Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating.

Mutations in the Kv3.3 potassium channel (KCNC3) cause cerebellar neurodegeneration and impair auditory processing. The cytoplasmic C terminus of Kv3.3 contains a proline-rich domain conserved in proteins that activate actin nucleation through Arp2/3. We found that Kv3.3 recruits Arp2/3 to the plasma membrane, resulting in formation of a relatively stable cortical actin filament network resistant to cytochalasin D that inhibits fast barbed end actin assembly. These Kv3.3-associated actin structures are required to prevent very rapid N-type channel inactivation during short depolarizations of the plasma membrane. The effects of Kv3.3 on the actin cytoskeleton are mediated by the binding of the cytoplasmic C terminus of Kv3.3 to Hax-1, an anti-apoptotic protein that regulates actin nucleation through Arp2/3. A human Kv3.3 mutation within a conserved proline-rich domain produces channels that bind Hax-1 but are impaired in recruiting Arp2/3 to the plasma membrane, resulting in growth cones with deficient actin veils in stem cell-derived neurons.

Learning Outcomes of "GetSMART," Education for Diagnostics and Targeted Treatment for HER2+ Metastatic Gastric and Colorectal Cancers.

The treatment landscape for patients affected by gastric and colorectal cancer (G&CRC) has significantly broadened over the past decade. Molecular diagnostic methods have improved with a precision oncology-driven approach to the development of treatment options tailored to specific molecular targets, including the human epidermal growth factor 2 (HER2). While scientific evidence on the role of HER2 in G&CRC has improved, there has been a lag in general understanding and applications of testing for HER2+ G&CRC and resulting targeting treatment in the wider oncology community. To better understand and address the root causes of this gap, a needs assessment deployed among 85 oncology care providers was conducted and informed the development of an accredited online educational program entitled "GetSMART." The program consisted of four modules developed and narrated by experts in gastrointestinal oncology. The educational content and assessment metrics were guided by a confidence-based assessment (CBA) model and the Moore, Green, and Gallis outcomes framework. Assessment methods consisted of quantitative pre- and post-activity tests, an evaluation embedded within the education (n = 163), and semi-structured interviews (n = 5) post-activity completion. Findings indicated that "GetSMART" enhanced participants' knowledge, confidence, and intent to change practice in relation to their (1) identification of HER2 aberrations, (2) selection of appropriate treatments for HER2+ G&CRC, and (3) ability to engage patients in shared decision-making and management of adverse events. "GetSMART" can therefore be a valuable educational resource for oncology HCPs caring for patients affected by HER2+ metastatic G&CRC, offering strategies to ensure an optimal team and patient-centered approach to the care being delivered.

Tyrosinase-Catalyzed Peptide Macrocyclization for mRNA Display.

mRNA display of macrocyclic peptides has proven itself to be a powerful technique to discover high-affinity ligands for a protein target. However, only a limited number of cyclization chemistries are known to be compatible with mRNA display. Tyrosinase is a copper-dependent oxidase that oxidizes tyrosine phenol to an electrophilic o-quinone, which is readily attacked by cysteine thiol. Here we show that peptides containing tyrosine and cysteine are rapidly cyclized upon tyrosinase treatment. Characterization of the cyclization reveals it to be widely applicable to multiple macrocycle sizes and scaffolds. We combine tyrosinase-mediated cyclization with mRNA display to discover new macrocyclic ligands targeting melanoma-associated antigen A4 (MAGE-A4). These macrocycles potently inhibit the MAGE-A4 binding axis with nanomolar IC50 values. Importantly, macrocyclic ligands show clear advantage over noncyclized analogues with ∼40-fold or greater decrease in IC50 values.

Vascular Impact of Cancer Therapies: The Case of BTK (Bruton Tyrosine Kinase) Inhibitors.

Novel targeted cancer therapies have revolutionized oncology therapies, but these treatments can have cardiovascular complications, which include heterogeneous cardiac, metabolic, and vascular sequelae. Vascular side effects have emerged as important considerations in both cancer patients undergoing active treatment and cancer survivors. Here, we provide an overview of vascular effects of cancer therapies, focusing on small-molecule kinase inhibitors and specifically inhibitors of BTK (Bruton tyrosine kinase), which have revolutionized treatment and prognosis for B-cell malignancies. Cardiovascular side effects of BTK inhibitors include atrial fibrillation, increased risk of bleeding, and hypertension, with the former 2 especially providing a treatment challenge for the clinician. Cardiovascular complications of small-molecule kinase inhibitors can occur through either on-target (targeting intended target kinase) or off-target kinase inhibition. We will review these concepts and focus on the case of BTK inhibitors, highlight the emerging data suggesting an off-target effect that may provide insights into development of arrhythmias, specifically atrial fibrillation. We believe that cardiac and vascular sequelae of novel targeted cancer therapies can provide insights into human cardiovascular biology.

Allylic alcohols and amines by carbenoid eliminative cross-coupling using epoxides or aziridines.

α-Lithiated terminal epoxides and N-(tert-butylsulfonyl)aziridines undergo eliminative cross-coupling with α-lithio ethers, to give convergent access to allylic alcohols and allylic amines, respectively. The process can be considered as proceeding by selective strain-relieving attack (ring-opening) of the lithiated three-membered heterocycle by the lithio ether and then selective ß-elimination of lithium alkoxide.

Predictors of Delayed Emergency Department Throughput Among Blunt Trauma Patients.

BACKGROUND: Delayed emergency department (ED) LOS has been associated with increased mortality and increased hospital length of stay (LOS) for various patient populations. Trauma patients often require significant effort in evaluation, workup, and disposition; however, patient and hospital characteristics associated with increased LOS in the ED for trauma patients remain unclear. METHODS: The Trauma Quality Improvement Project database (2014-2016) was queried for all adult blunt trauma patients. Patients discharged from the ED to the operating room were excluded. Univariate and multivariable linear regression analysis was conducted to identify independent predictors of ED LOS, controlling for patient characteristics (age, gender, race, insurance status), hospital characteristics (teaching status, ACS trauma verification level, geographic region), abbreviated injury scale and comorbid status. RESULTS: 412,000 patients met inclusion criteria for analysis. When controlling for covariates, an increase in age by 1 y resulted in 0.63 increased minutes in the ED (P < 0.001). In multivariable linear regression controlling for injury severity and comorbid conditions, non-white race groups, university status, and northeast region were associated with increased ED LOS. Black and Hispanic patients spent on average 41 and 42 more minutes, respectively, in the ED room when compared with white patients (P < 0.001). Patients seen at University hospitals spent 52 more minutes in the ED when compared with community hospitals, whereas patients at nonteaching hospitals spent 31 fewer minutes (P < 0.001). Patients seen in the Midwest spent the least amount of time in the ED, with patients in the South, West, and Northeast spending 45, 36, and 89 more minutes, respectively (P < 0.001). Non-Medicaid patients at level 1 trauma centers and those requiring intensive care admission had significantly decreased ED LOS. Medicaid patients took the longest to move through the ED with Medicare, BlueCross, and Private insurance outpacing them by 17, 23, and 23 min, respectively (P < 0.001). ACS level 1 trauma centers moved patients through the ED fastest, whereas ACS level II trauma centers and level III trauma centers moved patients through 50 and 130 min slower when compared with ACS level 1 trauma centers (P < 0.001). CONCLUSIONS: ED LOS varied significantly by patient and hospital characteristics. Medicaid patients and those patients at university hospitals were associated with significantly higher ED LOS, whereas ACS trauma verification level status had strong correlation with ED LOS. These results may allow targeted quality improvement programs to enhance ED LOS.

Model for End-Stage Liver Disease Sodium as a Predictor of Surgical Risk in Cirrhotic Patients With Ascites.

BACKGROUND: The Model for End-Stage Liver Disease Sodium (MELD-Na) incorporates hyponatremia into the MELD score and has been shown to correlate with surgical outcomes. The pathophysiology of hyponatremia parallels that of ascites, which purports greater surgical risk. This study investigates whether MELD-Na accurately predicts morbidity and mortality in patients with ascites undergoing general surgery procedures. MATERIALS AND METHODS: We used the National Surgical Quality Improvement Program database (2005-2014) to examine the adjusted risk of morbidity and mortality of cirrhotic patients with and without ascites undergoing inguinal or ventral hernia repair, cholecystectomy, and lysis of adhesions for bowel obstruction. Patients were stratified by the MELD-Na score and ascites. Outcomes were compared between patients with and without ascites for each stratum using low MELD-Na and no ascites group as a reference. RESULTS: A total of 30,391 patients were analyzed. Within each MELD-Na stratum, patients with ascites had an increased risk of complications compared with the reference group (low MELD-Na and no ascites): low MELD-Na with ascites odds ratio (OR) 4.33 (95% confidence interval [CI] 1.96-9.59), moderate MELD-Na no ascites OR 1.70 (95% CI 1.52-1.9), moderate MELD-Na with ascites OR 3.69 (95% CI 2.49-5.46), high MELD-Na no ascites OR 3.51 (95% CI 3.07-4.01), and high MELD-Na ascites OR 7.18 (95% CI 5.33-9.67). Similarly, mortality risk was increased in patients with ascites compared with the reference: moderate MELD-Na no ascites OR 3.55 (95% CI 2.22-5.67), moderate MELD-Na ascites OR 13.80 (95% CI 5.65-33.71), high MELD-Na no ascites OR 8.34 (95% CI 5.15-13.51), and high MELD-Na ascites OR 43.97 (95% CI 23.76-81.39). CONCLUSIONS: MELD-Na underestimates morbidity and mortality risk for general surgery patients with ascites.

Development of an Operative Trauma Course in Uganda-A Report of a Three-Year Experience.

BACKGROUND: Trauma is a leading cause of morbidity and mortality in low-income countries. Improved health care systems and training are potential avenues to combat this burden. We detail a collaborative and context-specific operative trauma course taught to postgraduate surgical trainees practicing in a low-resource setting and examine its effect on resident practice. METHOD: Three classes of second year surgical residents participated in trainings from 2017 to 2019. The course was developed and taught in conjunction with local faculty. The most recent cohort logged cases before and after the course to assess resources used during initial patient evaluation and operative techniques used if the patient was taken to theater. RESULTS: Over the study period, 52 residents participated in the course. Eighteen participated in the case log study and logged 117 cases. There was no statistically significant difference in patient demographics or injury severity precourse and postcourse. Postcourse, penetrating injuries were reported less frequently (40 to 21% P < 0.05) and road traffic crashes were reported more frequently (39 to 60%, P < 0.05). There was no change in the use of bedside interventions or diagnostic imaging, besides head CT. Of patients taken for a laparotomy, there was a nonstatistically significant increase in the use of four-quadrant packing 3.4 to 21.7%) and a decrease in liver repair (20.7 to 4.3%). CONCLUSIONS: The course did not change resource utilization; however, it did influence clinical decision-making and operative techniques used during laparotomy. Additional research is indicated to evaluate sustained changes in practice patterns and clinical outcomes after operative skills training.

Predictors of 30 Day Readmission Following Percutaneous Cholecystostomy.

BACKGROUND: High-risk patients undergoing cholecystectomy may experience increased morbidity and mortality. Percutaneous cholecystostomy (PC) has been utilized as a treatment option for acute cholecystitis in this cohort. Little is known about risk factors for readmission following PC. MATERIALS AND METHODS: Patients who had PC from 2013 to 2014 were identified from the National Readmission Database by the Healthcare Cost and Utilization Project. A 30-d readmission was defined as a subsequent admission within 30 d following the first admission discharge date. Multivariate logistic regression models using stepwise selection were employed to select significant predictive variables for subsequent readmission. RESULTS: Three thousand three hundred sixty-eight patients were identified with 698 (20.7%) readmissions during the study period. Of the readmitted patients, 79 (2.35%) had two readmissions and six patients (0.19%) had three or more readmissions within 30 d of their index procedure. In addition, alcohol use (odds ratios [OR] 1.58, confidence intervals [CI] 1.10-2.29), uncomplicated diabetes (OR 1.21, CI 1.00-1.47), congestive heart failure (OR 1.28, CI 1.03-2.44), depression (OR 1.42, CI 1.08-1.86), and metastatic cancer (OR 1.65, CI 1.11-2.46) were significantly correlated with risk for readmission. Readmitted patients had longer hospital stays (OR 1.38 CI 1.09-1.74, length of stay >8 d). CONCLUSIONS: A significant proportion of patients are readmitted within 30 d following PC. These patients may benefit from increase care coordination starting at their index admission. Studies are needed to determine patient selection for upfront cholecystectomy.

Correction to: FMTVDM-TFM©â„—: True quantification requires standardization of the tool being used to measure, with a known, unchanging standard to produce accurate, consistent and reproducible quantified measurements.

The Editor wishes to clarify that the authors of the above named Letter provided ICMJE Conflict of Interest forms at the time of submission, and that the Journal omitted to include the resulting statement in the published Letter.

Model for End-Stage Liver Disease Underestimates Morbidity and Mortality in Patients with Ascites Undergoing Colectomy.

BACKGROUND: The Model for End-Stage Liver Disease (MELD) score and ascites correlate with surgical morbidity and mortality. However, the MELD score does not account for ascites. We sought to evaluate whether the MELD score accurately risk stratifies patients with ascites. METHODS: We analyzed the American College of Surgeons National Surgical Quality Improvement Program (2005-2014) to examine the risk-adjusted morbidity and mortality of cirrhotic patients with and without ascites undergoing colectomy for diverticulitis. Patients were stratified by MELD score, and the presence of ascites and outcomes were compared between patients with and without ascites to the reference group of low MELD and no ascites. Multivariable logistic regression was used to control for demographic factors and comorbidities. RESULTS: A total of 16,877 colectomies were analyzed. For each MELD stratum, patients with ascites have increased risk of complications compared to those without ascites (P < 0.05 unless indicated): low MELD ascites OR 1.13, P = 0.69, moderate MELD no ascites OR 1.37, moderate MELD ascites OR 2.06, high MELD no ascites OR 1.93, and high MELD ascites OR 3.54. These trends hold true for mortality: low MELD ascites OR 2.91, P = 0.063, moderate MELD no ascites OR 1.47, moderate MELD ascites OR 5.62, high MELD no ascites OR 3.04, and high MELD ascites OR 9.91. CONCLUSION: Ascites predicts an increased risk for postoperative morbidity and mortality for cirrhotic patients undergoing colectomy for all MELD classifications. These findings suggest that the MELD score significantly underestimates postoperative risk as it does not account for ascites.

Recurrent Falls Among Elderly Patients and the Impact of Anticoagulation Therapy.

BACKGROUND: Falls are the leading source of injury and trauma-related hospital admissions for elderly adults in the USA. Elderly patients with a history of a fall have the highest risk of falling again, and the decision on whether to continue anticoagulation after a fall is difficult. To inform this decision, we evaluated the rate of recurrent falls and the impact of anticoagulation on outcomes. METHODS: All patients of age ≥ 65 years and hospitalized for a fall in the first 6 months of 2013 and 2014 were identified in the nationwide readmission database, a nationally representative all-payer database tracking patient readmissions. Readmissions for a recurrent fall within 6 months, and mortality and bleeding injuries (intracranial hemorrhage, solid organ bleed, and hemothorax) during readmission were identified. Logistic regression evaluated factors associated with mortality on repeat falls. RESULTS: Of the 331,982 patients admitted for a fall, 15,565 (4.7%) were admitted for a recurrent fall within 6 months. The median time to repeat fall was 57 days (IQR 19-111 days), and 9.0% (1406) of repeat fallers were on anticoagulation. The rate of bleeding injury was similar regardless of anticoagulation status (12.8 vs. 12.7% not on anticoagulation, p = 0.97); however, among patients with a bleeding injury, those on anticoagulation had significantly higher mortality (21.5 vs. 6.9% not on anticoagulation, p < 0.01). CONCLUSION: Among patients hospitalized for a fall, 4.7% will be hospitalized for a recurrent fall within 6 months. Patients on anticoagulation with repeat falls do not have increased rates of bleeding injury but do have significantly higher rates of death with a bleeding injury. This information is essential to discuss with patients when deciding to restart their anticoagulation.

Surgical referral coordination from a first-level hospital: a prospective case study from rural Nepal.

BACKGROUND: Patients in isolated rural communities typically lack access to surgical care. It is not feasible for most rural first-level hospitals to provide a full suite of surgical specialty services. Comprehensive surgical care thus depends on referral systems. There is minimal literature, however, on the functioning of such systems. METHODS: We undertook a prospective case study of the referral and care coordination process for cardiac, orthopedic, plastic, gynecologic, and general surgical conditions at a district hospital in rural Nepal from 2012 to 2014. We assessed the referral process using the World Health Organization's Health Systems Framework. RESULTS: We followed the initial 292 patients referred for surgical services in the program. 152 patients (52%) received surgery and four (1%) suffered a complication (three deaths and one patient reported complication). The three most common types of surgery performed were: orthopedics (43%), general (32%), and plastics (10%). The average direct and indirect cost per patient referred, including food, transportation, lodging, medications, diagnostic examinations, treatments, and human resources was US$840, which was over 1.5 times the local district's per capita income. We identified and mapped challenges according to the World Health Organization's Health Systems Framework. Given the requirement of intensive human capital, poor quality control of surgical services, and the overall costs of the program, hospital leadership decided to terminate the referral coordination program and continue to build local surgical capacity. CONCLUSION: The results of our case study provide some context into the challenges of rural surgical referral systems. The high relative costs to the system and challenges in accountability rendered the program untenable for the implementing organization.

Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis.

In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.

An Integrated Risk Reduction Intervention can reduce body mass index in individuals being treated for bipolar I disorder: results from a randomized trial.

OBJECTIVES: We conducted a randomized, controlled trial comparing the efficacy of an Integrated Risk Reduction Intervention (IRRI) to a control condition with the objective of improving mood stability and psychosocial functioning by reducing cardiometabolic risk factors in overweight/obese patients with bipolar I disorder. METHODS: A total of 122 patients were recruited from our outpatient services and randomly allocated to IRRI (n = 61) or psychiatric care with medical monitoring (n = 61). Individuals allocated to IRRI received psychiatric treatment and assessment, medical monitoring by a nurse, and a healthy lifestyle program from a lifestyle coach. Those allocated to the control condition received psychiatric treatment and assessment and referral, if indicated, for medical problems. A mixed-effects model was used to examine the impact of the interventions on body mass index (BMI). Exploratory moderator analyses were used to characterize those individuals likely to benefit from each treatment approach. RESULTS: Analyses were conducted on data for the IRRI (n = 58) and control (n = 56) participants with ≥ 1 study visit. IRRI was associated with a significantly greater rate of decrease in BMI (d = -0.51, 95% confidence interval: -0.91 to -0.14). Three variables (C-reactive protein, total cholesterol, and instability of total sleep time) contributed to a combined moderator of faster decrease in BMI with IRRI treatment. CONCLUSIONS: Overweight/obese patients with bipolar disorder can make modest improvements in BMI, even when taking medications with known potential for weight gain. Our finding that a combination of three baseline variables provides a profile of patients likely to benefit from IRRI will need to be tested further to evaluate its utility in clinical practice.

Uncovering gaps in management of vasomotor symptoms: findings from a national need assessment.

CONTEXT: This national needs assessment study explores the knowledge, attitude, beliefs, and practices (KABP) gaps related to vasomotor symptoms (VMS) associated with menopause among primary care and OB/GYN clinicians. VMS significantly impacts healthcare costs, workplace productivity, and patient psychosocial health, but a notable disconnect exists between healthcare providers and patients, with provider reticence and knowledge gaps playing a contributing role. OBJECTIVES: This study aims to identify and propose optimal educational strategies to address these barriers, with attention to health disparities affecting women of color. METHODS: Methods employed include a multimodal approach of literature review, expert opinion, qualitative interviews, surveys, focus groups, and case studies, ensuring diverse clinician input. Data collection involved in-depth clinician interviews, a nationally disseminated clinician survey, and focus groups. RESULTS: Results indicate a critical deficiency in healthcare providers' understanding and management of VMS, especially among OB/GYN residents, with 75 % showing limited knowledge. The study also highlights the disproportionate impact of knowledge gaps on women of color, emphasizing the need for a culturally informed approach in medical training and practice. There's a notable discrepancy between clinicians' current and desired abilities in managing VMS, indicating a need for ongoing professional development. Significant variability in approaches to diagnosing and treating VMS, as well as substantial knowledge gaps about treatment options, underscore the need for evidence-based protocols. CONCLUSIONS: Although VMS are a normal aspect of aging, they can significantly disrupt quality of life for many women, necessitating intervention. Beyond the immediate discomfort, VMS can impact quality of life and trigger insomnia and mood disturbances. This study exposes both new and previously recognized gaps in healthcare providers' knowledge and management skills concerning VMS treatment options, particularly regarding hormonal and nonhormonal therapies. Furthermore, our findings highlight the need for a deeper understanding of how VMS uniquely impacts women of diverse backgrounds. Research, including the Study of Women's Health Across the Nation (SWAN), suggests that the experience and severity of VMS may be influenced by socioeconomic status, race/ethnicity, body mass index (BMI), and smoking status. However, the complex interplay of these factors and their relative contributions remain unclear. Further investigation is crucial to facilitate equitable access to effective treatment for all women. To bridge these gaps, improved education starting as early as residency is essential. This education should address common misconceptions about VMS and its management. Healthcare providers must enhance their competence in discussing the broad spectrum of VMS impacts and employ effective communication strategies to ensure that patients are well-informed about their symptoms and available treatment options.