between state COVID-19 vaccine mandates for HCWs and vaccine uptake in this population.

DESIGN, SETTING, AND PARTICIPANTS: This repeated cross-sectional study included biweekly, individual-level data for adults aged 25 to 64 years who were working or volunteering in health care settings obtained from the Household Pulse Survey between May 26 and October 11, 2021. Analyses were conducted between November 2022 and October 2023.

EXPOSURE: Announcement of a state COVID-19 vaccine mandate for HCWs.

MAIN OUTCOMES AND MEASURES: An indicator for whether a sampled HCW ever received a COVID-19 vaccine and an indicator for whether an HCW completed or intended to complete the primary COVID-19 vaccination series. Event study analyses using staggered difference-in-differences methods compared vaccine uptake among HCWs in mandate and nonmandate states before and after each mandate announcement. The sample was further stratified by the availability of regular COVID-19 testing in place of a vaccination (ie, a test-out option) and by the ages of HCWs (25-49 or 50-64 years) to examine heterogeneous associations.

RESULTS: The study sample included 31 142 HCWs (mean [SD] age, 45.5 [10.6] years; 72.1% female) from 45 states, 16 of which introduced COVID-19 vaccine mandates for HCWs. Results indicated a mandate-associated 3.46-percentage point (pp) (95% CI, 0.29-6.63 pp; P = .03) increase in the proportion of HCWs ever vaccinated against COVID-19 and a 3.64-pp (95% CI, 0.72-6.57 pp; P = .02) increase in the proportion that completed or intended to complete the primary vaccination series 2 weeks after mandate announcement from baseline proportions of 87.98% and 86.12%, respectively. In the stratified analyses, positive associations were only detected in mandate states with no test-out option and among HCWs aged 25 to 49 years, which suggested vaccination increases of 3.32% to 7.09% compared with baseline proportions.

CONCLUSIONS AND RELEVANCE: This repeated cross-sectional study found that state COVID-19 vaccine mandates for HCWs were associated with increased vaccine uptake among HCWs, especially among younger HCWs and those in states with no test-out option. These findings suggest the potential for vaccine mandates to further promote vaccinations in an already highly vaccinated HCW population, especially when no test-out option is in place.

PMID:39141387 | DOI:10.1001/jamanetworkopen.2024.26847

JAMA Netw Open. 2024 Aug 1;7(8):e2427683. doi: 10.1001/jamanetworkopen.2024.27683.

ABSTRACT

IMPORTANCE: Firearm violence is a major public health problem in the US. However, relatively little research has focused particular attention on firearm violence in rural areas, and few studies have used research designs that draw on exogenous variation in the prevalence of firearms to estimate the association between firearm presence and shootings.

OBJECTIVE: To investigate the association between the start of deer hunting season and shootings in rural counties in the US.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, data from all rural US counties in states with available data on the timing of deer hunting season were matched with data on shootings from the Gun Violence Archive from January 1, 2014, to December 31, 2021.

EXPOSURE: Shootings in the first 3 weeks of deer hunting season were compared with the week prior to the start of deer hunting season.

MAIN OUTCOMES AND MEASURES: The main outcome was daily total shootings. The association between the start of deer hunting season and shootings was estimated using Poisson regression models to analyze change within counties while controlling for relevant calendar year, month of year, and seasonal effects.

RESULTS: The sample included 854 rural counties with a mean (SD) population of 16 416 (18 329) per county and 5.4 (13.3) annual shootings per 100 000 people. The county fixed-effects specification analyzing the association between deer hunting season and shootings showed that relative to the week prior to deer hunting season, the incidence rate ratio for total shootings was 1.49 (95% CI, 1.13-1.95) for the first week of deer hunting season and 1.41 (95% CI, 1.02-1.94) for the second week of deer hunting season. Estimates remained consistent when excluding hunting accidents and were most pronounced in states with more hunting licenses per capita.

CONCLUSIONS AND RELEVANCE: In this cohort study of the association between the start of deer hunting season and firearm violence, results showed that the start of deer hunting season was associated with a substantial increase in shootings. The findings highlight the role of firearm prevalence in gun violence and suggest the need for focused policies designed to reduce firearm violence in areas with substantial hunting activity during the first weeks of deer hunting season.

PMID:39141384 | DOI:10.1001/jamanetworkopen.2024.27683

Ophthalmic Physiol Opt. 2024 Aug 14. doi: 10.1111/opo.13378. Online ahead of print.

ABSTRACT

PURPOSE: To assess the long-term stability of clinical measures of convergence (near point of convergence [NPC] and positive fusional vergence [PFV]) in participants enrolled in the Convergence Insufficiency Treatment Trial-Attention and Reading Trial (CITT-ART) who received 16 weeks of office-based vergence/accommodative therapy.

METHODS: A total of 310 children, 9-14 years old, with symptomatic convergence insufficiency were enrolled in CITT-ART. Some 270 completed both their 16-week primary outcome visit followed by a 1-year follow-up visit. Of those 270, 181 (67%) were randomised to the vergence/accommodative therapy. Of the 181 in the vergence/accommodative group, 121 (67%) reported not receiving any additional treatment after the 16-week primary outcome visit. The mean change in NPC, PFV and percentages of children classified by the predetermined success criteria of convergence (normal NPC [<6 cm] and/or improved by ≥4 cm; normal PFV [passing Sheard’s criterion and base-out break >15Δ] and/or improved by ≥10Δ) were compared at the 16-week primary outcome visit and 1 year later.

RESULTS: Of the 121 who returned for their 1-year follow-up visit, there was no significant change in mean adjusted NPC (reduction of -0.2 cm; 95% CI: -1.0 to 0.5 cm) at 1 year. There was a statistically significant decrease in mean-adjusted PFV (-4.7∆; 95% CI: -6.5 to -2.8Δ) at 1 year. There were similar percentages of participants classified as ‘normal’ (p = 0.30), ‘normal and/or improved’ (p > 0.50) and ‘normal and improved’ (p > 0.14) based on NPC and PFV at the 1-year visit compared with the 16-week primary outcome visit.

CONCLUSION: The improvements in NPC and PFV following 16 weeks of vergence/accommodative therapy (with no reported additional treatment thereafter) in children with symptomatic convergence insufficiency persisted 1-year post-treatment.

PMID:39141379 | DOI:10.1111/opo.13378