Nevin Manimala

Clin Lung Cancer. 2022 Aug 15:S1525-7304(22)00186-3. doi: 10.1016/j.cllc.2022.08.007. Online ahead of print.

ABSTRACT

BACKGROUND: We investigated the impact of factors that influence TP53 mutations on the efficacy of EGFR-tyrosine kinase inhibitors and potential treatment strategies.

MATERIALS AND METHODS: Tumor samples were collected to screen gene mutations by next-generation sequencing, as well as the patients’ baseline characteristics. The overall response to treatment with TKIs was evaluated based on interval computed tomography scans at each follow-up time point. A Fisher’s exact test and log-rank test were used to determine the statistical differences in this study.

RESULTS: A total of 1134 clinical samples were collected from NSCLC patients, and TP53^mut was identified in 644 cases and EGFR^mut in 622 cases. A low frequency of TP53^mut or more than 50% EGFR co-mutation rate were related to the prognosis of TKI-treated patients. In addition, TP53^mut in the region outside of the DB domain had the strongest correlation with TKI resistance, whereas various types of mutations in the DB domain only had an impact on PFS. A grouping study of EGFR-TKI-based treatment revealed that EGFR-TKIs with chemotherapy were associated with more significant survival benefits for patients with prognostic TP53^mut, whereas EGFR-TKI therapy was favorable for TP53^wt patients. Furthermore, TP53^mut could shorten the time to the relapse of postoperative patients, who will also likely respond well to EGFR-TKIs with chemotherapy.

CONCLUSION: Various characteristics of TP53^mut affect the prognosis of TKI-treated patients to varying degrees. EGFR-TKIs with chemotherapy were benefit for patients’ survival with prognostic TP53^mut, which provides an important reference for treatment management of EGFR^mut patients.

PMID:36117108 | DOI:10.1016/j.cllc.2022.08.007

J Am Pharm Assoc (2003). 2022 Aug 19:S1544-3191(22)00284-9. doi: 10.1016/j.japh.2022.08.014. Online ahead of print.

ABSTRACT

BACKGROUND: The glass ceiling is a metaphor used to describe an invisible barrier that prevents an underrepresented group from rising beyond a certain level. Among pharmacists, underrepresented groups face various barriers and limitations to their successes.

OBJECTIVES: The purpose of this study was to apply the intersectionality framework to data collected from the 2019 National Pharmacist Workforce Study (NPWS) to understand the association of gender and race with leadership aspiration among pharmacists, including differences in perceived barriers and attractors for pursuing leadership.

METHODS: The 2019 NPWS was conducted using an electronic Qualtrics survey. Three e-mails containing the survey link were sent to a systematic random sample of 94,803 pharmacists through the National Association of Boards of Pharmacy Foundation e-profile system. The 2019 NPWS had an overall response rate of 6% (5705/94,803). A total of 8466 pharmacists clicked on the survey link, resulting in a usable response rate of 67.3% (5705/8466). Data were analyzed in SPSS software using descriptive and Pearson’s r and chi-square test statistics.

RESULTS: Black, Indigenous, and People of Color (BIPOC) pharmacists reported holding 10.7% of all leadership positions. Leadership positions included manager, assistant manager, executive, dean, director, chief pharmacy officer, owner or partner, and other leadership position types. White men and women reported the lowest interest in leadership (38.8% and 37.7%), whereas Black men (65.1%), Latinas (59.2%), Black women (58.5%), and Latinos (57.1%) had the highest interest in leadership. “The ability to make an impact” was the most frequently selected attractor for wanting to pursue leadership, selected by 92.5% and 79.6% of Black men and women, respectively, 77.8% of Other women, and 76.9% of Latinos. At graduation from pharmacy school, the student debt loan average of all graduation years ranged from $63,886 (± $73,701) for Other men to $112,384 (± $105,417) for Black women. Higher student loan debt was positively correlated with wanting to pursue a leadership position (r = 0.22, P < 0.001). Black women graduating 2011-2019 had the highest student loan debt at graduation ($194,456 ± $88,898).

CONCLUSION: Interest in leadership positions by BIPOC pharmacists compared with reported leadership roles were inversely correlated. Understanding the discrepancy in interest in leadership and reported leadership positions held, particularly with relation to race and gender, is essential to understanding equity in pharmacy leadership. Further research is warranted to understand the factors that impede the ascension of women and underrepresented pharmacists into leadership positions.

PMID:36117106 | DOI:10.1016/j.japh.2022.08.014

Clin Colorectal Cancer. 2022 Aug 12:S1533-0028(22)00073-1. doi: 10.1016/j.clcc.2022.08.002. Online ahead of print.

ABSTRACT

BACKGROUND: The real-world survival benefit of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus anti-VEGF therapy (Triplet) over doublet chemotherapy (Doublet) remains controversial in patients with BRAF^V600E mutant metastatic colorectal cancer (mCRC).

PATIENTS AND METHODS: WJOG13219G was a multicenter, retrospective, registry-based study of patients with BRAF^V600E mutant mCRC who received first-line triplet or doublet chemotherapy from January 2014 to December 2019 in Japan. Inverse probability of treatment weighting (IPTW) was used to adjust for patient background.

RESULTS: The analysis included 79 and 91 patients in the Triplet and Doublet groups, respectively. The Triplet group was significantly younger and had better performance status. No statistical difference was noted in progression-free survival (PFS; HR, 0.82; 95% CI, 0.60-1.13; P = .22) and overall survival (OS; HR, 0.88; 95% CI, 0.62-1.25; P = .48) between both groups. IPTW analysis also showed no difference between the 2 groups in PFS (HR, 0.86; 95% CI, 0.69-1.08; P = .20) and OS (HR, 0.93; 95% CI, 0.73-1.20; P = .59). The Triplet and Doublet groups had an objective response rate of 53% and 41%, respectively (P = .10). At least one grade 3 or 4 adverse event was seen in 51 (65%) and 43 (47%) patients in the Triplet and Doublet groups, respectively, with the incidence of neutropenia being significantly higher in the former.

CONCLUSION: Triplet therapy had no survival benefit versus doublet therapy in the overall and IPTW cohorts or specific subgroups for real-world patients with BRAF^V600E mutant mCRC.

PMID:36117091 | DOI:10.1016/j.clcc.2022.08.002

Schizophr Res. 2022 Sep 15:S0920-9964(22)00363-2. doi: 10.1016/j.schres.2022.09.021. Online ahead of print.

ABSTRACT

Catatonia is a neuropsychiatric disorder characterised by altered movement, speech, and behaviour. Clozapine is an established therapy for treatment-resistant schizophrenia, but its role in catatonia has not been systematically examined. In this systematic review, we aimed to assess the evidence for clozapine as a treatment for catatonia. Full text original research articles in English where at least one patient with catatonia was treated with clozapine were included, provided catatonia did not occur solely in the context of neuroleptic malignant syndrome. Results were tabulated with calculations of summary statistics presented. Risk of bias was assessed with the Tool for Evaluating the Methodological Quality of Case Reports and Case Series. 182 patients were included, 81 from cohort studies and 101 from case reports or case series. 119/182 patients (65 %) had a specified underlying diagnosis of schizophrenia. Over 80 % of reported patients with catatonia had at least partial remission following treatment with clozapine across both cohort studies and case reports and case series. Among the case reports and series, 24/101 patients (23.8 %) followed clozapine withdrawal. Overall, 25 studies were of low quality, 60 of moderate quality and 8 of high quality. Our findings should be interpreted with caution, as the reliance on case reports, case series and small cohort studies is susceptible to reporting biases, regression to the mean and confounding by other treatments. Future research could use large healthcare databases to ascertain outcomes in those on clozapine with a history of catatonia given the difficulty and expense of conducting randomised controlled trials.

PMID:36117082 | DOI:10.1016/j.schres.2022.09.021

J Pediatr Health Care. 2022 Sep 15:S0891-5245(22)00238-3. doi: 10.1016/j.pedhc.2022.08.005. Online ahead of print.

ABSTRACT

This survey aimed to evaluate contemporary pediatric nurse practitioner (PNP) practice as it relates to the competencies of both the primary and acute care population focus and settings of practice to guide curriculum revisions. The design of the study was a cross-sectional survey of PNPs certified by the Pediatric Nursing Certification Board. There were 2,265 surveys completed. Regardless of the certification type, PNPs report providing care across settings and integrating the competencies of both the primary and acute care PNP into practice. This warrants further consideration by programs to prepare future PNPs for dual primary and acute care certification.

PMID:36117073 | DOI:10.1016/j.pedhc.2022.08.005

J Heart Lung Transplant. 2022 Aug 15:S1053-2498(22)02071-X. doi: 10.1016/j.healun.2022.08.006. Online ahead of print.

ABSTRACT

BACKGROUND: Risk scores integrate clinical variables emphasizing symptoms, exercise capacity, and measures of cardiac strain to predict clinical outcome better than any single value in pulmonary arterial hypertension (PAH). Risk scores have demonstrated prognostic utility for outcomes in registries, and recent studies have suggested that they are also therapy-responsive in controlled trials.

METHODS: FREEDOM-EV, a global, placebo-controlled, event-driven study, randomized 690 PAH participants 1:1 to oral treprostinil (TRE) or placebo. Clinical assessments were performed every 12 weeks to calculate the non-invasive French risk assessment (FRA), 4-strata COMPERA, REVEAL 2.0, and REVEAL Lite 2; median follow-up was 58 weeks. The Week 12 risk scores were used to predict time to clinical worsening (from Week 12) with Kaplan-Meier product-limit estimates. Log-rank test was used to calculate the statistical difference among risk categories, and mediation analysis tested the hypothesis that improvements in risk score contributed to reduced likelihood for clinical worsening. We assessed the previously proposed “net clinical benefit” (achievement of FRA low-risk status and absence of clinical worsening).

RESULTS: Both REVEAL scores, COMPERA, and FRA at Week 12 predicted subsequent clinical worsening better than baseline risk. Mediation analysis demonstrated that Week 12 risk score reduction explained part of TRE’s effect on clinical worsening, especially for those with higher baseline risk. TRE assigned participants were more likely to achieve the previously proposed “net clinical benefit” at Weeks 24 and beyond. Few participants who achieved ‘net clinical benefit’ had subsequent clinical worsening.

CONCLUSIONS: Contemporary risk scores were therapy responsive in FREEDOM-EV and early improvements predicted subsequent outcomes. This post hoc analysis suggests that risk scores may be a surrogate for clinical worsening.

PMID:36117055 | DOI:10.1016/j.healun.2022.08.006

J Foot Ankle Surg. 2022 Aug 9:S1067-2516(22)00229-0. doi: 10.1053/j.jfas.2022.07.008. Online ahead of print.

ABSTRACT

We examined outcomes following metatarsophalangeal joint cheilectomy with decompression osteotomy to evaluate the efficacy of this technique for treatment of hallux limitus/rigidus. At a minimum follow-up of 5 years, we identified 94 patients who fit the inclusion criteria. Chart review was performed to obtain range of motion (ROM) of the first metatarsophalangeal joint (MTPJ) preoperatively and at 6 weeks, 6 months, and 5 years postoperatively. Additionally, time to traditional shoe gear return, need for revision arthrodesis, radiographic findings, and postoperative visual analog scale (VAS) pain scores were reviewed. Statistical analysis was conducted by 1-way analysis of variance with post-hoc analysis and independent sample t-test. At an average follow-up of 6.3 ± 0.9 years, 42.3% (33/78) of females and 25.0% (4/16) of males reported limited ROM of the first MTPJ with 5 patients requiring first MTPJ arthrodesis. MTPJ ROM improved on average from 11.0° to 36.3° by 5-year minimum follow-up after surgery (p < .001). Analysis of variance revealed a significant difference of the preoperative ROM when compared to all postoperative time points (F[3,368] = 69.4, p < .001). Mean postoperative VAS pain scores after decompression osteotomy of the 5 patients who required MTPJ fusion were higher when compared to the rest of the patient cohort at final follow-up (7.4 ± 0.6 vs 1.5 ± 1.3; p < .001). Cheilectomy with decompression osteotomy for treatment of hallux limitus/rigidus leads to satisfactory long-term outcomes.

PMID:36117052 | DOI:10.1053/j.jfas.2022.07.008

Neurobiol Aging. 2022 Jul 11:S0197-4580(22)00146-4. doi: 10.1016/j.neurobiolaging.2022.07.002. Online ahead of print.

ABSTRACT

Using exome sequencing, we analyzed 196 participants of the Cretan Aging Cohort (CAC; 95 with Alzheimer’s disease [AD], 20 with mild cognitive impairment [MCI], and 81 cognitively normal controls). The APOE ε4 allele was more common in AD patients (23.2%) than in controls (7.4%; p < 0.01) and the PSEN2 p.Arg29His and p.Cys391Arg variants were found in 3 AD and 1 MCI patient, respectively. Also, we found the frontotemporal dementia (FTD)-associated TARDBP gene p.Ile383Val variant in 2 elderly patients diagnosed with AD and in 2 patients, non CAC members, with the amyotrophic lateral sclerosis/FTD phenotype. Furthermore, the p.Ser498Ala variant in the positively selected GLUD2 gene was less frequent in AD patients (2.11%) than in controls (16%; p < 0.01), suggesting a possible protective effect. While the same trend was found in another local replication cohort (n = 406) and in section of the ADNI cohort (n = 808), this finding did not reach statistical significance and therefore it should be considered preliminary. Our results attest to the value of genetic testing to study aged adults with AD phenotype.

PMID:36117051 | DOI:10.1016/j.neurobiolaging.2022.07.002

Dent Traumatol. 2022 Sep 18. doi: 10.1111/edt.12790. Online ahead of print.

ABSTRACT

BACKGROUND/AIM: Evidence on the risk of injury at concerts is scant. The aim of this study was to collect data on general and dental injuries incurred by concertgoers in Switzerland and to investigate whether the frequency of accidents was related to music genre, gender and consumption of alcohol.

MATERIALS AND METHODS: A questionnaire-based, cross-sectional study comprising 451 concertgoers in Switzerland was conducted on the timeframe January 2019 to February 2021. The survey gathered data on general and dental injuries, alcohol consumption and drug use. The statistical analysis included Fisher’s exact tests, chi-squared tests, rank sum tests and logistic regressions (α = .05).

RESULTS: There were 28.8% of respondents who reported an injury incurred at a concert. Contusion was the most prevalent injury, accounting for 33.8% of all injuries. Legs were the most commonly injured body part (34.6%). Injuries to their mouth/lips/teeth were reported by 17.7% of respondents. Dental injuries, accounting for 4.6% of all reported injuries, comprised four tooth fractures, one lateral luxation and one avulsion. The risk of injury while attending punk rock concerts was 8.6 times higher than for pop concerts (p < .001). In comparison with pop concerts, metal and rock concerts had an increased risk of injury by factors of 5.1 and 2.3, respectively (p ≤ .029). Neither gender nor drug use had a significant effect on the injury risk (p ≥ .3). Heavy alcohol consumption (>5 standard glasses) increased the risk of injury by a factor of 2.3 (p = .028).

CONCLUSIONS: This study suggests that concert attendees at rock, metal and punk concerts face an increased risk of injury, which is likely due to the frequency of aggressive dance styles such as moshing. Heavy alcohol consumption leads to a greater risk of injury at concerts.

PMID:36116120 | DOI:10.1111/edt.12790

Chemistry. 2022 Sep 18. doi: 10.1002/chem.202200947. Online ahead of print.

ABSTRACT

Transmission electron microscopy (TEM) observations of negatively stained cell membrane (CM)-coated polymeric nanoparticles (NPs) reveal a characteristic core-shell structure. However, negative staining agents can create artifacts that complicate the determination of the actual NP structure. Herein, we demonstrate with various bare polymeric core NPs, such as poly(lactic-co-glycolic acid) (PLGA), poly(ethylene glycol) methyl ether-block-PLGA, and poly(caprolactone), that certain observed core-shell structures are actually artifacts caused by the staining process. To address this issue, we use fluorescence quenching to quantify the proportion of fully coated NPs and use statistical TEM analysis to identify and differentiate whether the observed core-shell structures of CM-coated PLGA (CM-PLGA) NPs are due to artifacts or to the CM coating. Integrated shells in TEM images of negatively stained CM-PLGA NPs are identified as artifacts. The present results challenge current understanding of the structure of CM-coated polymeric NPs and encourage researchers should use the proposed characterization approach to avoid misinterpretations.

PMID:36116117 | DOI:10.1002/chem.202200947