Major ß cell-specific functions of NKX2.2 are mediated via the NK2-specific domain.

The consolidation of unambiguous cell fate commitment relies on the ability of transcription factors (TFs) to exert tissue-specific regulation of complex genetic networks. However, the mechanisms by which TFs establish such precise control over gene expression have remained elusive-especially in instances in which a single TF operates in two or more discrete cellular systems. In this study, we demonstrate that ß cell-specific functions of NKX2.2 are driven by the highly conserved NK2-specific domain (SD). Mutation of the endogenous NKX2.2 SD prevents the developmental progression of ß cell precursors into mature, insulin-expressing ß cells, resulting in overt neonatal diabetes. Within the adult ß cell, the SD stimulates ß cell performance through the activation and repression of a subset of NKX2.2-regulated transcripts critical for ß cell function. These irregularities in ß cell gene expression may be mediated via SD-contingent interactions with components of chromatin remodelers and the nuclear pore complex. However, in stark contrast to these pancreatic phenotypes, the SD is entirely dispensable for the development of NKX2.2-dependent cell types within the CNS. Together, these results reveal a previously undetermined mechanism through which NKX2.2 directs disparate transcriptional programs in the pancreas versus neuroepithelium.

Surgical Delay of Thoracodorsal Artery Perforator Flaps for Total Autologous Breast Reconstruction.

BACKGROUND: When abdomen-based free flap reconstruction is contraindicated, the muscle-sparing thoracodorsal artery perforator (TDAP) flap may be considered for total autologous breast reconstruction. The TDAP flap is often limited by volume and is prone to distal flap necrosis. We aim to demonstrate our experience combining the delay phenomenon with TDAP flaps for total autologous breast reconstruction. METHODS: Patients presenting for autologous breast reconstruction between April 2021 and August 2023 were recruited for surgically delayed TDAP flap reconstruction when abdominally based free flap reconstruction was contraindicated because of previous abdominal surgery or poor perforator anatomy. We dissected the TDAP flap except for a distal skin bridge and then reconstructed the breast 1 to 7 days later. Data included flap dimensions (in centimeters × centimeters), delay time (in days), predelay and postdelay perforator caliber (in millimeters) and flow (in centimeters per second), operative time (in minutes), hospital length of stay (in days), complications/revisions, and follow-up time (in days). RESULTS: Fourteen patients and 16 flaps were included in this study. Mean age and body mass index of patients were 55.9 ± 9.6 years and 30.1 ± 4.3 kg/m2, respectively. Average flap skin island length and width were 32.1 ± 3.3 cm (n = 8 flaps) and 8.8 ± 0.7 cm (n = 5 flaps), respectively. Beveled flap width reached 16.0 ± 2.2 cm (n = 3 flaps). Average time between surgical delay and reconstruction was 2.9 days, ranging from 1 to 7 days (n = 18 flaps). Mean predelay and postdelay TDAP vessel caliber and flow measured by Doppler ultrasound increased from 1.4 ± 0.3 to 1.8 ± 0.3 mm (P = 0.03) and 13.3 ± 5.2 to 43.4 ± 18.8 cm/s (P = 0.03), respectively (n = 4 flaps). Complications included 1 donor site seroma and 1 mastectomy skin flap necrosis. Follow-up ranged from 4 to 476 days (n = 17 operations). CONCLUSIONS: We demonstrate surgically delayed TDAP flaps as a viable option for total autologous breast reconstruction. Our series of flaps demonstrated increased perforator caliber and flow and enlarged volume capabilities and had no incidences of flap necrosis.

Achievement of glycaemic targets with weight loss and without hypoglycaemia in type 2 diabetes with the once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide: A post hoc analysis of the SURPASS-1 to -5 studies.

AIM: To assess composite endpoints combining glycaemic control (HbA1c < 7.0%, ≤ 6.5% or < 5.7%) with weight loss (≥ 5%, ≥ 10% or ≥ 15%) and without hypoglycaemia with tirzepatide in type 2 diabetes (T2D). MATERIALS AND METHODS: Data from the phase 3 SURPASS programme were evaluated post hoc by trial. Participants with T2D were randomized to tirzepatide (5, 10 and 15 mg), placebo (SURPASS-1,5), semaglutide 1 mg (SURPASS-2) or titrated basal insulin (SURPASS-3,4). The proportions of participants achieving the composite endpoints were compared between tirzepatide and the respective comparator groups at week 40/52. RESULTS: The proportions of participants achieving an HbA1c value of less than 7.0% with 5% or more weight loss and without hypoglycaemia ranged from 43% to 82% with tirzepatide across the SURPASS-1 to -5 trials versus 4%-5% with placebo, 51% with semaglutide 1 mg and 5% with basal insulin (P < .001 vs. all comparators). The proportions of participants achieving an HbA1c value of less than 7.0% with 10% or more, or 15% or more weight loss and without hypoglycaemia were significantly higher with all tirzepatide doses versus comparators across trials (P < .001 or P < .05). Similar results were observed for all other combinations of endpoints with an HbA1c value of 6.5% or less, or less than 5.7%, with more tirzepatide-treated participants achieving these endpoints versus those in the comparator groups, including semaglutide. CONCLUSIONS: Across the SURPASS-1 to -5 clinical trials, more tirzepatide-treated participants with T2D achieved clinically meaningful composite endpoints, which included reaching glycaemic targets with various degrees of weight loss and without hypoglycaemia, than those in the comparator groups.

Efficacy and Safety of Tirzepatide in Adults With Type 2 Diabetes: A Perspective for Primary Care Providers.

This article reviews the efficacy and safety data of tirzepatide, a once-weekly, novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1) receptor agonist approved in the United States, the European Union, and other regions for the treatment of type 2 diabetes. All doses of tirzepatide demonstrated superiority in reducing A1C and body weight from baseline versus placebo or active comparators. The safety profile of tirzepatide was consistent with that of the GLP-1 receptor agonist class, with mild to moderate and transient gastrointestinal side effects being the most common adverse events. With clinically and statistically significant reductions in A1C and body weight without increased risk of hypoglycemia in various populations, tirzepatide has demonstrated potential as a first-in-class treatment option for many people with type 2 diabetes.

Efficacy of tirzepatide 5, 10 and 15 mg versus semaglutide 2 mg in patients with type 2 diabetes: An adjusted indirect treatment comparison.

AIM: To conduct an adjusted indirect treatment comparison (aITC) of the efficacy of tirzepatide 5/10/15 mg versus semaglutide 2 mg in patients with type 2 diabetes. MATERIALS AND METHODS: The primary analysis was a Bucher aITC of the change from baseline at week 40 in HbA1c (%) and body weight (kg). Aggregate data from the SURPASS-2 study that met the HbA1c inclusion criterion of the SUSTAIN FORTE study and from SUSTAIN FORTE metformin-only treated patients were used for primary analysis. RESULTS: The SURPASS-2 refined population comprised 238/245/240 and 240 participants for tirzepatide 5/10/15 mg and semaglutide 1 mg, respectively. The SUSTAIN FORTE metformin-only population comprised 222 and 227 participants for semaglutide 1 and 2 mg, respectively. In this aITC, tirzepatide 10 and 15 mg significantly reduced HbA1c versus semaglutide 2 mg with an estimated treatment difference (ETD) of -0.36% (95% confidence interval [CI] -0.63, -0.09) and -0.4% (95% CI -0.67, -0.13), respectively. Tirzepatide 10 and 15 mg significantly reduced body weight versus semaglutide 2 mg with an ETD of -3.15 kg (95% CI -4.84, -1.46) and -5.15 kg (95% CI -6.85, -3.45), respectively. There were no significant differences between tirzepatide 5 mg and semaglutide 2 mg on change from baseline in HbA1c and body weight. CONCLUSIONS: In this aITC, HbA1c and weight reductions were significantly greater for tirzepatide 10 and 15 mg versus semaglutide 2 mg and were similar for tirzepatide 5 mg versus semaglutide 2 mg. These findings provide comparative effectiveness insights in the absence of a head-to-head clinical trial.

Examining the evidence for weight management in individuals with type 2 diabetes.

The obesity epidemic has been linked to the worsening diabetes epidemic. Despite this, weight reduction for individuals with obesity is seen as a secondary, or even tertiary, consideration in the treatment of type 2 diabetes (T2D). The aim of this review is to examine the benefits of weight management in individuals with T2D. A literature review of current available published data on the benefits of weight reduction in individuals with T2D was conducted. In individuals with T2D who have obesity or overweight, modest and sustained weight reduction results in improvement in glycaemic control and decreased utilization of glucose-lowering medication. A total body weight loss of 5% or higher reduces HbA1c levels and contributes to mitigating risk factors of cardiovascular disease, such as hyperlipidaemia and hypertension, as well as other disease-related complications of obesity. Progressive improvements in glycaemic control and cardiometabolic risk factors can occur when the total body weight loss increases to 10% or more. In the approach to treating patients with T2D and obesity, prioritizing weight management and the use of therapeutics that offer glycaemic control as well as the additional weight loss should be emphasized given their potential to attenuate the progression and severity of T2D.

Coronavirus Disease (COVID-19)-Related Disseminated Leukoencephalopathy: A Retrospective Study of Findings on Brain MRI.

Among 2820 inpatients with coronavirus disease (COVID-19), 59 (2.1%) underwent brain MRI. Of them, six (10.2%) had MRI findings suspicious for COVID-19-related disseminated leukoencephalopathy (CRDL), which is characterized by extensive confluent or multifocal white matter lesions (with characteristics and locations atypical for other causes), microhemorrhages, diffusion restriction, and enhancement. CRDL is an uncommon but important differential consideration in patients with neurologic manifestations of COVID-19.

Serial Neurologic Assessment in Pediatrics (SNAP): A New Tool for Bedside Neurologic Assessment of Critically Ill Children.

OBJECTIVES: We developed a tool, Serial Neurologic Assessment in Pediatrics, to screen for neurologic changes in patients, including those who are intubated, are sedated, and/or have developmental disabilities. Our aims were to: 1) determine protocol adherence when performing Serial Neurologic Assessment in Pediatrics, 2) determine the interrater reliability between nurses, and 3) assess the feasibility and acceptability of using Serial Neurologic Assessment in Pediatrics compared with the Glasgow Coma Scale. DESIGN: Mixed-methods, observational cohort. SETTING: Pediatric and neonatal ICUs. SUBJECTS: Critical care nurses and patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serial Neurologic Assessment in Pediatrics assesses Mental Status, Cranial Nerves, Communication, and Motor Function, with scales for children less than 6 months, greater than or equal to 6 months to less than 2 years, and greater than or equal to 2 years old. We assessed protocol adherence with standardized observations. We assessed the interrater reliability of independent Serial Neurologic Assessment in Pediatrics assessments between pairs of trained nurses by percent- and bias- adjusted kappa and percent agreement. Semistructured interviews with nurses evaluated acceptability and feasibility after nurses used Serial Neurologic Assessment in Pediatrics concurrently with Glasgow Coma Scale during routine care. Ninety-eight percent of nurses (43/44) had 100% protocol adherence on the standardized checklist. Forty-three nurses performed 387 paired Serial Neurologic Assessment in Pediatrics assessments (149 < 6 mo; 91 ≥ 6 mo to < 2 yr, and 147 ≥ 2 yr) on 299 patients. Interrater reliability was substantial to near-perfect across all components for each age-based Serial Neurologic Assessment in Pediatrics scale. Percent agreement was independent of developmental disabilities for all Serial Neurologic Assessment in Pediatrics components except Mental Status and lower extremity Motor Function for patients deemed "Able to Participate" with the assessment. Nurses reported that they felt Serial Neurologic Assessment in Pediatrics, compared with Glasgow Coma Scale, was easier to use and clearer in describing the neurologic status of patients who were intubated, were sedated, and/or had developmental disabilities. About 92% of nurses preferred to use Serial Neurologic Assessment in Pediatrics over Glasgow Coma Scale. CONCLUSIONS: When used by critical care nurses, Serial Neurologic Assessment in Pediatrics has excellent protocol adherence, substantial to near-perfect interrater reliability, and is feasible to implement. Further work will determine the sensitivity and specificity for detecting clinically meaningful neurologic decline.

How to increase the role of social workers in suicide preventive interventions.

OBJECTIVE: Suicide is a serious public health issue that affects individuals, families and societies all over the world. International studies provide consistent evidence that the presence of psychiatrists in a region is associated with lesser suicide rates. However, many psychiatric patients including suicidal patients do not have access to psychiatrists. This indicates that mental health and non-mental health social workers need to be involved in suicide prevention efforts. This paper is the first comprehensive work that discusses how to increase the role of social workers in the area of suicide prevention. METHODS: A review of the relevant literature. RESULTS: Increasing the role of social workers in suicide prevention efforts may reduce suicide risk in groups and people at elevated risk for suicide, as well as the general population. CONCLUSION: Recommendations are provided for how the social work profession can improve upon suicide prevention while incorporating universal, selective and indicated suicide preventive interventions. Social work research efforts should focus on how to increase the role of social workers in suicide prevention and the management of suicidal patients. Social work education programmes should modify their curricula and increase their attention on suicide prevention. Mental health social workers need to educate the patient and their family on suicide risk factors. Furthermore, mental health and non-mental health social workers need to educate the general public on suicide risk factors.

Early Management of Infants With Robin Sequence: An International Survey and Algorithm.

PURPOSE: There is no widely accepted protocol for management of infants with Robin sequence (RS) who present with airway obstruction and feeding impairment. The purposes of this study were to evaluate diagnostic and treatment preferences of clinicians from the United States and non-US countries and to use these data to propose an algorithm for early management of infants with RS. MATERIALS AND METHODS: A cross-sectional study was implemented using a survey, which was distributed to craniofacial surgeons and non-surgeon physicians involved in management of infants with RS. Predictor variables were nationality, specialty, and surgical volume. Outcome variables included survey responses regarding preferences for evaluation and early treatment of patients with RS. A diagnostic and early treatment algorithm was proposed based on the most common survey responses. Descriptive and analytic statistics were calculated and a P less than .05 was considered significant. RESULTS: A total of 275 responses were received and 82 were excluded, leaving a final sample of 193 participants: 155 (80%) surgeons and 38 (20%) non-surgeon physicians. Thirty-seven US states were represented by 143 (74%) respondents and 50 (26%) participants were from 19 non-US countries. There were 96 (50%) low-volume and 97 (50%) high-volume respondents. There was general agreement in methods for evaluation and early treatment among respondents; the only significant differences were 1) US surgeons operate earlier to address airway obstruction than those from other countries (P = .001), 2) high-volume providers tend to operate earlier (P = .017) and to choose mandibular distraction more frequently (P = .003) than low-volume respondents, and 3) mandibular distraction is the preferred operation in the United States, but several operations for airway improvement are used equally in non-US countries (P < .001). CONCLUSION: Despite variation in the evaluation and treatment of infants with RS, this international and multispecialty survey showed trends that could represent best practices. An algorithm based on these findings is proposed.

Readmissions After Mechanical Thrombectomy for Acute Ischemic Stroke in the United States: A Nationwide Analysis.

OBJECTIVE: Mechanical thrombectomy after acute ischemic stroke has been shown to improve clinical outcomes. Data on short-term hospitalization outcomes after thrombectomy are needed. Our objective was to quantify 30- and 90-day readmissions after thrombectomy and identify factors associated with readmissions. METHODS: Retrospective observational analysis of adult patients hospitalized between January and November 2014, using data from the 2014 Nationwide Readmissions Database. Readmission rates were calculated and examined according to patient, clinical, and hospital characteristics using descriptive statistics. Weighted unconditional logistic regression models estimated the odds of readmission and examine the associations between select characteristics and readmission. RESULTS: 4850 individuals who underwent mechanical thrombectomy for acute ischemic stroke in 2014 were eligible for 30-day readmissions analyses. The nonelective readmission rate was 12.5% at 30 days, 20.7% at 90 days. Sepsis and stroke were the most common reasons for readmission. Female sex (adjusted odds ratio [AOR] 1.34, 1.02-1.77 at 30 days), discharge to inpatient postacute care facility (AOR 1.61, 1.07-2.41 at 30 days, AOR 1.99, 1.47-2.69 at 90 days), and longer initial length of stay (AOR 1.52, 1.04-2.23 at 30 days, AOR 1.67, 1.14-2.43 at 90 days) were associated with a higher likelihood of readmission. Thrombectomy complications were rare and not associated with readmission. CONCLUSIONS: 1 in 8 thrombectomy patients had a short-term readmission in 2014. Characteristics suggestive of a complicated hospital course or greater physical disability were the primary predictors of readmission. This study provides preliminary data for evaluations of the public health impact of mechanical thrombectomy in real world settings.

SGLT2-I in the Hospital Setting: Diabetic Ketoacidosis and Other Benefits and Concerns.

PURPOSE OF REVIEW: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of antihyperglycemic agents. They are increasingly being prescribed in the outpatient diabetic population. In this review, we examine the risks and benefits of continuation and initiation of SGLT2 inhibitors in the inpatient setting. RECENT FINDINGS: There are currently no published data regarding safety and efficacy of SGLT2 inhibitor use in the hospital. Outpatient data suggests that SGLT2 inhibitors have low hypoglycemic risk. They also decrease systolic blood pressure and can prevent cardiovascular death. The EMPA-REG study also showed a decrease in admissions for acute decompensated heart failure. There have been increasing cases of diabetic ketoacidosis, and specifically the euglycemic manifestation, associated with SGLT2 inhibitors use. We present two cases of inpatient SGLT2 inhibitor use, one of continuation of outpatient therapy and one of new initiation of therapy. We then discuss potential risks and methods to mitigate these as well as benefits of these medications in the inpatient setting. We cautiously suggest the use of SGLT2 inhibitors in the hospital. However, these must be used judiciously and the practitioner must be aware of euglycemic diabetic ketoacidosis and its risk factors in this population.

Failed Maximal Defibrillation Threshold Testing in the Subcutaneous Implantable Cardioverter Defibrillator.

The subcutaneous implantable cardioverter defibrillator (S-ICD) registry included very few patients with a body mass index (BMI) greater than 40. We present a case of a 40-year-old male with a BMI of 44 and ejection fraction of 25% who underwent S-ICD implantation for primary prevention of sudden cardiac death in the setting of a nonischemic cardiomyopathy. Defibrillation threshold (DFT) testing failed at high output. A posterior to anterior radiograph demonstrated migration of the components despite positioning under fluoroscopy. After repositioning, repeat DFT testing showed an inconsistent efficacy. We discuss the probabilistic nature of DFT testing, clinical factors affecting the S-ICD implant in the obese population and offer a novel insight from this specific experience.

Elevated Red Cell Distribution Width is Associated with Cerebral Infarction in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Elevated red blood cell distribution width (RDW) has been associated with thrombotic disorders including myocardial infarction, venous thromboembolism, and ischemic stroke, independent of other inflammatory and coagulation biomarkers. The purpose of this study was to determine whether elevated RDW is associated with cerebral infarction and poor outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: In this retrospective single-center cohort of aSAH patients (October 2009-September 2014), elevated RDW was defined as a mean RDW >14.5 % during the first 14 days after aSAH. Outcomes included cerebral infarction (CI) by any mechanism and poor functional outcome, defined as discharge modified Rankin Scale (mRS) >4, indicating severe disability or death. RESULTS: Of 179 patients, 27 % had a high Hunt-Hess grade (IV-V), and 76 % were women. Twenty-four patients (13.4 %) underwent red blood cell (RBC) transfusion and compared to patients with normal RDW, patients with an elevated RDW were at greater odds of RBC transfusion (OR 2.56 [95 % CI, 1.07-6.11], p = 0.035). In univariate analysis, more patients with elevated RDW experienced CI (30.8 vs. 13.7 %, p = 0.017). In the multivariable model, elevated RDW was significantly associated with CI (OR 3.08 [95 % CI, 1.30-7.32], p = 0.011), independent of known confounders including but not limited to age, sex, race, high Hunt-Hess grade, and RBC transfusion. In multivariable analysis, RDW elevation was also associated with poor functional outcome (mRS > 4) at discharge (OR 2.59 [95 % CI, 1.04-629], p = 0.040). CONCLUSIONS: RDW elevation is associated with cerebral infarction and poor outcome after aSAH. Further evaluation of this association is warranted as it may shed light on mechanistic relations between anemia, inflammation, and thrombosis after aSAH.

Concussion and football: a review and editorial.

The issue of concussion in football is of substantial interest to players, coaches, fans, and physicians. In this article, we review specific cultural hindrances to diagnosis and treatment of concussion in football. We review current trends in management and identify areas for improvement. We also discuss the obligations that physicians, particularly neurosurgeons and neurologists, have toward brain-injured football players and the larger societal role they may play in helping to minimize football-associated brain injury.

Autologous breast reconstruction: preoperative magnetic resonance angiography for perforator flap vessel mapping.

BACKGROUND: Selection of a vascular pedicle for autologous breast reconstruction is time consuming and depends on visual evaluation during the surgery. Preoperative imaging of donor site for mapping the perforator artery anatomy greatly improves the efficiency of perforator selection and significantly reduces the operative time. In this article, we present our experience with magnetic resonance angiography (MRA) for perforator vessel mapping including MRA technique and interpretation. METHODS: We have performed over 400 MRA examinations from August 2008 to August 2013 at our institution for preoperative imaging of donor site for mapping the perforator vessel anatomy. Using our optimized imaging protocol with blood pool magnetic resonance imaging contrast agents, multiple donor sites can be imaged in a single MRA examination. Following imaging using the postprocessing and reporting tool, we estimated incidence of commonly used perforators for autologous breast reconstruction. RESULTS: In our practice, anterior abdominal wall tissue is the most commonly used donor site for perforator flap breast reconstruction and deep inferior epigastric artery perforators are the most commonly used vascular pedicle. A thigh flap, based on the profunda femoral artery perforator has become the second most used flap at our institution. In addition, MRA imaging also showed evidence of metastatic disease in 4% of our patient subset. CONCLUSION: Our MRA technique allows the surgeons to confidently assess multiple donor sites for the best perforator and flap design. In conclusion, a well-performed MRA with specific postprocessing provides an accurate method for mapping perforator vessel, at the same time avoiding ionizing radiation.