Perforated peptic ulcer disease in transferred patients is associated with significant increase in length of stay.

BACKGROUND: Perforated peptic ulcer disease (PPUD) has a prevalence of 0.004-0.014% with mortality of 23.5% (Tarasconi et al. in World J Emerg Surg 15(PG-3):3, 2020). In this single center study, we examined the impact associated with patient transfer from outside facilities to our center for definitive surgical intervention (exploratory laparotomy). METHODS: Using EPIC report workbench, we identified 27 patients between 2018 and 2021 undergoing exploratory laparotomy with a concurrent diagnosis of peptic ulcer disease, nine of which were transferred to our institution for care. We queried this population for markers of disease severity including mortality, length of stay, intensive care unit (ICU) length of stay, and readmission rates. Manual chart reviews were performed to examine these outcomes in more detail and identify patients who had been transferred to our facility for surgery from an outside hospital. RESULTS: A total of 27 patients were identified undergoing exploratory laparotomy for definitive treatment of PPUD. The majority of patients queried underwent level A operations, the most urgent level of activation. In our institution, a Level A operation needs to go to the operating room within one hour of arrival to the hospital. Average mortality for this patient population was 14.8%. The readmission rate was 40.1%, and average length of ICU stay post-operatively was 16 days, with 83% of non-transfer patients requiring ICU admission and 100% of transfer patients requiring ICU admission, although this was not found to be statistically significant. Average length of hospital stay was 27 days overall. For non-transfer patients and transfer patients, LOS was 20 days and 41 days, respectively, which was statistically significant by one-sided t-test (p = 0.05). CONCLUSION: Patients transferred for definitive care of PPUD in a population otherwise notable for high mortality and high readmission rates: their average length of stay compared to non-transfer patients was over twice the length, which was statistically significant. Transferred patients also had higher rates of ICU care requirement although this was not statistically significant. Further inquiry to identify modifiable variables to facilitate the care of transferred patients is warranted, especially in the context of improving quality metrics known to enhance patient outcomes, satisfaction, and value.

GM-CSF is a marker of compartmentalised intrathecal inflammation in multiple sclerosis.

BACKGROUND: Granulocyte-macrophage colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine secreted by various immune cells. Several studies have demonstrated an expansion of GM-CSF producing T cells in the blood or CSF of people with MS (pwMS). However, whether this equates to greater concentrations of circulating cytokine remains unknown as quantification is difficult with traditional assays. OBJECTIVE: To determine whether GM-CSF can be quantified and whether GM-CSF levels are elevated in pwMS. METHODS: We employed Single Molecule Array (Simoa) to measure GM-CSF in both CSF and blood. We then investigated relationships between GM-CSF levels and measures of blood-CSF-barrier integrity. RESULTS: GM-CSF was quantifiable in all samples and was significantly higher in the CSF of pwMS compared with controls. No association was found between CSF GM-CSF levels and Q-Albumin - a measure of blood-CSF-barrier integrity. CSF GM-CSF correlated with measures of intrathecal inflammation, and these relationships were greater in primary progressive MS compared with relapsing-remitting MS. CONCLUSION: GM-CSF levels are elevated specifically in the CSF of pwMS. Our results suggest that elevated cytokine levels may reflect (at least partial) intrathecal production, as opposed to simple diffusion across a dysfunctional blood-CSF-barrier.

Two new mouse models of Gjb1-associated Charcot-Marie-Tooth disease type 1X.

BACKGROUND: Charcot-Marie-Tooth disease type 1X is caused by mutations in GJB1, which is the second most common gene associated with inherited peripheral neuropathy. The GJB1 gene encodes connexin 32 (CX32), a gap junction protein expressed in myelinating glial cells. The gene is X-linked, and the mutations cause a loss of function. AIMS: A large number of disease-associated variants have been identified, and many result in mistrafficking and mislocalization of the protein. An existing knockout mouse lacking Gjb1 expression provides a valid animal model of CMT1X, but the complete lack of protein may not fully recapitulate the disease mechanisms caused by aberrant CX32 proteins. To better represent the spectrum of human CMT1X-associated mutations, we have generated a new Gjb1 knockin mouse model. METHODS: CRISPR/Cas9 genome editing was used to produce mice carrying the R15Q mutation in Gjb1. In addition, we identified a second allele with an early frame shift mutation in codon 7 (del2). Mice were analyzed using clinically relevant molecular, histological, neurophysiological, and behavioral assays. RESULTS: Both alleles produce protein detectable by immunofluorescence in Schwann cells, with some protein properly localizing to nodes of Ranvier. However, both alleles also result in peripheral neuropathy with thinly myelinated and demyelinated axons, as well as degenerating and regenerating axons, predominantly in distal motor nerves. Nerve conduction velocities were only mildly reduced at later ages and compound muscle action potential amplitudes were not reduced. Levels of neurofilament light chain in plasma were elevated in both alleles. The del2 mice have an onset at ~3 months of age, whereas the R15Q mice had a later onset at 5-6 months of age, suggesting a milder loss of function. Both alleles performed comparably to wild type littermates in accelerating rotarod and grip strength tests of neuromuscular performance. INTERPRETATION: We have generated and characterized two new mouse models of CMT1X that will be useful for future mechanistic and preclinical studies.

Detection of companion galaxies around hot dust-obscured hyper-luminous galaxy W0410-0913.

The phase transition between galaxies and quasars is often identified with the rare population of hyper-luminous, hot dust-obscured galaxies. Galaxy formation models predict these systems to grow via mergers, that can deliver large amounts of gas toward their centers, induce intense bursts of star formation and feed their supermassive black holes. Here we report the detection of 24 galaxies emitting Lyman-α emission on projected physical scales of about 400 kpc around the hyper-luminous hot dust-obscured galaxy W0410-0913, at redshift z = 3.631, using Very Large Telescope observations. While this indicates that W0410-0913 evolves in a very dense environment, we do not find clear signs of mergers that could sustain its growth. Data suggest that if mergers occurred, as models expect, these would involve less massive satellites, with only a moderate impact on the internal interstellar medium of W0410-0913, which is sustained by a rotationally-supported fast-rotating molecular disk, as Atacama Large Millimeter Array observations suggest.

A dusty compact object bridging galaxies and quasars at cosmic dawn.

Understanding how super-massive black holes form and grow in the early Universe has become a major challenge1,2 since it was discovered that luminous quasars existed only 700 million years after the Big Bang3,4. Simulations indicate an evolutionary sequence of dust-reddened quasars emerging from heavily dust-obscured starbursts that then transition to unobscured luminous quasars by expelling gas and dust5. Although the last phase has been identified out to a redshift of 7.6 (ref. 6), a transitioning quasar has not been found at similar redshifts owing to their faintness at optical and near-infrared wavelengths. Here we report observations of an ultraviolet compact object, GNz7q, associated with a dust-enshrouded starburst at a redshift of 7.1899 ± 0.0005. The host galaxy is more luminous in dust emission than any other known object at this epoch, forming 1,600 solar masses of stars per year within a central radius of 480 parsec. A red point source in the far-ultraviolet is identified in deep, high-resolution imaging and slitless spectroscopy. GNz7q is extremely faint in X-rays, which indicates the emergence of a uniquely ultraviolet compact star-forming region or a Compton-thick super-Eddington black-hole accretion disk at the dusty starburst core. In the latter case, the observed properties are consistent with predictions from cosmological simulations7 and suggest that GNz7q is an antecedent to unobscured luminous quasars at later epochs.

Moving Forward from the COVID-19 Pandemic: Needed Changes in Movement Disorders Care and Research.

PURPOSE OF REVIEW: The COVID-19 pandemic has dramatically affected the health and well-being of individuals with movement disorders. This manuscript reviews these effects, discusses pandemic-related changes in clinical care and research, and suggests improvements to care and research models. RECENT FINDINGS: During the on-going COVID-19 pandemic, individuals with movement disorders have experienced worsening of symptoms, likely due to decreased access to care, loss of social connection, and decreased physical activity. Through telemedicine, care has moved out of the clinic and into the home. Clinical research has also been significantly disrupted, and there has been a shift to decentralized approaches. The pandemic has highlighted disparities in access to care and representation in research. We must now translate these experiences into better care and research models with a focus on equitable integration of telemedicine, better support of patients and caregivers, the development of meaningful digital endpoints, and optimization of decentralized research designs.

Inflammatory breast cancer defined: proposed common diagnostic criteria to guide treatment and research.

PURPOSE: Inflammatory breast cancer is a deadly and aggressive type of breast cancer. A key challenge relates to the need for a more detailed, formal, objective definition of IBC, the lack of which compromises clinical care, hampers the conduct of clinical trials, and hinders the search for IBC-specific biomarkers and treatments because of the heterogeneity of patients considered to have IBC. METHODS: Susan G. Komen, the Inflammatory Breast Cancer Research Foundation, and the Milburn Foundation convened patient advocates, clinicians, and researchers to review the state of IBC and to propose initiatives to advance the field. After literature review of the defining clinical, pathologic, and imaging characteristics of IBC, the experts developed a novel quantitative scoring system for diagnosis. RESULTS: The experts identified through consensus several "defining characteristics" of IBC, including factors related to timing of onset and specific symptoms. These reflect common pathophysiologic changes, sometimes detectable on biopsy in the form of dermal lymphovascular tumor emboli and often reflected in imaging findings. Based on the importance and extent of these characteristics, the experts developed a scoring scale that yields a continuous score from 0 to 48 and proposed cut-points for categorization that can be tested in subsequent validation studies. CONCLUSION: To move beyond subjective 'clinical diagnosis' of IBC, we propose a quantitative scoring system to define IBC, based on clinical, pathologic, and imaging features. This system is intended to predict outcome and biology, guide treatment decisions and inclusion in clinical trials, and increase diagnostic accuracy to aid basic research; future validation studies are necessary to evaluate its performance.

Normal, dust-obscured galaxies in the epoch of reionization.

Over the past decades, rest-frame ultraviolet (UV) observations have provided large samples of UV luminous galaxies at redshift (z) greater than 6 (refs. 1-3), during the so-called epoch of reionization. While a few of these UV-identified galaxies revealed substantial dust reservoirs4-7, very heavily dust-obscured sources at these early times have remained elusive. They are limited to a rare population of extreme starburst galaxies8-12 and companions of rare quasars13,14. These studies conclude that the contribution of dust-obscured galaxies to the cosmic star formation rate density at z > 6 is sub-dominant. Recent ALMA and Spitzer observations have identified a more abundant, less extreme population of obscured galaxies at z = 3-6 (refs. 15,16). However, this population has not been confirmed in the reionization epoch so far. Here, we report the discovery of two dust-obscured star-forming galaxies at z = 6.6813 ± 0.0005 and z = 7.3521 ± 0.0005. These objects are not detected in existing rest-frame UV data and were discovered only through their far-infrared [C II] lines and dust continuum emission as companions to typical UV-luminous galaxies at the same redshift. The two galaxies exhibit lower infrared luminosities and star-formation rates than extreme starbursts, in line with typical star-forming galaxies at z ≈ 7. This population of heavily dust-obscured galaxies appears to contribute 10-25% to the z > 6 cosmic star formation rate density.

The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy.

Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. In this study, we used in vivo, cell type­specific transcriptional and translational profiling to show that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of Gcn2 alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT.

Exceptional Changes in Skeletal Anatomy under Domestication: The Case of Brachycephaly.

"Brachycephaly" is generally considered a phenotype in which the facial part of the head is pronouncedly shortened. While brachycephaly is characteristic for some domestic varieties and breeds (e.g., Bulldog, Persian cat, Niata cattle, Anglo-Nubian goat, Middle White pig), this phenotype can also be considered pathological. Despite the superficially similar appearance of "brachycephaly" in such varieties and breeds, closer examination reveals that "brachycephaly" includes a variety of different cranial modifications with likely different genetic and developmental underpinnings and related with specific breed histories. We review the various definitions and characteristics associated with brachycephaly in different domesticated species. We discern different types of brachycephaly ("bulldog-type," "katantognathic," and "allometric" brachycephaly) and discuss morphological conditions related to brachycephaly, including diseases (e.g., brachycephalic airway obstructive syndrome). Further, we examine the complex underlying genetic and developmental processes and the culturally and developmentally related reasons why brachycephalic varieties may or may not be prevalent in certain domesticated species. Knowledge on patterns and mechanisms associated with brachycephaly is relevant for domestication research, veterinary and human medicine, as well as evolutionary biology, and highlights the profound influence of artificial selection by humans on animal morphology, evolution, and welfare.

La braquicefalia generalmente se considera un fenotipo en el que el cráneo, específicamente el hocico, es notablemente acortado. Mientras que la braquicefalia es característica de algunas variedades domésticas y razas (p.e. Bulldog, gato persa, vaca ñata, cabra anglo nubiana, cerdo Middle White), también se puede interpretar como un fenotipo patológico. A pesar de que la braquicefalia tiene una apariencia semejante, por lo menos superficial, en estas variedades y razas, al examinarla más en detalle se descubre que la "braquicefalia" incluye una variedad de diferentes modificaciones del cráneo que probablemente tienen diferentes subyacentes genéticos y de desarrollo y que están relacionados con la historia de la raza. Revisamos las diferentes definiciones y propiedades relacionadas con la braquicefalia en varias especies domésticas. Describimos diferentes tipos de braquicefalia (tipo bulldog, "katantognático" y braquicefalia alométrica) y analizamos condiciones morfológicas relacionadas con la braquicefalia incluyendo enfermedades (p.e. síndrome obstructivo respiratorio). Además, examinamos los complejos procesos genéticos y de desarrollo subyacentes y los motivos culturales y de desarrollo por las que variedades braquicéfalas pueden ser más o menos prevalentes en ciertas especies domésticas. El conocimiento de patrones y mecanismos asociados a la braquicefalia son relevantes para la investigación sobre la domesticación, medicina veterinaria y humana, así como para la biología evolutiva y destaca la profunda influencia de la selección artificial sobre la morfología y bienestar de los animales y su evolución.

The burden of heat-related mortality attributable to recent human-induced climate change.

Climate change affects human health; however, there have been no large-scale, systematic efforts to quantify the heat-related human health impacts that have already occurred due to climate change. Here, we use empirical data from 732 locations in 43 countries to estimate the mortality burdens associated with the additional heat exposure that has resulted from recent human-induced warming, during the period 1991-2018. Across all study countries, we find that 37.0% (range 20.5-76.3%) of warm-season heat-related deaths can be attributed to anthropogenic climate change and that increased mortality is evident on every continent. Burdens varied geographically but were of the order of dozens to hundreds of deaths per year in many locations. Our findings support the urgent need for more ambitious mitigation and adaptation strategies to minimize the public health impacts of climate change.

Superiority of continuous over intermittent intraoperative nerve monitoring in preventing vocal cord palsy.

BACKGROUND: Continuous intraoperative nerve stimulation (IONM) with uninterrupted monitoring is likely better than intermittent IONM in preventing vocal cord palsy after thyroid surgery. METHODS: This was a comparative study of intermittent versus continuous IONM in patients with benign and malignant thyroid disease treated at a tertiary centre over 10 years. Early postoperative and permanent vocal cord palsy rates were estimated. Multivariable logistic regression analysis was used to quantify the contributions of clinical and histopathological variables to early postoperative and permanent vocal cord palsy. RESULTS: A total of 6029 patients were included, of whom 3139 underwent continuous and 2890 intermittent IONM. Based on nerves at risk (5208 versus 5024 nerves), continuous IONM had a 1·7-fold lower early postoperative vocal cord palsy rate than intermittent monitoring (1·5 versus 2·5 per cent). This translated into a 30-fold lower permanent vocal cord palsy rate (0·02 versus 0·6 per cent). In multivariable logistic regression analysis, continuous IONM independently reduced early postoperative vocal cord palsy 1·8-fold (odds ratio (OR) 0·56) and permanent vocal cord palsy 29·4-fold (OR 0·034) compared with intermittent IONM. One permanent vocal cord palsy per 75·0 early vocal cord palsies was observed with continuous IONM, compared with one per 4·2 after intermittent IONM. Early postoperative vocal cord palsies were 17·9-fold less likely to become permanent with continuous than intermittent IONM. CONCLUSION: Continuous IONM is superior to intermittent IONM in preventing vocal cord palsy.

Risk of skin cancer in new users of thiazides and thiazide-like diuretics: a cohort study using an active comparator group.

BACKGROUND: Case-control studies report a dose-dependent increased risk of skin cancer in users of hydrochlorothiazide (HCTZ) vs. nonusers. The degree to which other thiazides and thiazide-like diuretics (TZs) are associated with skin cancer is less certain. OBJECTIVES: To assess the risk of skin cancer in new users of different TZs compared with new users of calcium channel blockers (CCBs). METHODS: We conducted a cohort study using a UK primary-care database (1998-2017), including 271 154 new TZ users [87·6% bendroflumethiazide (BFT), 5·8% indapamide and 3·6% HCTZ] and 275 263 CCB users. The outcomes were basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). We estimated incidence rates (IRs) and IR ratios (IRRs) in short-term (< 20 prescriptions) and long-term (≥ 20 prescriptions) users of TZs and CCBs using negative binomial regression, and calculated rate differences (RDs) for selected results. We used fine stratification on the propensity score (PS) to control for 23 baseline covariates. RESULTS: Long-term use of HCTZ increased absolute and relative risks of SCC [PS-weighted IRR 1·95; 95% confidence interval (CI) 1·87-2·02; RD per 100 000 person-years 87.4], but not of BCC or CMM. Long-term use of indapamide was associated with an increased incidence of CMM (IRR 1·43; 95% CI 1·35-1·50). BFT was not meaningfully associated with the risk of any type of skin cancer. CONCLUSIONS: Our results corroborate the previously reported increased risk of SCC (but not of BCC or CMM) for long-term use of HCTZ. BFT may be a safer alternative for patients at increased risk of skin cancer.

Combining the production of L-lactic acid with the production of feed protein concentrates from alfalfa.

The production of L-lactic acid was investigated in combination with the production of protein concentrates in the frame of a green biorefinery for efficient utilization of grasses and legume crops. Alfalfa green juice was the sole substrate utilized for initial lactic acid fermentation with Lactobacillus salivarius, Lactobacillus paracasei or Bacillus coagulans in order to drop the pH and precipitate the plant proteins present in the juice. Afterwards, proteins were separated by microfiltration with 40-42% of protein recovery into protein concentrates, suited for feeding monogastric animals. The (residual) brown juice was investigated as source of nutrients for producing L-lactic acid from glucose or xylose with B. coagulans A107 or B. coagulans A166, respectively. Fermentation of glucose (30, 60, 100 g L-1) resulted in productivities of 2.8-4.0 g L-1 h-1 and yields of 0.85-0.91 g LA per g consumed glucose. Fermentation of xylose (30, 60 g L-1) resulted productivities of 1.1-2.3 g L-1 h-1 and yields of 0.83-0.88 g LA per g consumed xylose. Comparing different brown juices, initial green juice fermentation with B. coagulans is recommended if the brown juice is to be used for producing L-lactic acid. Based on our results, it is possible to combine protein recovery with lactic acid production, and the brown juice proved to be a good nutrient source for L-lactic acid production with high optical purities.

Assessing resilience of healthcare infrastructure exposed to COVID-19: emerging risks, resilience indicators, interdependencies and international standards.

In the moment of preparation of this paper, the world is still globally in grip of the Corona (COVID-19) crisis, and the need to understand the broader overall framework of the crisis increases. As in similar cases in the past, also with this one, the main interest is on the "first response". Fully appreciating the efforts of those risking their lives facing pandemics, this paper tries to identify the main elements of the larger, possibly global, framework, supported by international standards, needed to deal with new (emerging) risks resulting from threats like Corona and assess the resilience of systems affected. The paper proposes that future solutions should include a number of new elements, related to both risk and resilience. That should include broadening the scope of attention, currently focused onto preparation and response phases, to the phases of "understanding risks", including emerging risks, and transformation and adaptation. The paper suggests to use resilience indicators in this process. The proposed approach has been applied in different cases involving critical infrastructures in Europe (energy supply, water supply, transportation, etc., exposed to various threats), including the health system in Austria. The detailed, indicator-based, resilience analysis included mapping resilience, resilience stress-testing, visualization, etc., showing, already before the COVID-19, the resilience (stress-testing) limits of the infrastructures. A simpler (57 indicator based) analysis has, then been done for 11 countries (including Austria). The paper links these results with the options available in the area of policies, standards, guidelines and tools (such as the RiskRadar), with focus on interdependencies and global standards-especially the new ISO 31,050, linking emerging risks and resilience.

Cell size sets the diameter of the budding yeast contractile ring.

The formation and maintenance of subcellular structures and organelles with a well-defined size is a key requirement for cell function, yet our understanding of the underlying size control mechanisms is limited. While budding yeast cell polarization and subsequent assembly of a septin ring at the site of bud formation has been successfully used as a model for biological self-assembly processes, the mechanisms that set the size of the septin ring at the bud neck are unknown. Here, we use live-cell imaging and genetic manipulation of cell volume to show that the septin ring diameter increases with cell volume. This cell-volume-dependence largely accounts for modulations of ring size due to changes in ploidy and genetic manipulation of cell polarization. Our findings suggest that the ring diameter is set through the dynamic interplay of septin recruitment and Cdc42 polarization, establishing it as a model for size homeostasis of self-assembling organelles.

Anomalous pressure dependence of the electronic transport and anisotropy in SrIrO3 films.

Iridate oxides display exotic physical properties that arise from the interplay between a large spin-orbit coupling and electron correlations. Here, we present a comprehensive study of the effects of hydrostatic pressure on the electronic transport properties of SrIrO3 (SIO), a system that has recently attracted a lot of attention as potential correlated Dirac semimetal. Our investigations on untwinned thin films of SIO reveal that the electrical resistivity of this material is intrinsically anisotropic and controlled by the orthorhombic distortion of the perovskite unit cell. These effects provide another evidence for the strong coupling between the electronic and lattice degrees of freedom in this class of compounds. Upon increasing pressure, a systematic increase of the transport anisotropies is observed. The anomalous pressure-induced changes of the resistivity cannot be accounted for by the pressure dependence of the density of the electron charge carriers, as inferred from Hall effect measurements. Moreover, pressure-induced rotations of the IrO6 octahedra likely occur within the distorted perovskite unit cell and affect electron mobility of this system.

A 6-month randomized, double-blind, placebo-controlled trial of weekly exenatide in adolescents with obesity.

BACKGROUND: Pharmacological treatment options for adolescents with obesity are very limited. Glucagon-like-peptide-1 (GLP-1) receptor agonist could be a treatment option for adolescent obesity. OBJECTIVE: To investigate the effect of exenatide extended release on body mass index (BMI)-SDS as primary outcome, and glucose metabolism, cardiometabolic risk factors, liver steatosis, and other BMI metrics as secondary outcomes, and its safety and tolerability in adolescents with obesity. METHODS: Six-month, randomized, double-blinded, parallel, placebo-controlled clinical trial in patients (n = 44, 10-18 years, females n = 22) with BMI-SDS > 2.0 or age-adapted-BMI > 30 kg/m2 according to WHO were included. Patients received lifestyle intervention and were randomized to exenatide extended release 2 mg (n = 22) or placebo (n = 22) subcutaneous injections given once weekly. Oral glucose tolerance tests (OGTT) were conducted at the beginning and end of the intervention. RESULTS: Exenatide reduced (P < .05) BMI-SDS (-0.09; -0.18, 0.00), % BMI 95th percentile (-2.9%; -5.4, -0.3), weight (-3 kg; -5.8, -0.1), waist circumference (-3.2 cm; -5.8, -0.7), subcutaneous adipose tissue (-552 cm3 ; -989, -114), 2-hour-glucose during OGTT (-15.3 mg/dL; -27.5, -3.1), total cholesterol (11.6 mg/dL; -21.7, -1.5), and BMI (-0.83 kg/m2 ; -1.68, 0.01) without significant change in liver fat content (-1.36; -3.12, 0.4; P = .06) in comparison to placebo. Safety and tolerability profiles were comparable to placebo with the exception of mild adverse events being more frequent in exenatide-treated patients. CONCLUSIONS: Treatment of adolescents with severe obesity with extended-release exenatide is generally well tolerated and leads to a modest reduction in BMI metrics and improvement in glucose tolerance and cholesterol. The study indicates that the treatment provides additional beneficial effects beyond BMI reduction for the patient group.