Category: Nevin Manimala

Cutis. 2022 Jun;109(6):E36-E38. doi: 10.12788/cutis.0551.

ABSTRACT

Residency is both physically and mentally taxing. Although some tout these struggles as a rite of passage to practice medicine, rates of physician burnout and suicide unfortunately remain higher than the general population. Limitations on work hours, mandatory reporting of work hour violations, and resident wellness programs have aimed to improve these statistics, but the time constraints and physical demands of residency offer little room for trainees to focus on their mental health. In 2020, the COVID-19 pandemic tested an already strained health care system, bringing to light the prevalence of depression and anxiety among residents. This article explores this prevalence and highlights several modalities available to residents who are seeking to prioritize their mental health.

PMID:35960972 | DOI:10.12788/cutis.0551

Hum Vaccin Immunother. 2022 Aug 12:2087412. doi: 10.1080/21645515.2022.2087412. Online ahead of print.

ABSTRACT

This article describes the results of a preclinical safety and immunogenicity study of QazCovid-in®, the first COVID-19 vaccine developed in Kazakhstan, on BALB/c mice, rats, ferrets, Syrian hamsters and rhesus macaques (Macaca mulatta). The study’s safety data suggests that this immunobiological preparation can be technically considered a Class 5 nontoxic vaccine. The series of injections that were made did not produce any adverse effect or any change in the general condition of the model animals’ health, while macroscopy and histology studies identified no changes in the internal organs of the BALB/c mice and rats. This study has demonstrated that a double immunization enhances the growth of antibody titers as assessed by the microneutralization assay (MNA) and the enzyme-linked immunosorbent assay (ELISA) in a pre-clinical immunogenicity test on animal models. The best GMT results were assessed in MNA and ELISA 7 days after re-vaccination; however, we noted that GMT antibody results in ELISA were lower than in MNA. A comparative GMT assessment after the first immunization and the re-immunization identified significant differences between model animal groups and a growth of GMT antibodies in all of them; also, differences between the gender groups were statistically significant. Moreover, the most marked MNA immune response to the QazCovid-in® vaccine was seen in the Syrian hamsters, while their SARS-CoV-2-specific antibody activity as assessed with ELISA was the lowest.

PMID:35960911 | DOI:10.1080/21645515.2022.2087412

J Clin Oncol. 2022 Aug 12:JCO2102815. doi: 10.1200/JCO.21.02815. Online ahead of print.

ABSTRACT

PURPOSE: In the phase II ELOQUENT-3 trial (ClinicalTrials.gov identifier: NCT02654132), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved progression-free survival (PFS) versus pomalidomide/dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide and a proteasome inhibitor (PI). Here, we present the final overall survival (OS) results.

METHODS: Patients with RRMM who had received ≥ 2 prior lines of therapy, with disease refractory to last therapy and either refractory or relapsed and refractory to lenalidomide and a PI were randomly assigned (1:1) to receive EPd or Pd. The primary end point was PFS per investigator assessment. ORR and OS were secondary end points planned to be tested hierarchically.

RESULTS: A total of 117 patients were randomly assigned to EPd (n = 60) and Pd (n = 57). Among treated patients (EPd 60, Pd 55), there were 37 (61.7%) deaths in the EPd group and 41 (74.5%) in the Pd group, most commonly because of disease progression (EPd 41.7%, Pd 49.1%). Median (95% CI) OS was significantly improved with EPd (29.8 [22.9 to 45.7] months) versus Pd (17.4 [13.8 to 27.7] months), with a hazard ratio of 0.59 (95% CI, 0.37 to 0.93; P = .0217). OS benefit with EPd was observed in most patient subgroups. The safety profile of EPd was consistent with prior reports with no new safety signals detected.

CONCLUSION: EPd demonstrated a statistically significant improvement in OS versus Pd in patients with RRMM previously treated with lenalidomide and a PI who had disease refractory to last therapy. In this setting, ELOQUENT-3 is the first randomized study of a triplet regimen incorporating a monoclonal antibody and Pd to improve both PFS and OS significantly.

PMID:35960908 | DOI:10.1200/JCO.21.02815

J Clin Oncol. 2022 Aug 12:JCO2200405. doi: 10.1200/JCO.22.00405. Online ahead of print.

ABSTRACT

PURPOSE: A DNA repair deficiency (DRD) phenotype exists within a subset of metastatic urothelial carcinomas (mUC) predicting benefit from platinum-based chemotherapy. We tested switch maintenance therapy with the poly ADP-ribose polymerase inhibitor rucaparib, following chemotherapy, for DRD biomarker-positive mUC.

METHODS: DRD biomarker-positive mUC patients, within 10 weeks of chemotherapy, and without cancer progression, were randomly assigned (1:1) to maintenance rucaparib 600 mg twice a day orally, or placebo, until disease progression. The primary end point was progression-free survival (PFS). Statistical analysis targeted a hazard ratio of 0.5 with a 20% one-sided α for this signal-seeking trial. PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model.

RESULTS: Out of 248 patients, 74 (29.8%) were DRD biomarker-positive and 40 were randomly assigned. A total of 12 (60%) and 20 (100%) PFS events occurred in the rucaparib and placebo arms, respectively (median follow-up was 94.6 weeks in those still alive). Median PFS was 35.3 weeks (80% CI, 11.7 to 35.6) with rucaparib and 15.1 weeks (80% CI, 11.9 to 22.6) with placebo (hazard ratio, 0.53; 80% CI, 0.30 to 0.92; one-sided P = .07). In the safety population (n = 39) treatment-related adverse events were mostly low grade. Patients received a median duration of 10 rucaparib or six placebo cycles on treatment. Treatment-related adverse events (all grades) of fatigue (63.2% v 30.0%), nausea (36.8% v 5.0%), rash (21.1% v 0%), and raised alanine aminotransferase (57.9% v 10%) were more common with rucaparib.

CONCLUSION: Maintenance rucaparib, following platinum-based chemotherapy, extended PFS in DRD biomarker-selected patients with mUC and was tolerable. Further investigation of poly ADP-ribose polymerase inhibition in selected patients with mUC is warranted.

PMID:35960902 | DOI:10.1200/JCO.22.00405

J Clin Oncol. 2022 Aug 12:JCO2102831. doi: 10.1200/JCO.21.02831. Online ahead of print.

ABSTRACT

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The purpose of this update was to determine differences in patient-reported chronic toxicity and disease outcomes with intensity-modulated radiation therapy (IMRT) compared with conventional pelvic radiation. Patients with cervical and endometrial cancers who received postoperative pelvic radiation were randomly assigned to conventional radiation therapy (CRT) or IMRT. Toxicity and quality of life were assessed using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domains, and Functional Assessment of Cancer Therapy-General. Between 2012 and 2015, 279 eligible patients were enrolled to the study with a median follow-up of 37.8 months. There were no differences in overall survival (P = .53), disease-free survival (P = .21), or locoregional failure (P = .81). One year after RT, patients in the CRT arm experienced more high-level diarrhea frequency (5.8% IMRT v 15.1% CRT, P = .042) and a greater number had to take antidiarrheal medication two or more times a day (1.2% IMRT v 8.6% CRT, P = .036). At 3 years, women in the CRT arm reported a decline in urinary function, whereas the IMRT arm continued to improve (mean change in EPIC urinary score = 0.5, standard deviation = 13.0, IMRT v -6.0, standard deviation = 14.3, CRT, P = .005). In conclusion, IMRT reduces patient-reported chronic GI and urinary toxicity with no difference in treatment efficacy at 3 years.

PMID:35960897 | DOI:10.1200/JCO.21.02831

J Clin Oncol. 2022 Aug 12:JCO2102911. doi: 10.1200/JCO.21.02911. Online ahead of print.

ABSTRACT

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized, open-label, phase III NEJ009 study, gefitinib plus chemotherapy significantly improved progression-free survival (PFS) and overall survival (OS) compared with gefitinib-alone in patients with untreated non-small-cell lung cancer harboring mutations in epidermal growth factor receptor. Herein, we report the updated survival outcome and long-term tolerability. Patients were randomly assigned to gefitinib (gefitinib 250 mg orally, once daily) and gefitinib combined with carboplatin plus pemetrexed (GCP in a 3-week cycle for six cycles followed by concurrent gefitinib and pemetrexed maintenance) groups. At the data cutoff (May 22, 2020), GCP demonstrated significantly better PFS2 (hazard ratio, 0.77; 95% CI, 0.62 to 0.97; P = .027) than gefitinib. However, the updated median OS was 38.5 months (95% CI, 31.1 to 47.1) and 49.0 months (95% CI, 41.8 to 56.7) in the gefitinib and GCP groups, respectively (hazard ratio, 0.82; 95% CI, 0.64 to 1.06; P = .127). The OS in both groups was similar for the overall patient population. No severe adverse events occurred since the first report. This updated analysis revealed that the GCP regimen improved PFS and PFS2 with an acceptable safety profile compared with gefitinib-alone. GCP is more efficient than gefitinib monotherapy as a first-line treatment for non-small-cell lung cancer with epidermal growth factor receptor mutations.

PMID:35960896 | DOI:10.1200/JCO.21.02911

Otol Neurotol. 2022 Aug 2. doi: 10.1097/MAO.0000000000003652. Online ahead of print.

ABSTRACT

OBJECTIVE: To identify demographic and clinical features impacting initial treatment pathway for vestibular schwannoma.

STUDY DESIGN: Retrospective chart review.

SETTING: Tertiary care academic medical center.

PATIENTS: Patients diagnosed with vestibular schwannoma between 2009 and 2019.

INTERVENTIONS: Observation, stereotactic radiosurgery, or microsurgical resection.

MAIN OUTCOME MEASURES: χ2 Test, one-way analysis of variance, and multivariate logistic regression were used to correlate demographic and clinical factors with initial treatment pathway for 197 newly diagnosed vestibular schwannoma patients.

RESULTS: Among 197 patients, 93 (47%) were initially treated with observation, 60 (30%) with stereotactic radiation (Gamma Knife) and 44 (22%) with surgical resection. Age univariately had no statistically significant impact on initial pathway, but those undergoing surgery trended toward a younger demographic (49.1 yr [surgery] versus 57.2 yr [observation] versus 59.0 yr [Gamma Knife]). Men were more likely to be initially observed than women (p = 0.04). Patients initially observed were more likely to have a lower Koos classification (p < 0.001) and have better tumor-ear hearing (p = 0.03). Only 34.4% of patients living outside the local geographic region were initially observed compared with 53.0% living locally (p = 0.055). Surgeon correlated with initial treatment (p = 0.04) but did not maintain significance when adjusting for hearing level or tumor size. A multiple linear regression model found age, maximum tumor diameter, and Koos class to correlate with initial treatment pathway (p < 0.0001, r2 = 0.42).

CONCLUSION: Initial treatment pathway for newly diagnosed vestibular schwannoma is impacted by demographic factors such as age, sex, and geographic proximity to the medical center. Clinical features including hearing level and tumor size also correlated with initial treatment modality.

PMID:35960883 | DOI:10.1097/MAO.0000000000003652

J Med Chem. 2022 Aug 12. doi: 10.1021/acs.jmedchem.2c01004. Online ahead of print.

ABSTRACT

Current fragment-based drug design relies on the efficient exploration of chemical space by using structurally diverse libraries of small fragments. However, structurally dissimilar compounds can exploit the same interactions and thus be functionally similar. Using three-dimensional structures of many fragments bound to multiple targets, we examined if a better strategy for selecting fragments for screening libraries exists. We show that structurally diverse fragments can be described as functionally redundant, often making the same interactions. Ranking fragments by the number of novel interactions they made, we show that functionally diverse selections of fragments substantially increase the amount of information recovered for unseen targets compared to the amounts recovered by other methods of selection. Using these results, we design small functionally efficient libraries that can give significantly more information about new protein targets than similarly sized structurally diverse libraries. By covering more functional space, we can generate more diverse sets of drug leads.

PMID:35960886 | DOI:10.1021/acs.jmedchem.2c01004

Biomed Tech (Berl). 2022 Aug 15. doi: 10.1515/bmt-2021-0019. Online ahead of print.

ABSTRACT

Transcranial magnetic stimulation (TMS) has widespread clinical applications from diagnosis to treatment. We combined TMS with non-contact magnetic detection of TMS-evoked muscle activity in peripheral limbs to explore a new diagnostic modality that enhances the utility of TMS as a clinical tool by leveraging technological advances in magnetometry. We recorded measurements in a regular hospital room using an array of optically pumped magnetometers (OPMs) inside a portable shield that encloses only the forearm and hand of the subject. We present magnetomyograms (MMG)s of TMS-evoked movement in a human hand, together with a simultaneous surface electromyograph (EMG) data. The biomagnetic signals recorded in the MMG provides detailed spatial and temporal information that is complementary to that of the electric signal channels. Moreover, we identify features in the magnetic recording beyond that of the EMG. This system demonstrates the value of biomagnetic signals in TMS-based clinical approaches and widens its availability and practical potential.

PMID:35960879 | DOI:10.1515/bmt-2021-0019

Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2200061119. doi: 10.1073/pnas.2200061119. Epub 2022 Aug 12.

ABSTRACT

DNA looping has emerged as a central paradigm of transcriptional regulation, as it is shared across many living systems. One core property of DNA looping-based regulation is its ability to greatly enhance repression or activation of genes with only a few copies of transcriptional regulators. However, this property based on a small number of proteins raises the question of the robustness of such a mechanism with respect to the large intracellular perturbations taking place during growth and division of the cell. Here we address the issue of sensitivity to variations of intracellular parameters of gene regulation by DNA looping. We use the lac system as a prototype to experimentally identify the key features of the robustness of DNA looping in growing Escherichia coli cells. Surprisingly, we observe time intervals of tight repression spanning across division events, which can sometimes exceed 10 generations. Remarkably, the distribution of such long time intervals exhibits memoryless statistics that is mostly insensitive to repressor concentration, cell division events, and the number of distinct loops accessible to the system. By contrast, gene regulation becomes highly sensitive to these perturbations when DNA looping is absent. Using stochastic simulations, we propose that the observed robustness to division emerges from the competition between fast, multiple rebinding events of repressors and slow initiation rate of the RNA polymerase. We argue that fast rebinding events are a direct consequence of DNA looping that ensures robust gene repression across a range of intracellular perturbations.

PMID:35960846 | DOI:10.1073/pnas.2200061119