Citations

Cholangiocarcinoma (CCA) is a highly aggressive form of liver cancer and is an increasing cause of cancer‐related death worldwide. Despite its increasing incidence globally and alarming mortality, treatment options for CCA have largely remained unchanged, stressing the importance of developing new effective therapies. YAP activation is common in CCA, and its major transcriptional signaling partners are the TEAD proteins. CA3 is a small‐molecule YAP‐TEAD disrupter discovered utilizing a TEAD reporter assay. Utilizing CCA, gastric cancer cell lines, and patient‐derived xenograft models (PDX), we demonstrate that CA3 is effective in inducing cell death and delaying tumor growth in both FGFR2 fusion and wild‐type models. CA3 was associated with on‐target decreases in YAP‐TEAD target gene expression, TEAD reporter activity, and overall TEAD levels. Hippo pathway signaling was not altered as there was no change in YAP phosphorylation status in the cells exposed to CA3. RNA sequencing of gastric cancer and CCA models demonstrated upregulation of an androgen receptor–mediated transcriptional program following exposure to CA3 in five unique models tested. Consistent with this upstream regulator analysis, CA3 exposure in CCA cells was associated with increased AR protein levels, and combinatorial therapy with CA3 and androgen receptor blockade was associated with increased cancer cell death. CA3 behaves functionally as a YAP‐TEAD disrupter in the models tested and demonstrated therapeutic efficacy. Exposure to CA3 was associated with compensatory androgen receptor signaling and dual inhibition improved the therapeutic effect.

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase–mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G αi2 mutations had clinical presentations that included impaired immunity. Mutant G αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G αi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)–activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal–regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)–AKT S6 signaling to drive cellular growth and proliferation.

Three-dimensional reconstruction of airways has shown increased luminal area in patients with COVID-19 and post-acute sequelae of COVID-19 when compared with healthy controls. These findings suggest the role of large conducting airways in the pathogenesis of post-acute sequelae of COVID 19.

AbstractIntroductionDirect oral anticoagulants (DOACs) become the recommended treatment over vitamin K antagonists (VKA) in patients with non‐valvular atrial fibrillation (AF). However, their effectiveness in reducing cognitive impairment and dementia compared to VKA remains unclear.MethodsA systematic literature search was conducted on Ovid MEDLINE, EMBASE, and Cochrane Database. Randomized controlled trials, cohort, or case–control study that assessed incident dementia between AF patients who received DOAC compared to VKA were selected. Relevant study characteristics and the number of incident dementia diagnosis or hazard ratios (HRs) for incident dementia and each dementia subtypes were extracted. Random‐effects model was used to perform meta‐analysis. Standardized mean differences (SMDs) were used to estimate effect sizes for continuous data.ResultsTwelve cohort studies comprising 1 451 069 individuals were included. The incidence of dementia was lower in AF patients prescribed DOACs compared to VKA (HR 0.88, 95% CI 0.83–0.93, I 2 = 61.2%). A lower incident dementia in DOACs group relative to VKA was significantly observed in those less than 75 years of age (< 65 years, HR 0.83 (95% CI 0.72–0.97, I 2 = 0%); 65–74 years, HR 0.86 (95% CI 0.81–0.92, I 2 = 55.4%); and ≥ 75 years, HR 1.07 (95% CI 0.74–1.55, I 2 = 92.5%)) and for the subgroup of patients with vascular dementia (HR 0.91, 95% CI 0.824–0.997, I 2 = 0%).ConclusionsThis meta‐analysis reveals a reduction in incidence of dementia in AF patients prescribed DOACs compared to VKA, particularly in those less than 75 years old and in the vascular dementia subtype.

» Perioperative corticosteroids are strongly recommended for reducing the incidence and severity of postoperative nausea and vomiting following elective total hip or total knee arthroplasty. » Corticosteroids may reduce postoperative pain and opioid requirements. Similarly, corticosteroids appear to have a neutral-to-positive effect on length of stay, venous thromboembolism, mobility, delirium, acute kidney injury, and bone cement implantation syndrome (i.e., decreased length of stay). » Perioperative corticosteroids may induce hyperglycemia among both diabetic and nondiabetic patients; however, there is no strong evidence indicating that these transient corticosteroid-induced glycemic derangements may increase the risk of postoperative infectious complications. » The dosage and frequency of perioperative corticosteroid administration play a critical role in optimizing postoperative outcomes, with higher doses showing promise in reducing opioid consumption, postoperative pain, and length of stay. » The optimal dosage and frequency of corticosteroids remain unclear; however, the perioperative administration of 8 to 16 mg dexamethasone, or equivalent steroid, appears reasonable and safe in most cases.

Introduction The sharpened Romberg test (SRT) is a physical maneuver that has been used to identify ataxia in individuals in resource-limited settings. Previous research has suggested that performance on balance testing may be affected by hypocapnia. In this study, we sought to determine whether acute hyperventilation-induced hypocapnia affects performance on the SRT at 501 meters above sea level. Methods We recruited 22 healthy subjects. Each subject performed a baseline SRT. Subjects were then asked to hyperventilate to the point of hypocapnia, confirmed by measurement with a capnometer. Subjects were then asked to re-perform SRT. The primary endpoint was time to loss of balance, measured as time-to-stepout. Results Time-to-stepout (TTS) on SRT at baseline had a mean ± standard deviation of 101 ± 117 s. In the hypocapnic condition, TTS was reduced to 48 ± 68 s. TTS normalized to 121 ± 132 s after recovery to normal capnic levels. Time-to-stepout was found to be significantly shorter in the hypocapnic measurement compared to the baseline measurement ( P = .0128). Statistical analysis was conducted using one-tailed, paired sample T-tests using a P-value of < .05. Conclusions Our study found a statistically and clinically significant reduction in performance on a balance test (SRT) when exposed to acute hyperventilation-induced hypocapnia compared to a eucapnic control. Our results suggest that acute hypocapnia may contribute to neurological dysfunction independently of hypobaric hypoxia.

AbstractINTRODUCTIONCardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD).METHODSTwo hundred forty‐seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non‐carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing.RESULTSAmong variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories.DISCUSSIONBetter baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD.Highlights Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia.

Study Design: A retrospective chart review. Objective: The authors aim to investigate the role of clinical and radiographic parameters in patients who underwent posterior cervical surgery, and their association with C5 palsy severity and time to recovery. Background: Postoperative C5 palsy affects 1%–30% of patients undergoing posterior decompression, with or without fusion. Causation and avoidance of this complication remain widely debated. Materials and Methods: A single institution review of patients who underwent posterior cervical spine surgery was focused on using specific Common Procedural Technology codes associated with the patient population of interest. Patients were excluded if they had inadequate pre and postoperative imaging, as well as a history of prior cervical spine surgery, concurrent anterior surgery, intradural pathology, spinal tumor, or spinal trauma. Radiographic measurements of the pre and postoperative images were completed with subsequent intraclass correlation coefficient analysis to confirm the precision of measurements. Results: Out of 105 total patients, 35 (33%) patients developed a C5 palsy. Twenty-four (69%) of those palsies completely resolved, with a median time to recovery of 8 months. Preoperative demographics and radiographic parameters demonstrated heterogeneity among those patients who did and did not have a resolution of palsy. Patients with increased change in C2–C7 lordosis (P = 0.011) after surgery were associated with decreased likelihood of recovery. Patients without a smoking history (P = 0.009) had an increased likelihood of recovering from C5 palsy. Conclusions: The degree of increased lordosis in the treatment of degenerative cervical disease plays a role in the rate of recovery from C5 palsy. This should be considered during preoperative planning in determining the amount of lordosis desired. In addition, patients without a smoking history were associated with a higher rate of recovery. Level of Evidence: Level IV.