Clinical correlates in an experimental model of repetitive mild brain injury.

OBJECTIVE: Although there is growing awareness of the long-term cognitive effects of repetitive mild traumatic brain injury (rmTBI; eg, sports concussions), whether repeated concussions cause long-term cognitive deficits remains controversial. Moreover, whether cognitive deficits depend on increased amyloid ß deposition and tau phosphorylation or are worsened by the apolipoprotein E4 allele remains unknown. Here, we use an experimental model of rmTBI to address these clinical controversies. METHODS: A weight drop rmTBI model was used that results in cognitive deficits without loss of consciousness, seizures, or gross or microscopic evidence of brain damage. Cognitive function was assessed using a Morris water maze (MWM) paradigm. Immunostaining and enzyme-linked immunosorbent assay (ELISA) were used to assess amyloid ß deposition and tau hyperphosphorylation. Brain volume and white matter integrity were assessed by magnetic resonance imaging (MRI). RESULTS: Mice subjected to rmTBI daily or weekly but not biweekly or monthly had persistent cognitive deficits as long as 1 year after injuries. Long-term cognitive deficits were associated with increased astrocytosis but not tau phosphorylation or amyloid ß (by ELISA); plaques or tangles (by immunohistochemistry); or brain volume loss or changes in white matter integrity (by MRI). APOE4 was not associated with worse MWM performance after rmTBI. INTERPRETATION: Within the vulnerable time period between injuries, rmTBI produces long-term cognitive deficits independent of increased amyloid ß or tau phosphorylation. In this model, cognitive outcome is not influenced by APOE4 status. The data have implications for the long-term mental health of athletes who suffer multiple concussions.

Effects of novel Coronavirus (COVID-19) on presentation, management, and outcomes of acute cholecystitis at an academic tertiary care center cholecystitis management during COVID-19.

Background: The COVID-19 pandemic necessitated adjustments to nearly all aspects of healthcare, including surgical care. The effects of these adjustments have not been well studied on acute surgical problems conventionally managed non-electively in large, tertiary care centers. Methods: A retrospective analysis of admitted patients with acute cholecystitis at a US academic tertiary care center was performed. We compared the presentation, management, and 30-day outcomes of patients admitted during a 2-month time period during early COVID, to a pre-COVID control group of admitted cholecystitis patients over a 2-month span. Results: The study cohort captured 24 patients, while the control cohort encompassed 53 patients. A non-significant trend toward non-operative management in the COVID cohort is reported. There was no delay in time-to-surgery or complication rate. No surgically managed patient developed COVID within 30 days of operation. Conclusions: Operative management of acute cholecystitis during the COVID-19 pandemic, with pre-operative testing and personal protective equipment guidelines, remained safe and effective.

Pre-operative chemoradiotherapy with or without induction chemotherapy for operable locally-advanced esophageal cancer.

Background: For patients with operable locally advanced esophageal carcinoma (LA-EC), we hypothesized that pre-operative induction chemotherapy followed by chemoradiotherapy (IC-CRT) would improve progression-free survival (PFS) and overall survival (OS) when compared to chemoradiotherapy (CRT). Methods: This was a single institution retrospective cohort study including patients with LA-EC who received preoperative-intent IC-CRT vs. CRT between 2013-2019. The Kaplan-Meier method was used to estimate OS and PFS. Cox proportional hazards regression was used to assess for variables associated with survival. The impact of treatment group on pathologic response was assessed by chi-square. Results: Ninty-five patients were included for analysis (IC-CRT n=59; CRT n=36) and the median follow-up was 37.7 months (IQR: 16.8-56.1). There was no difference in median PFS or OS for IC-CRT or CRT, 22 months (95% CI: 12-59) vs. 32 months (95% CI: 10-57) (P=0.64) and 39 months (95% CI: 23-not reached) vs. 56.5 months (95% CI: 38-not reached) (P=0.36), respectively. Amongst the subset of patients with adenocarcinoma histology, there was no difference in median PFS or OS, nor was there when analyses were further restricted to those who received ≥3 cycles of induction 5-fluorouracil and platinum, or for those who underwent esophagectomy. Pathologic complete response occurred in 45% vs. 29% (P=0.24) and N-stage regression occurred in 72% vs. 58% (P=0.28) of patients in the IC-CRT and CRT cohorts, respectively. Distant metastasis occurred in 44% of patients in each treatment cohort. Conclusions: For patients with LA-EC, preoperative-intent IC-CRT was not associated with improved PFS or OS when compared with CRT.

GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism.

CONTEXT: Multiglandular and familial parathyroid disease constitute important fractions of primary hyperparathyroidism (PHPT). Germline missense variants of GCM2, a regulator of parathyroid development, were observed in familial isolated hyperparathyroidism and sporadic PHPT. However, as these previously reported GCM2 variants occur at relatively high frequencies in the population, understanding their potential clinical utility will require both additional penetrance data and functional evidence relevant to tumorigenicity. OBJECTIVE: Determine the frequency of GCM2 variants of interest among patients with sporadic multigland or familial parathyroid disease and assess their penetrance. DESIGN AND PATIENTS: DNA-encoding PHPT-associated GCM2 germline variants were polymerase chain reaction-amplified and sequenced from 107 patients with either sporadic multigland or suspected/confirmed familial parathyroid tumors. RESULTS: GCM2 variants were observed in 9 of 107 cases (8.4%): Y282D in 4 patients (6.3%) with sporadic multigland disease; Y394S in 2 patients (11.1%) with familial PHPT and 3 (4.8%) with sporadic multigland disease. Compared with the general population, Y282D was enriched 5.9-fold in multigland disease, but its penetrance was very low (0.02%). Y394S was enriched 79-fold in sporadic multigland disease and 93-fold in familial PHPT, but its penetrance was low (1.33% and 1.04%, respectively). CONCLUSIONS: Observed in vitro-activating GCM2 variant alleles are significantly overrepresented in PHPT patients with multiglandular or familial disease compared to the general population, yet penetrance values are very low; that is, most individuals with these variants in the population have a very low risk of developing PHPT. The potential clinical utility of detecting these GCM2 variants requires further investigation, including assessing their possible role as pathogenic/low-penetrance alleles.