Tag: nevin manimala

Angew Chem Int Ed Engl. 2022 Apr 29. doi: 10.1002/anie.202200983. Online ahead of print.

ABSTRACT

Understanding how mutations render a drug ineffective is a problem of immense relevance. Often the mechanism through which mutations cause drug resistance can be explained purely through thermodynamics. However, the more perplexing situation is when two proteins have the same drug binding affinities but different residence times. In this work, we demonstrate how all-atom molecular dynamics simulations using recent developments grounded in statistical mechanics can provide a detailed mechanistic rationale for such variances. We discover dissociation mechanisms for the anti-cancer drug Imatinib (Gleevec) against wild-type and the N368S mutant of Abl kinase. We show how this point mutation triggers far-reaching changes in protein’s flexibility and leads to a different, much faster, drug dissociation pathway. We believe that this work marks an efficient and scalable approach to obtain mechanistic insight into resistance mutations in biomolecular receptors that are hard to explain using a structural perspective.

PMID:35486370 | DOI:10.1002/anie.202200983

Acad Psychiatry. 2022 Apr 29. doi: 10.1007/s40596-022-01635-y. Online ahead of print.

ABSTRACT

OBJECTIVE: This study describes the supply, distribution, and characteristics of international medical graduate (IMG) psychiatrists who provide services in the USA.

METHODS: Cross-sectional study design, using descriptive statistics based on combined data from the American Medical Association (2020 Physician Masterfile) and the Educational Commission for Foreign Medical Graduates.

RESULTS: International medical graduates continue to make significant contributions to the US physician workforce. As a group, they represent 29% of active psychiatrists in the USA, compared to 23% in all other medical specialties. Many IMG psychiatrists were US citizens who obtained their medical degrees outside the USA or Canada, often in the Caribbean. In some states (i.e., Florida, New Jersey), over 40% of active psychiatrists are IMGs. Over 30% of IMG psychiatrists graduated from medical schools in India and Pakistan.

CONCLUSIONS: This study provides an overview of the psychiatric workforce in the USA, quantifying the specific contribution of IMGs. Several factors, including immigration policies, continued expansion of US medical schools, and the number of available residency positions, could impact the flow of IMGs to the US. Longitudinal studies are needed to better understand the implications for workforce composition and distribution, and their potential impact on the care of psychiatric patients.

PMID:35486365 | DOI:10.1007/s40596-022-01635-y

CJEM. 2022 Apr 29. doi: 10.1007/s43678-022-00297-x. Online ahead of print.

ABSTRACT

PURPOSE: Empathy and quality of educational environment appear to be inversely correlated with burnout but the relationship between the two is largely unknown. Our primary objective was to examine the relationship between postgraduate educational environment and empathy. Secondary objectives included impact of gender, residency year and on- versus off-service context on levels of empathy and educational environment.

METHODS: A modified Dillman approach was used to conduct an email survey of Canadian Royal College Emergency Medicine residents in June 2020. The survey instrument included: demographic data, Toronto Empathy Questionnaire (TEQ) and Scan of Postgraduate Educational Environment Domains (SPEED). Logistic and linear regressions evaluated the association between TEQ and SPEED, and mean SPEED scores and covariates, respectively.

RESULTS: Response rate was 38% (138/363) with representation from all programs. Respondents were mean 30 years of age, 59% men and 25%, 20%, 18%, 24%, and 13% in postgraduate year (PGY) 1-5, respectively. There was no statistically significant association between high/low TEQ scores and mean SPEED score (p = 0.97). There were no statistically significant associations between any of the covariates and high/low TEQ scores (gender, p = 0.21; PGY, p = 0.58; on-versus off-service, p = 0.46) or mean SPEED score (gender, p = 0.95; PGY, p = 0.48; on- versus off-service, p = 0.07). Emergency medicine residents rated their educational environment on average 3.44 (+/- 0.43) out of four. 39 of 134 residents were found to have low empathy.

CONCLUSION: There was no association between empathy and educational environment. Further research is needed to elucidate modifiable factors contributing to the development of low empathy in emergency medicine residents.

PMID:35486367 | DOI:10.1007/s43678-022-00297-x

Drugs Aging. 2022 Apr 29. doi: 10.1007/s40266-022-00937-y. Online ahead of print.

ABSTRACT

BACKGROUND: The success of intravitreal treatment for neovascular age-related macular degeneration (nAMD) depends on maximal adherence to treatment, which in turn requires patient satisfaction.

OBJECTIVE: The aim of this study was to assess the factors associated with nAMD patient satisfaction to implement actions to improve treatment experiences and increase adherence.

DESIGN: This was a prospective, observational, analytical, cross-sectional study.

SUBJECTS: Our study included 100 consecutive nAMD patients under intravitreal treatment for at least 1 year.

METHODS: Patients completed the Macular Disease Treatment Satisfaction Questionnaire (MacTSQ) and the EuroQol Visual Analog Scale (EQ VAS). A logistic regression was estimated to model the low values of the satisfaction score (MacTSQ < 50).

RESULTS: The mean age of patients was 82.1 ± 7.8 years and 62% were female. Males (p = 0.002) and patients who improved their visual acuity (p = 0.004) were more satisfied, while patients who received a higher number of injections (p = 0.036) and treatment in both eyes (p = 0.001) were less satisfied. Higher health-related quality of life was related to higher satisfaction. The sensitivity and specificity of the predictive model were 75.8% and 76.1%, respectively. Factors independently associated with low satisfaction were female sex (odds ratio [OR] 6.84), going to the clinic alone (OR 8.51), longer duration of treatment (OR 0.62), receiving treatment in both eyes (OR 3.54), and suffering a decline in visual acuity (OR 3.30). The questionnaire revealed patients’ needs for more information and injection points closer to their homes.

CONCLUSIONS: Well-defined areas for improvement were identified, i.e. to improve the information offered to each patient, to incorporate new long-acting drugs, and to establish locations for injection services in peripheral areas.

PMID:35486357 | DOI:10.1007/s40266-022-00937-y

J Exp Orthop. 2022 Apr 29;9(1):38. doi: 10.1186/s40634-022-00474-y.

ABSTRACT

PURPOSE: The purpose of this study was to compare the medial meniscus (MM) degeneration, meniscus extrusion, and tibial joint inclination by using MRI to consider the pathogenesis of posterior root tear (PRT) in medial-type knee osteoarthritis (KOA) both with and without medial meniscus posterior root tear (MMPRT).

METHODS: This study used open MRI with flexion sagittal view and included 324 medial-type osteoarthritic knees with a Kellegren-Lawrence grade of 2 or less. Following the exclusion process, 151 knees were selected for MRI analysis. MM degeneration grading was performed according to Jerosch by 5 degrees of 0-4 in four different portions from anterior to posterior. MM medial extrusion (MMME), MM posterior extrusion (MMPE), medial tibial medial slope (MTMS), and medial tibial posterior slope (MTPS) were measured according to previous studies.

RESULTS: MM degeneration in the anterior portion to MCL averaged 1.72 ± 0.67 in the PRT group (n = 48) and 1.40 ± 0.78 in the non-PRT group (n = 103). The degeneration grade was statistically higher in the PRT group than in the non-PRT group (p = 0.050). There was no difference in MM degeneration in the other three portions. MMME averaged 4.02 ± 1.12 mm in the PRT group and 3.11 ± 1.11 mm in the non-PRT group. MMPE averaged 4.22 ± 0.87 mm in the PRT group and 2.83 ± 1.12 mm in the non-PRT group. Both MMME and MMPE in the PRT group were statistically larger than those in the non-PRT group (p < 0.001). There was no difference in MTMS between the two groups. MTPS averaged 6.34 ± 2.25° in the PRT group and 5.28 ± 2.23° in the non-PRT group. The MTPS of the PRT group was statistically larger than that of the non-PRT group (p = 0.007).

CONCLUSION: The severity of MM degeneration, extrusion of MM, and degree of tibial slope were compared between medial-type KOA with and without PRT using an open MRI. MM degeneration was more severe anteriorly in the PRT group. The PRT group showed larger MMME and MMPE with greater MTPS.

LEVEL OF EVIDENCE: III. Retrospective cohort study.

PMID:35486331 | DOI:10.1186/s40634-022-00474-y

Drugs R D. 2022 Apr 29. doi: 10.1007/s40268-022-00389-0. Online ahead of print.

ABSTRACT

BACKGROUND: The caspase recruitment domain-containing protein 9 (CARD9) inhibitor BRD5529 has been shown to be an effective in vitro inhibitor of Pneumocystis β-glucan-induced proinflammatory signaling, suggesting its viability as a candidate for preliminary anti-Pneumocystis drug testing in the rodent Pneumocystis pneumonia (PCP) model.

METHODS: Mice were injected intraperitoneally (IP) daily with either vehicle or BRD5529 at 0.1 or 1.0 mg/kg for 2 weeks. Mouse weights were taken daily. At day 14, mice were euthanized, weighed, and analyzed by flexiVent™ for lung stiffness. Lungs, liver, and kidney were then harvested for hematoxylin and eosin (H&E) staining and pathology scoring. Lung samples were further analyzed for proinflammatory cytokines via enzyme-linked immunosorbent assay (ELISA) and extracellular matrix generation via quantitative polymerase chain reaction (qPCR). Blood collection postmortem was performed for blood chemistry analysis. Furthermore, administration of BRD5529 prior to the intratracheal inoculation of fungal β-glucans, which are known proinflammatory mediators via the Dectin-1-CARD9 pathway, resulted in significant reductions in lung tissue interleukin-6 and tumor necrosis factor-α, suggesting the exciting possibility of the use of this CARD9 inhibitor as an additional therapeutic tool in fungal infections.

RESULTS: BRD5529 at both IP doses resulted in no significant changes in daily or final weight gain, and analysis of lung stiffness by flexiVent™ showed no significant differences between the groups. Furthermore, ELISA results of proinflammatory cytokines showed no major differences in the respective groups. qPCR analysis of extracellular matrix transcripts were statistically similar. Examination and pathology scoring of H&E slides from lung, liver, and kidney in all groups, as well as subsequent pathology scoring, showed no significant change. Blood chemistry analysis revealed similar, non-significant patterns.

CONCLUSIONS: In our initial general safety and toxicology assessments, BRD5529 displayed no inherent safety concerns in the analyzed parameters. These data support broader in vivo testing of the inhibitor as a timed adjunct therapy to the deleterious proinflammatory host immune response often associated with anti-Pneumocystis therapy.

PMID:35486318 | DOI:10.1007/s40268-022-00389-0

J Neurooncol. 2022 Apr 29. doi: 10.1007/s11060-022-04019-2. Online ahead of print.

ABSTRACT

PURPOSE: We sought to evaluate the effects of concurrent temozolomide-based chemoradiation therapy on neurocognitive function in patients with low-grade glioma (LGG).

MATERIALS/METHODS: We included adult patients with LGG who were treated postoperatively with radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). Patients were evaluated with comprehensive psychometric tests at baseline (prior to RT + TMZ) and at various time intervals following RT + TMZ. Baseline cognitive performance was analyzed by sex, age, education history, history of seizures, IDH mutation status, and 1p/19q codeletion status. Changes in neurocognitive performance were evaluated over time.

RESULTS: Thirty-seven LGG patients (mean age 43.6, 59.5% male) had baseline neurocognitive evaluation. Patients with an age > 40 years old at diagnosis and those with an education > 16 years demonstrated superior baseline verbal memory as assessed by HVLT. No other cognitive domains showed differences when stratified by the variables mentioned above. A total of 22 LGG patients had baseline and post RT + TMZ neurocognitive evaluation. Overall, patients showed no statistical difference between group mean test scores prior to and following RT + TMZ on all psychometric measures (with the exception of HVLT Discrimination).

CONCLUSION: Cognitive function remained stable following RT + TMZ in LGG patients evaluated prospectively up to 2 years. The anticipated analysis of RTOG 0424 will provide valuable neurocognitive outcomes specifically for high risk LGG patients treated with RT + TMZ.

PMID:35486307 | DOI:10.1007/s11060-022-04019-2

Int J Comput Assist Radiol Surg. 2022 Apr 29. doi: 10.1007/s11548-022-02626-y. Online ahead of print.

ABSTRACT

PURPOSE: In craniomaxillofacial (CMF) surgery planning, a preoperative reconstruction of the CMF reference model is crucial for surgical restoration, especially the reconstruction of bilateral defects. Current reconstruction algorithms mainly generate reference models from the image analysis aspect, however, clinical indicators of the CMF reference model mostly consider the distribution of anatomical landmarks. Generating a reference model with optimal clinical evaluation helps promote the feasibility of an algorithm.

METHODS: We first build a dataset with 100 normal skull models and then calculate a statistical shape model (SSM) and the distribution of normal cephalometric values, which indicate the statistical features of a population. To further generate personalized reference models, we apply non-rigid registration to align the SSM with the defect skull model. An evaluation standard to select the optimal reference model considers both global performance and anatomical evaluation. Moreover, we develop a landmark detection network to improve the automatic level of the algorithm.

RESULTS: The proposed method performs better than methods including Iterative Closest Point and SSM. From a global evaluation aspect, the results show that the RMSE between the reference model and the ground truth is [Formula: see text] mm, the percentage of vertices with error below 2 mm is [Formula: see text]% and the average faces distance is [Formula: see text] mm (better than the state-of-the-art method). From the anatomical evaluation aspect, the target registration error between the landmark pairs is [Formula: see text] mm. In addition, the clinical application confirms that the reference model can meet clinical requirements.

CONCLUSION: To the best of our knowledge, we propose the first CMF reconstruction method considering the global performance of reconstruction and anatomically local evaluation from clinical experience. Simulated experiments and clinical cases prove the general applicability and strength of the method.

PMID:35486302 | DOI:10.1007/s11548-022-02626-y

Community Ment Health J. 2022 Apr 29. doi: 10.1007/s10597-022-00976-0. Online ahead of print.

ABSTRACT

Lack of access to primary and behavioral healthcare is prevalent in communities experiencing systematically greater obstacles to healthcare. This study describes the implementation of the Coordinated Care Model in a nurse-led primary care clinic and identifies the essential factors for sustained integration. A mixed-methods explanatory sequential study design was used to collect and analyze quantitative and qualitative data. Participants reported an overall statistically significant mean increase (M = 2.47, SD ± 2.01, p < 0.001) in the level of integration pre-and post-integration. Qualitative results indicated that the optimization and accentuation of team strengths, the Lundeen model of holistic care, and addressing physical and psychological barriers lead to sustained level of integration. Integrated practices are essential in assessing and supporting the holistic needs of individuals, families, and communities. Future studies should examine facilitators or impediments to integrated practice in other healthcare settings, long-term health outcomes of clients in integrated care, and the cost-effectiveness of integration.

PMID:35486305 | DOI:10.1007/s10597-022-00976-0

Obes Surg. 2022 Apr 29. doi: 10.1007/s11695-022-06069-x. Online ahead of print.

ABSTRACT

PURPOSE: Little is known about the consequences of COVID-19 lockdowns on physical activity (PA), eating behavior, and mental health in post-bariatric surgery (BS) patients. We aimed to analyze the relations between changes in PA during COVID-19 lockdowns and changes in body weight and a comprehensive set of lifestyle and psychological outcomes in patients who have undergone BS.

MATERIAL AND METHODS: In April-May 2020 (lockdown#1), we performed an online survey in a cohort of 937 adults who underwent BS and were followed-up at our university medical center for at least one year. We assessed changes in PA, eating behavior, body weight, fatigue, and depression (PHQ-9). In November-December 2020 (lockdown#2), we recorded body weight in 280 patients who had reported decreased PA during lockdown #1.

RESULTS: During lockdown #1 (N = 420 patients included, 44% response rate), decreased PA was reported by 67% patients. Compared to those who reported increased or unchanged PA, patients with decreased PA were more likely to report a ≥ 5% weight gain (OR (95% CI): 3.15 (1.46-7.65), increased fatigue (2.08 (1.36-3.23)), a worsening of eating behavior (2.29 (1.47-3.58)), and moderate-to-severe depressive symptoms (4.74 (2.14-11.76)). During lockdown #2 (N = 225 patients, 80% response rate), significant weight gain since before lockdown #1 was reported (+ 2.8 (95% CI: 1.7-3.8) kg, p < 0.001), with 36% patients reporting a ≥ 5% weight gain.

CONCLUSIONS: PA may counteract detrimental effects of COVID-19 lockdown on post-BS weight trajectories and mental health outcomes. Follow-up measures are needed in this setting to assess the long-term impact of lockdown.

PMID:35486289 | DOI:10.1007/s11695-022-06069-x