Category: Nevin Manimala

Circulation. 2023 Mar 15. doi: 10.1161/CIRCULATIONAHA.122.060002. Online ahead of print.

ABSTRACT

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare, fatal, premature aging disease caused by a toxic protein called progerin. Circulating progerin has not been previously detected, precluding research using readily available biological samples. This study aimed to develop a plasma progerin assay to evaluate progerin’s quantity, response to progerin-targeted therapy, and relationship to patient survival.

METHODS: Biological samples were collected by The Progeria Research Foundation Cell and Tissue Bank from a non-HGPS cohort cross-sectionally and a HGPS cohort longitudinally. HGPS donations occurred at baseline and intermittently while treated with farnesylation inhibitors lonafarnib±pravastatin and zoledronate, within 3 sequential open-label clinical trials at Boston Children’s Hospital totaling >10 years of treatment. An ultrasensitive single-molecule counting progerin immunoassay was developed with prespecified performance parameters. Intra- and interpatient group statistics were descriptive. The relationship between progerin and survival was assessed by using joint modeling with time-dependent slopes parameterization.

RESULTS: The assay’s dynamic detection range was 59 to 30 000 pg/mL (R²=0.9987). There was no lamin A cross-reactivity. Mean plasma progerin in non-HGPS participants (n=69; 39 male, 30 female; age, 0.2-71.3 years) was 351±251 pg/mL, and in drug-naive participants with HGPS (n=74; 37 female, 37 male; age, 2.1-17.5 years) was 33 261±12 346 pg/mL, reflecting a 95-fold increase in affected children (P<0.0001). Progerin levels did not differ by sex (P=0.99). Lonafarnib treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (all P<0.005); effects were not augmented by adding pravastatin and zoledronate. Progerin levels fell within 4 months of therapy and remained lower for up to 10 years. The magnitude of progerin decrease positively associated with patient survival (P<0.0001; ie, 15 000 pg/mL decrease yields a 63.9% decreased risk of death). For any given decrease in progerin, life expectancy incrementally increased with longer treatment duration.

CONCLUSIONS: A sensitive, quantitative immunoassay for progerin was developed and used to demonstrate high progerin levels in HGPS plasma that decreased with lonafarnib therapy. The extent of improved survival was associated with both the magnitude of progerin decrease and duration at lower levels. Thus, plasma progerin is a biomarker for HGPS whose reduction enables short- and long-term assessment of progerin-targeted treatment efficacy.

REGISTRATION: URL: https://www.

CLINICALTRIALS: gov. Unique identifiers: NCT00879034 and NCT00916747.

PMID:36919608 | DOI:10.1161/CIRCULATIONAHA.122.060002

Circ Res. 2023 Mar 15. doi: 10.1161/CIRCRESAHA.122.321693. Online ahead of print.

ABSTRACT

BACKGROUND: Extracellular renal interstitial cGMP inhibits renal proximal tubule (RPT) sodium (Na⁺) reabsorption via Src (Src family kinase) activation. Through which target extracellular cGMP acts to induce natriuresis is unknown. We hypothesized that cGMP binds to the extracellular α1-subunit of NKA (sodium-potassium ATPase) on RPT basolateral membranes to inhibit Na⁺ transport similar to ouabain-a cardiotonic steroid.

METHODS AND RESULTS: Urine Na⁺ excretion was measured in uninephrectomized 12-week-old female Sprague-Dawley rats that received renal interstitial infusions of vehicle (5% dextrose in water), cGMP (18, 36, and 72 μg/kg per minute; 30 minutes each), or cGMP+rostafuroxin (12 ng/kg per minute) or were subjected to pressure-natriuresis±rostafuroxin infusion. Rostafuroxin is a digitoxigenin derivative that displaces ouabain from NKA. Renal interstitial cGMP and raised renal perfusion pressure induced natriuresis and increased phosphorylated Src^Tyr416 and Erk 1/2 (extracellular signal-regulated protein kinase 1/2)^{Thr202/Tyr204}; these responses were abolished with rostafuroxin coinfusion. To assess cGMP binding to NKA, we performed competitive binding studies with isolated rat RPTs using bodipy-ouabain (2 μM)+cGMP (10 µM) or rostafuroxin (10 µM) and 8-biotin-11-cGMP (2 μM)+ouabain (10 μM) or rostafuroxin (10 µM). cGMP or rostafuroxin reduced bodipy-ouabain fluorescence intensity, and ouabain or rostafuroxin reduced 8-biotin-11-cGMP staining. We cross-linked isolated rat RPTs with 4-N₃-PET-8-biotin-11-cGMP (2 μM); 8-N₃-6-biotin-10-cAMP served as negative control. Precipitation with streptavidin beads followed by immunoblot analysis showed that RPTs after cross-linking with 4-N₃-PET-8-biotin-11-cGMP exhibited a significantly stronger signal for NKA than non-cross-linked samples and cross-linked or non-cross-linked 8-N₃-6-biotin-10-cAMP RPTs. Ouabain (10 μM) reduced NKA in cross-linked 4-N₃-PET-8-biotin-11-cGMP RPTs confirming fluorescence staining. 4-N₃-PET-8-biotin-11-cGMP cross-linked samples were separated by SDS gel electrophoresis and slices corresponding to NKA molecular weight excised and processed for mass spectrometry. NKA was the second most abundant protein with 50 unique NKA peptides covering 47% of amino acids in NKA. Molecular modeling demonstrated a potential cGMP docking site in the ouabain-binding pocket of NKA.

CONCLUSIONS: cGMP can bind to NKA and thereby mediate natriuresis.

PMID:36919600 | DOI:10.1161/CIRCRESAHA.122.321693

Ann Med. 2023 Dec;55(1):926-945. doi: 10.1080/07853890.2023.2185808.

ABSTRACT

BACKGROUND: Pregnant women participated in multifaceted case management (MCM) to prevent Fetal Alcohol Spectrum Disorders (FASD).

METHODS: Women recruited from antenatal clinics for a longitudinal child development study were screened for alcohol use. Forty-four pregnant women were defined as high-risk drinkers on the Alcohol Use Disorder Identification Test (AUDIT) by an AUDIT score ≥8 and participated in 18 months of MCM to facilitate reduction or cessation of alcohol consumption. Forty-one women completed MCM. Fifty-five equally high-risk women who received standard antenatal care comprised the comparison/control group. Development in offspring was evaluated by a blinded interdisciplinary team of examiners through 5 years of age.

RESULTS: At five years of age, more children (34%) of MCM participating women did not meet the criteria for FASD vs. non-MCM offspring (22%). Furthermore, a statistically significant (p = .01) lower proportion of MCM offspring (24%) was diagnosed with fetal alcohol syndrome (FAS) compared to controls (49%). Children of MCM participants had significantly (p < .05) better physical outcomes: lower total dysmorphology scores, larger head circumferences, longer palpebral fissures, and higher midfacial measurements. Neurodevelopment results showed mixed outcomes. While Bayley developmental scores indicated that MCM offspring were performing significantly worse on most domains through 18 months, group scores equalized and were not significantly different on Kaufman Assessment Battery neurobehavioral measures by five years. Regression analyses indicated that offspring of women who received standard antenatal care were associated with significantly more negative outcomes than MCM offspring: a diagnosis of FAS (OR = 3.2; 95% CI: 1.093-9.081), microcephaly (OR = 5.3; 95% CI: 2.1-13.5), head circumference ≤10th centile (OR = 4.3; 95%CI: 1.8-10.4), and short palpebral fissures (OR = 2.5; 95% CI: 1.0-5.8).

CONCLUSION: At age five, proportionally fewer children of MCM participants qualified for a diagnosis of FAS, and proportionally more had physical outcomes indicating better prenatal brain development. Neurobehavioral indicators were not significantly different from controls by age five.KEY MESSAGESMultifaceted Case Management (MCM) was designed and employed for 18 months during the prenatal and immediate postpartum period to successfully meet multiple needs of women who had proven to be very high risk for birthing children with fetal alcohol spectrum disorders (FASD).Offspring of the women who participated in MCM were followed up through age five years and were found to have significantly better physical outcomes on multiple variables associated with fetal alcohol syndrome (FAS) and FASD, such as larger head circumferences and fewer minor anomalies, than those children born to equally at-risk women not receiving MCM.Fewer children of women receiving MCM were diagnosed with FASD than the offspring of equally-at-risk controls, and significantly (p = .01) fewer MCM offspring had FAS, the most severe FASD diagnosis.

PMID:36919586 | DOI:10.1080/07853890.2023.2185808

J Sports Sci. 2022 Oct;40(20):2217-2224. doi: 10.1080/02640414.2022.2139881.

ABSTRACT

We aimed to clarify the differences in soccer instep kicking dynamics between sex groups. The instep kicking of seven female (height: 160.3 ± 6.1 cm; mass: 54.3 ± 5.2 kg) and seven male (height: 173.0 ± 5.9 cm; mass: 70.0 ± 9.0 kg) players were recorded by a motion capture system (500 Hz). Joint moments of the kicking leg were computed and normalized by the body mass and height. Statistical parametric mapping was used to compare the entire kicking motion between the two groups. Significantly slower resultant ball velocity seen in female players was most likely explained by their significantly slower run-up velocity, shorter leg length and lower foot-ball velocity ratio. Female players exhibited significantly smaller knee joint moment in the latter part (80-86%) of kicking. Also, significantly smaller positive work done by knee extension moment and the ratio of work (knee extension/hip flexion) were found in female players. These results suggested that the suppressed knee extension moment action was identified as a key kinetic characteristic in the instep kicking of female players, and to compensate for this action, they more rely on the work due to hip flexion moment to execute the instep kicking.

PMID:36919566 | DOI:10.1080/02640414.2022.2139881

Expert Rev Med Devices. 2023 Mar 15:1-8. doi: 10.1080/17434440.2023.2190019. Online ahead of print.

ABSTRACT

BACKGROUND: Powered intraosseous (IO) systems are valuable devices for emergent situations, with limited data on user preferences. A simulation/survey-based study was conducted among emergency medical service (EMS) providers to evaluate attitudes toward general powered IO system features to measure preferences/satisfaction for the most-commonly used and a novel powered IO system (with a passive safety needle, battery life indicator, and snap-securement/dressing).

RESEARCH DESIGN AND METHODS: Forty-two EMS providers completed a simulated activity using both powered IO systems and a 30-item questionnaire, including multiple choice, free-text, ranking, and Likert-like questions. Ranking scores were reported using a scale of 0 (least important/satisfactory) to 100 (most important/satisfactory). Statistical significances were evaluated via Wilcoxon signed-rank sum test.

RESULTS: Providers indicated driver performance (mean score ± SD; 77.8 ± 27.5) and IO needle safety mechanism (63.1 ± 27.9) as the most important features. Participants reported significantly higher (p < 0.001) satisfaction with the novel IO system overall, and its needle safety, battery life indicator, securement/dressing, and ease-of-use. Powered driver performance satisfaction was similar and favorable for the novel (88.1 ± 18.2) and traditional (87.1 ± 15.3) systems.

CONCLUSIONS: These findings highlight the value of clinician/user input and demonstrate EMS providers are more satisfied with a powered IO system featuring design elements intended to enhance safety and ease-of-use.

PMID:36919560 | DOI:10.1080/17434440.2023.2190019

Med Educ Online. 2023 Dec;28(1):2189553. doi: 10.1080/10872981.2023.2189553.

ABSTRACT

PURPOSE: The goal of this systematic review was to examine self-directed learning (SDL) assessment practices in undergraduate health professions education.

METHODS: Seven electronic databases were searched (PubMed, Embase, PsycINFO, ERIC, CINAHL, Scopus, and Web of Science) to retrieve English-language articles published between 2015 and July of 2022, investigating assessment of SDL learning outcomes. Extracted data included the sample size, field of study, study design, SDL activity type, SDL assessment method, number of SDL assessments used, study quality, number of SDL components present utilising the framework the authors developed, and SDL activity outcomes. We also assessed relationships between SDL assessment method and number of SDL components, study quality, field of study, and study outcomes.

RESULTS: Of the 141 studies included, the majority of study participants were medical (51.8%) or nursing (34.8%) students. The most common SDL assessment method used was internally-developed perception surveys (49.6%). When evaluating outcomes for SDL activities, most studies reported a positive or mixed/neutral outcome (58.2% and 34.8%, respectively). There was a statistically significant relationship between both number and type of assessments used, and study quality, with knowledge assessments (median-IQR 11.5) being associated with higher study quality (p < 0.001). Less than half (48.9%) of the studies used more than one assessment method to evaluate the effectiveness of SDL activities. Having more than one assessment (mean 9.49) was associated with higher quality study (p < 0.001).

CONCLUSIONS: The results of our systematic review suggest that SDL assessment practices within undergraduate health professions education vary greatly, as different aspects of SDL were leveraged and implemented by diverse groups of learners to meet different learning needs and professional accreditation requirements. Evidence-based best practices for the assessment of SDL across undergraduate healthcare professions education should include the use of multiple assessments, with direct and indirect measures, to more accurately assess student performance.

PMID:36919556 | DOI:10.1080/10872981.2023.2189553

J Psychoactive Drugs. 2023 Mar 15:1-11. doi: 10.1080/02791072.2023.2186286. Online ahead of print.

ABSTRACT

Medical cannabis use among U.S. Veterans has continued to rise. However, data on cannabis use by older Veterans is generally less available. This study aims to understand the characteristics of older Veterans who enrolled in the Medical Cannabis Patient Program in Illinois and analyze their health outcomes and co-use of cannabis and opioids using longitudinal survey data. Overall, participants reported positive outcomes for pain, sleep, and emotional problems because of cannabis use in two survey periods. Approximately, 62% and 85% respondents reported no change in memory and falls, respectively, with only 3% and 1% reporting a negative outcome for the conditions in both surveys. About 20.4% of those who indicated cannabis use only in the initial survey started to co-use opioids in the follow-up survey, while 44.1% of those who indicated the use of both substances in the initial survey reported no longer using opioids in the follow-up survey. However, these changes were not statistically significant ($\alpha =0.05).$ The logistic regression showed that both clinical and contextual factors affected co-use. In conclusion, older U.S. Veterans may be using cannabis to alleviate their pain and other chronic conditions. More research is needed to understand the effect of cannabis use on reducing or substituting opioids.

PMID:36919533 | DOI:10.1080/02791072.2023.2186286

J Periodontol. 2023 Mar 15. doi: 10.1002/JPER.22-0654. Online ahead of print.

ABSTRACT

BACKGROUND: Trans fatty acid (TFA) consumption has been reported to harbor pro-inflammatory and increasing oxidative stress properties, but there has been little research into its association with periodontitis. This study aimed to explore the potential association between TFAs and periodontitis.

METHODS: This large population-based study included participants from the National Health and Nutrition Examination Survey (2009-2010). Weighted binary and ordinal logistic regressions were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the relationship between plasma TFAs and periodontitis.

RESULTS: A total of 1433 eligible participants, 793 (55.3%) participants with periodontitis and 640 (44.7%) without periodontitis were included. Univariate logistic regression revealed significant associations between plasma trans-11-octadecenoic acid, trans-9-octadecenoic acid, the sum of trans-octadecenoic acids, and the sum of TFAs and periodontitis (all P<0.01). After controlling for the potential confounders, these four types of TFAs remained significantly associated with periodontitis (the ORs and 95% CIs per interquartile range increase were 1.16 (1.01-1.33), 1.20 (1.03-1.39), 1.18 (1.02-1.35), and 1.17 (1.01-1.35), respectively). Notably, these positive associations were more pronounced among overweight/obese populations. Additionally, plasma trans-9-octadecenoic acid levels were found to be associated with periodontitis severity.

CONCLUSIONS: This study suggests a significant positive association between certain plasma TFAs and chronic periodontitis, especially among overweight/obese populations. These findings provide new insights into periodontitis prevention from a dietary perspective. This article is protected by copyright. All rights reserved.

PMID:36919529 | DOI:10.1002/JPER.22-0654

Clin Shoulder Elb. 2023 Mar;26(1):49-54. doi: 10.5397/cise.2022.01375. Epub 2023 Feb 23.

ABSTRACT

BACKGROUND: Lateral epicondylitis is an increasingly debilitating condition in working population. Evidence for conservative treatment modalities has been inconclusive. Percutaneous pie crusting of the common extensor origin at the lateral epicondyle at the time of local corticosteroid injection (CSI) has been proposed sparsely. The objective of this study was to analyze if concomitant CSI and pie-crusting of the common extensor origin provides better outcome than CSI alone in lateral epicondylitis.

METHODS: This case-control study on 236 patients was conducted at a single center between January 1, 2020, and May 31, 2022. Patients were divided into two groups (n=118 each) based on their preference. Group A underwent CSI alone and group B underwent pie crusting along with CSI. The clinical and functional outcomes of all patients were evaluated at 2, 4, 6, and 12-week post-procedure using the visual analog scale (VAS) and Nirschl score. The mean time for return to daily activities was also compared.

RESULTS: Both groups showed significant improvement in post-procedure outcome at successive follow-ups on intragroup longitudinal analysis (VAS: F=558.384 vs. F=1,529.618, Nirschl: F=791.468 vs. F=1,284.951). On intergroup analysis, VAS of group B was superior to that of group A; however, it was statistically significant (P&lt;0.05) only from the 6-week follow-up onwards. Nirschl score of group B was significantly better throughout the period of follow-up (P&lt;0.05). Group B returned to daily activities faster than Group A (6.2±0.44 weeks vs. 7.18±0.76 weeks).

CONCLUSIONS: Concomitant pie crusting with CSI is recommended for lateral epicondylitis as it provides significantly better results than CSI alone.

PMID:36919507 | DOI:10.5397/cise.2022.01375

Clin Shoulder Elb. 2023 Mar;26(1):41-48. doi: 10.5397/cise.2022.01305. Epub 2023 Feb 22.

ABSTRACT

BACKGROUND: Shoulder instability procedures have low morbidity; however, complications can arise that result in readmission to an inpatient healthcare facility. The purpose of this study is to identify the demographics and risk factors associated with unplanned 30-day readmission and reoperation following arthroscopic and open treatment for shoulder instability.

METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried to find patients who underwent shoulder instability surgery from 2015 to 2019. Independent sample Student t-tests, chi-square, and (where appropriate) Fisher’s exact tests were used in univariate analyses to identify demographic, lifestyle, and perioperative variables related to 30-day readmission and reoperation following repair for shoulder instability. Multivariate logistic regression modeling was subsequently performed.

RESULTS: Of the 11,230 cases included in our sample, only 0.54% were readmitted, and 0.23% underwent reoperation within the 30-day postoperative period. Multivariate logistic regression modeling confirmed that the following patient variables were associated with statistically significantly increased odds of readmission and reoperation: open repair, congestive heart failure (CHF), and hospital length of stay.

CONCLUSIONS: Unplanned 30-day readmission and reoperation after shoulder instability surgery is infrequent. Patients with American Society of Anesthesiologists class II, CHF, longer than average hospital length of stay, or an open procedure have higher odds of readmission than patients without those factors. Patients who have CHF, longer than average hospital length of stay, and open surgery have higher odds of reoperation than others. Arthroscopic procedures should be used to manage shoulder instability, if possible.

PMID:36919506 | DOI:10.5397/cise.2022.01305