Model-based simulation of glycaemic effect and body weight loss when switching from semaglutide or dulaglutide to once weekly tirzepatide.

OBJECTIVE: To evaluate the efficacy endpoints of HbA1c and body weight loss after switching from the GLP-1 receptor agonists, semaglutide or dulaglutide, to treatment with the GIP/GLP-1 receptor agonist (RA) tirzepatide. METHODS: Models were developed and validated to describe the HbA1c and weight loss time course for semaglutide (SUSTAIN 1-10), dulaglutide (AWARD-11) and tirzepatide (SURPASS 1-5, phase 3 global T2D program). The impact of switching from once weekly GLP-1 RAs to tirzepatide was described by simulating the efficacy time course. Semaglutide and dulaglutide doses were escalated in accordance with their respective labels. RESULTS: Model-predicted mean decreases from baseline in HbA1c and body weight for semaglutide 0.5 mg, 1 mg, and 2 mg were 1.22 to 1.79% and 3.62 to 6.87 kg respectively, at Week 26. Model-predicted mean decreases from baseline in HbA1c and body weight for dulaglutide 1.5 mg, 3 mg and 4.5 mg were 1.53 to 1.84% and 2.55 to 3.71 kg respectively, at Week 26. After switching to tirzepatide 5, 10 and 15 mg HbA1c reductions were predicted to range between 1.95 to 2.46% and body weight reductions between 6.50 to 12.1 kg by Week 66. CONCLUSION: In this model-based simulation, switching from approved maintenance doses of semaglutide or dulaglutide to tirzepatide, even at the lowest approved maintenance dose of 5 mg, showed the potential to further improve HbA1c and body weight reductions.

Type 2 diabetes is a disease of elevated blood sugar levels. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a type of medication used to treat type 2 diabetes that work on GLP-1 receptors in the body. Semaglutide and dulaglutide are examples of GLP-1 RAs, which lower blood sugar and body weight. Tirzepatide is a newer medication, which works on both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. It reduces blood sugar and body weight in people living with type 2 diabetes. Healthcare professionals and patients are interested in how switching medication from semaglutide or dulaglutide to tirzepatide might change blood glucose levels and body weight. However, because tirzepatide is a newer medication, there is not much information available on this aspect. Data from clinical trials of these medications were used to predict the effects of switching from semaglutide or dulaglutide to tirzepatide. These model-based simulations showed that switching to tirzepatide may further reduce HbA1c (a measure of blood sugar) and body weight. This may provide useful information to healthcare professionals and patients when making decisions about treatment with these medications.

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.

Angioinvasive Trichophyton rubrum associated necrotizing fasciitis in an immunocompromised patient.

Angioinvasive dermatophytosis with necrotizing fasciitis can be a rare complication in immunocompromised patients with early surgical debridement, 12 weeks of oral terbinafine, and reduction in immunosuppression being a viable management strategy.

Histoplasmosis mimicking a tumor of the thumb in a patient with neurofibromatosis type I: A case report and review of the literature.

We describe an immunocompromised 73-year-old male with a history of neurofibromatosis type 1 (NF1) who presented with a lesion on the thumb concerning for malignancy that was found to be histoplasmosis. This unique case highlights the importance of a thorough history and a broad differential diagnosis in the management of new osteoarticular lesions.

Stroke and Disseminated Intravascular Coagulation in a Patient With Metastatic Prostate Cancer.

Cancer and stroke comprise two of the most common causes of death worldwide. Despite a significantly increased risk of stroke among patients with cancer, most stroke trials have excluded patients with malignancy. There is thus limited evidence to help guide management decisions in this complex population. We present the case of a 78-year-old man with recurrent strokes - both ischemic and hemorrhagic - in the setting of newly-identified metastatic prostate cancer. An atypical cause of cancer-associated stroke is reviewed and the management is discussed.

The delay procedure in deep inferior epigastric artery perforator flap breast reconstruction.

BACKGROUND: The delay procedure in DIEP flap breast reconstruction, in which the reduced-caliber choke vessels play a major role, can provide more well-perfused tissue than a standard DIEP flap. The aim of this study was to review our experience with this technique, to evaluate the indications, and to analyze the surgical outcomes. METHODS: A retrospective study was conducted of all consecutive DIEP delay procedures performed between March 2019 and June 2021. Patient demographics, operative details, and complications were registered. Patients had preoperative imaging by MRA to select dominant perforators. The surgical technique involves a two-stage operation. During the first operation the flaps were pedicled on a dominant perforator and a lateral skin bridge extending towards the lateral flank and lumbar fat, and in a second stage the flap is harvested and transferred. RESULTS: A total of 82 extended DIEP delay procedures were performed to reconstruct 154 breasts. The majority were bilateral breast reconstructions (87.8%). The delay procedure was used for 38 primary reconstructions (46.3%) and 32 tertiary reconstructions (39.0%). The primary indication was the need for additional volume (79.3%), followed by extensive abdominal scarring and liposuction. After the first operation seroma was the most frequently observed complication (7.3%). After the second operation three total flap losses (1.9%) were observed. CONCLUSIONS: The delay procedure in DIEP flap breast reconstruction results in the harvest of a good amount of abdominal tissue by adding a preliminary procedure. This technique can convert patients previously considered unsuitable into suitable candidates for abdominal-based breast reconstruction.

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.

A Case Series Evaluating Postoperative Complications of Foot and Ankle Surgeries in Adult Patients With Neuromuscular Disease.

Background: Patients with neuromuscular diseases such as cerebral palsy (CP) are living longer because of advances in medicine, yielding a larger number of adult patients that could benefit from corrective surgery. However, some surgeons are hesitant to offer surgery to these patients because of concern for postoperative complications. A paucity of literature exists that describes complications in patients undergoing foot and ankle surgery for neuromuscular diseases. The primary study outcome was to identify the postoperative complication rates associated with foot and ankle surgery in adult patients with neuromuscular disease. Methods: The charts of patients with neuromuscular diseases who had foot and ankle surgery by the senior author at a single institution from March 2010 to March 2020 were reviewed. Patient charts were reviewed for demographic data, medical history and diagnoses, and surgical treatment information. Only patients' index procedures with the senior author were evaluated for surgical data. Patient charts were assessed to determine the presence or absence of a postoperative complication following an index procedure. Results: In a cohort of 42 patients, females comprised 60% of the patient cohort. The average age was 35 (range, 20-69) years old. CP was the most common neuromuscular diagnosis at 52% (22 of 42) patients. Eighteen percent (11 of 60) of the index surgeries had 1 or more complication with a total of 13 complications. The overall wound complication rate was 10% (6 of 60), infection rate was 8% (5 of 60), and the nonunion rate following arthrodesis was 10% (2 of 21). Conclusion: We conclude that foot and ankle surgery in this complex population can be done safely, with postoperative complication rates similar to the average population. Although these patients may present with unique challenges, surgeons should not forgo surgery out of concern for postoperative complications. Level of Evidence: Level IV, retrospective cohort study at a single institution.

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 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.

Role of PAI-1 in hepatic steatosis and dyslipidemia.

Plasminogen activator inhibitor 1 (PAI-1) is a functional biomarker of the metabolic syndrome. Previous studies have demonstrated that PAI-1 is a mechanistic contributor to several elements of the syndrome, including obesity, hypertension and insulin resistance. Here we show that PAI-1 is also a critical regulator of hepatic lipid metabolism. RNA sequencing revealed that PAI-1 directly regulates the transcriptional expression of numerous genes involved in mammalian lipid homeostasis, including PCSK9 and FGF21. Pharmacologic or genetic reductions in plasma PAI-1 activity ameliorates hyperlipidemia in vivo. These experimental findings are complemented with the observation that genetic deficiency of PAI-1 is associated with reduced plasma PCSK9 levels in humans. Taken together, our findings identify PAI-1 as a novel contributor to mammalian lipid metabolism and provides a fundamental mechanistic insight into the pathogenesis of one of the most pervasive medical problems worldwide.

Palliative Care in Patients With High-Grade Gliomas in the Neurological Intensive Care Unit.

BACKGROUND: Palliative care improves quality of life in patients with malignancy; however, it may be underutilized in patients with high-grade gliomas (HGGs). We examined the practices regarding palliative care consultation (PCC) in treating patients with HGGs in the neurological intensive care unit (NICU) of an academic medical center. METHODS: We conducted a retrospective cohort study of patients admitted to the NICU from 2011 to 2016 with a previously confirmed histopathological diagnosis of HGG. The primary outcome was the incidence of an inpatient PCC. We also evaluated the impact of PCC on patient care by examining its association with prespecified secondary outcomes of code status amendment to do not resuscitate (DNR), discharge disposition, 30-day mortality, and 30-day readmission rate, length of stay, and place of death. RESULTS: Ninety (36% female) patients with HGGs were identified. Palliative care consultation was obtained in 16 (18%) patients. Palliative care consultation was associated with a greater odds of code status amendment to DNR (odds ratio [OR]: 18.15, 95% confidence interval [CI]: 5.01-65.73), which remained significant after adjustment for confounders (OR: 27.20, 95% CI: 5.49-134.84), a greater odds of discharge to hospice (OR: 24.93, 95% CI: 6.48-95.88), and 30-day mortality (OR: 6.40, 95% CI: 1.96-20.94). CONCLUSION: In this retrospective study of patients with HGGs admitted to a university-based NICU, PCC was seen in a minority of the sample. Palliative care consultation was associated with code status change to DNR and hospice utilization. Further study is required to determine whether these findings are generalizable and whether interventions that increase PCC utilization are associated with improved quality of life and resource allocation for patients with HGGs.

The Safety of Multimodality Monitoring Using a Triple-Lumen Bolt in Severe Acute Brain Injury.

BACKGROUND: Multimodality monitoring is used frequently to guide care of patients with severe acute brain injury. The aim of this study was to examine the safety and reliability of multimodality monitoring. METHODS: From a prospective observational database at a Level I trauma center, 501 patients, including 300 men and 201 women (mean age 58 ± 39 years) were identified retrospectively. Each patient received a triple-lumen bolt and 3 monitors: intracranial pressure, brain temperature, and brain oxygen. Intensive care unit and hospital records were examined to identify complications, reasons for device replacement, malfunction and infection. Head computed tomography (CT) scans performed before and after the monitors were inserted were examined for evidence of monitor-related adverse effects. RESULTS: A total of 696 triple-lumen bolts were placed. Median duration of monitoring was 78.88 hours (interquartile range, 33.0-133.2 hours). Bilateral monitors were inserted in 22 (3.16%) patients. Ten (1.43%) monitors were replaced to allow magnetic resonance imaging, and 40 (5.74%) monitors were replaced to facilitate additional cranial surgery. Of 35 (5.02%) monitors that were replaced because they were thought to not be functioning properly, 19 (54.29%) were subsequently found to be functioning normally. Follow-up CT scans were compared with CT scans obtained before insertion of monitors; 9 (2.13%) small contusions and 10 (2.36%) extra-axial hematomas associated with the devices were identified. Based on the CT findings, the hematomas were thought to be associated with the insertion technique rather than the device; 4 hematomas required treatment. Twenty-two (3.16%) devices were incorrectly placed (e.g., the probe was in an infarct or an already existing contusion). Only 1 associated infection was identified. CONCLUSIONS: Placement of intracranial monitors for multimodality neuromonitoring using a triple-lumen bolt appears to be safe. The complication rate is similar to published complication rates for single-lumen bolts and single monitors.

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.

The Stacked Hemiabdominal Extended Perforator Flap for Autologous Breast Reconstruction.

BACKGROUND: Options for bilateral autologous breast reconstruction in thin women are limited. The aim of this study was to introduce a novel approach to increase abdominal flap volume with the stacked hemiabdominal extended perforator (SHAEP) flap. The authors describe the surgical technique and analyze their results. METHODS: A retrospective study was conducted of all SHAEP flap breast reconstructions performed since February of 2014. Patient demographics, operative details, complications, and flap reexplorations were recorded. The bipedicled hemiabdominal flap was designed as a combination of the deep inferior epigastric artery perforator (DIEP) and a second, more lateral pedicle: the deep or superficial circumflex iliac perforator vessels, the superficial inferior epigastric artery, or a lumbar artery or intercostal perforator. RESULTS: A total of 90 SHAEP flap breast reconstructions were performed in 49 consecutive patients. Median operative time was 500 minutes (range, 405 to 797 minutes). Median hemiabdominal flap weight that was used for reconstruction was 598 g (range, 160 to 1389 g). No total flap losses were recorded. Recipient-site complications included partial flap loss (2.2 percent), hematoma (3.3 percent), fat necrosis (2.2 percent), and wound problems (4.4 percent). Minor donor-site complications occurred in five patients (10.2 percent). Most flaps were harvested on a combination of the DIEP and deep circumflex iliac artery vessels. CONCLUSIONS: This study demonstrated that the SHAEP flap is an excellent option for bilateral autologous breast reconstruction in women who require significant breast volume but have insufficient abdominal tissue for a bilateral DIEP flap. The bipedicled SHAEP flap allows for enhanced flap perfusion, increased volume, and abdominal contour improvement using a single abdominal donor site. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

CENTRAL DIABETES INSIPIDUS AND CHEMOTHERAPY: USE OF A CONTINUOUS ARGININE VASOPRESSIN INFUSION FOR FLUID AND SODIUM BALANCE.

OBJECTIVE: Central diabetes insipidus can occur in the setting of primary or metastatic tumors that disrupt the hypothalamic-pituitary axis. Usual treatment consists of water intake to replace ongoing fluid losses and desmopressin administration aimed at decreasing the urine output to enable maintenance of eunatremia without polyuria. Marked derangement in plasma sodium concentration can occur when high-volume intravenous fluid administration is required during chemotherapy to prevent nephrotoxicity, particularly if obligate fluid intake exceeds the total daily fluid intake necessary to maintain eunatremia. METHODS: We developed a protocol for a rapidly titratable low-dose continuous intravenous arginine vasopressin infusion to maintain eunatremia in patients with central diabetes insipidus during periods of obligate fluid intake. RESULTS: We successfully maintained eunatremia in 2 patients with central nervous system lymphoma who underwent several cycles of obligate intravenous fluid administration with 5% dextrose in 0.45% sodium chloride for chemotherapy. CONCLUSION: Obligate fluid administration can result in dangerous and severe fluctuations in plasma sodium concentration in patients with central diabetes insipidus receiving conventional desmopressin therapy. The use of a rapidly titratable low-dose continuous vasopressin infusion successfully maintained eunatremia in this setting. This protocol can be replicated to prevent the wide and potentially dangerous fluctuations in plasma sodium concentration that can occur in patients with central diabetes insipidus who require high-volume intravenous fluid administration. This protocol has not been assessed among patients with impaired renal function and, thus, may not be generalizable to this population. (AACE Clinical Case Rep. 2018;4:e487-e492).

Dapagliflozin-Induced Acute-on-Chronic Liver Injury.

Sodium-glucose cotransporter 2 inhibitors are a new class of oral hypoglycemic agents, and thus safety data are limited. We present a 48-year-old woman with type 2 diabetes mellitus and Child's Class A cirrhosis secondary to nonalcoholic steatohepatitis presenting with jaundice and acute cholestatic liver injury. Other than starting dapagliflozin, she reported no medication changes or supplement use. Before treatment, her total bilirubin was 1.2 mg/dL. On admission, her liver values were elevated and liver biopsy was consistent with drug-induced liver injury. This report raises awareness about the potential hepatotoxic effects of dapagliflozin, particularly in patients with chronic liver disease.