Munozcolon2188

We assessed whether sodium-glucose co-transporter type 2 (SGLT2) inhibitors are associated with a higher incidence rate of venous thromboembolism in patients with type 2 diabetes.

We conducted a population-based cohort study using the InGef database including patients with type 2 diabetes newly treated with noninsulin antidiabetic drugs between 2012 and 2018. Cases of venous thromboembolism identified during follow-up were matched to 40 controls on age, sex, cohort entry date, and duration of follow-up. Using a nested case-control approach, conditional logistic regression estimated incidence rate ratios (RRs) with 95% confidence intervals (CIs) of venous thromboembolism adjusted for sociodemographic and clinical variables, comparing current use of SGLT2 inhibitors with current use of dipeptidyl peptidase-4 (DPP-4) inhibitors.

In a cohort of 219,538 patients, we identified 2152 cases of venous thromboembolism and matched them to 85,104 controls. Compared with DPP-4 inhibitors, current use of SGLT2 inhibitors was associated with a lower rate of venous thromboembolism (RR, 0.75; 95% CI, 0.59-0.94). Effect estimates were similar for dapagliflozin (RR, 0.77; 95% CI, 0.57-1.03) and empagliflozin (RR, 0.71; 95% CI, 0.52-0.98).

Compared with DPP-4 inhibitors, SGLT2 inhibitors were not associated with a higher rate of venous thromboembolism, providing reassurance regarding their thromboembolic safety.

Compared with DPP-4 inhibitors, SGLT2 inhibitors were not associated with a higher rate of venous thromboembolism, providing reassurance regarding their thromboembolic safety.

Sleeve gastrectomy has quickly become the most commonly performed bariatric surgery. In light of its increasing popularity, the prevalence of gastric sleeve stenosis (GSS) continues to rise. Management with serial pneumatic dilation is highly successful but underused because of a lack of quantitative diagnostic criteria. We aimed to develop quantifiable endoscopic criteria to characterize GSS based on the (1) ratio of narrowest to widest gastric lumen diameter, (2) endoscope angulation/trajectory required for passage, and (3) presence of bilious fluid pooling in the proximal sleeve and compare it with endoluminal functional lumen imaging probe (EndoFLIP) diameter and distensibility indices (DIs) and endoscopic documentation of gastric lumen morphology.

We retrospectively reviewed a prospectively maintained database of patients undergoing endoscopy to assess for GSS. Endoscopic images were reviewed in a blinded fashion by 2 bariatric endoscopists. The narrowest and widest part of the gastric lumen diameterompared with those without stenosis (.27 ± .14 vs .48 ± .77, P= .01). Diameter ratios were also inversely related to severity of sleeve stenosis (β= -.08, P= .01). Patients with stenosis were also more likely to have fluid pooling (96.2% vs 25%, P< .001). There was no significant difference in the trajectory of endoscope passage between the 2 groups.

Endoscopic criteria for diagnosis of GSS are lacking. Our data suggest the ratio between the narrowest and widest gastric lumen diameters and presence of pooled fluid is associated with diagnosis of stenosis by EndoFLIP and gastric lumen morphology. Future studies to validate these criteria are needed.

Endoscopic criteria for diagnosis of GSS are lacking. Our data suggest the ratio between the narrowest and widest gastric lumen diameters and presence of pooled fluid is associated with diagnosis of stenosis by EndoFLIP and gastric lumen morphology. Future studies to validate these criteria are needed.

Some data suggest that individuals with numerous,<10-mm, rectosigmoid hyperplastic polyps (HPs) are at average risk for the development of metachronous advanced adenomatous neoplasia. Guidelines suggest that these individuals do not need surveillance colonoscopy and should be followed akin to individuals with a normal colonoscopy. Less is known of the risk of metachronous neoplasia because of≥1 HPs<10mm proximal to the sigmoid colon. We compared the risk of metachronous neoplasia between individuals with small HPs and those with normal colonoscopy, specifically addressing the impact of location and number of HPs on risk.

Colonoscopy and pathology reports from patients with≥2 colonoscopies between 2004 and 2014 were reviewed. Exclusions included inpatients; age<40 or >75 years; and family or personal history of colorectal cancer, inflammatory bowel disease, previous colorectal surgery, or a previous colonoscopy with any adenoma, sessile serrated lesion (SSL), or HP≥10mm. The risk of metachronouarger cohorts.The pharmaceutical industry has experienced great successes with protein therapeutics in the last two decades and with novel modalities, including cell therapies and gene therapies, more recently. Biotherapeutics are complex in structure and present challenges for discovery, development, regulatory, and life cycle management. Biotherapeutics can interact with the immune system that may lead to undesired immunological responses, including immunogenicity, hypersensitivity reactions (HSR), injection site reactions (ISR), and others. Many product and process related critical quality attributes (CQAs) have the potential to trigger or augment such immunological responses to the product. Tremendous efforts, both clinically and preclinically, have been invested to understand the impact of product and process related CQAs on adverse immunological effects. The information and knowledge are critical for the implementation of Quality by Design (QbD), which requires risk assessment and establishment of specifications and control strategies for CQAs. A quality target product profile (QTPP) that identifies the key CQAs through process development can help assign severity scores based on safety, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of the molecule. Gaps and future directions related to biotherapeutics and emerging novel modalities are presented.Amino acids, for example L-arginine, are used in lyophilisation as crystalline bulking, buffering, viscosity reducing or stabilising excipients. In this study, arginine was formulated with different counter ions (hydrochloride, citrate, lactobionate, phosphate, and succinate). A monoclonal antibody was investigated in sugar-free arginine formulations and mixtures with sucrose regarding cake appearance and protein aggregation and fragmentation. Arginine hydrochloride formulations collapsed during lyophilisation due to its low Tg' and partially crystallised during storage, but provided the best protein stability at low antibody concentration, followed by arginine succinate. learn more Arginine citrate/phosphate/lactobionate formulations resulted in amorphous elegant cakes, but inferior protein stability. Addition of sucrose improved cake appearance and protein stability. Arginine phosphate with sucrose resulted in similar protein stability as the sucrose reference. Mixtures of sucrose with arginine hydrochloride/lactobionate/succinate provided better stability than sucrose alone. While 50 mg/mL antibody improved the cake appearance, only arginine lactobionate provided sufficient protein stability next to sucrose. Overall, sugar-free arginine hydrochloride and lactobionate lyophilisates stabilised the antibody comparably or better than sucrose depending on antibody concentration. The best protein stability was found for mixtures of arginine hydrochloride/lactobionate/succinate with sucrose.The tertiary structures and conformational dynamics of transmembrane (TM) helical proteins are maintained by the interhelical interaction network in membranes, although it is complicated to analyze the underlying driving forces because the amino acid sequences can involve multiple and various types of interactions. To obtain insights into basal and common effects of the number of membrane-spanning segments and membrane cholesterol, we measured stabilities of helix bundles composed of simple TM helices (AALALAA)3 (1TM) and (AALALAA)3-G5-(AALALAA)3 (2TM). Association-dissociation dynamics for 1TM-1TM, 1TM-2TM, and 2TM-2TM pairs were monitored to compare stabilities of 2-, 3-, and 4-helical bundles, respectively, with single-pair fluorescence resonance energy transfer (sp-FRET) in liposome membranes. Both thermodynamic and kinetic stabilities of the helix bundles increased with a greater number of membrane-spanning segments in POPC. The presence of 30 mol% cholesterol strongly enhanced the formation of 1TM-1TM and 1TM-2TM bundles (~ - 9 kJ mol-1), whereas it only weakly stabilized the 2TM-2TM bundle (~ - 3 kJ mol-1). Fourier transform infrared-polarized attenuated total reflection (ATR-FTIR) spectroscopy revealed an ~30° tilt of the helix axis relative to bilayer normal for the 1TM-2TM pair in the presence of cholesterol, suggesting the formation of a tilted helix bundle to release high lateral pressure at the center of cholesterol-containing membranes. These results demonstrate that the number of membrane-spanning segments affects the stability and structure of the helix bundle, and their cholesterol-dependences. Such information is useful to understand the basics of folding and assembly of multispanning TM proteins.

IV pushes of phenylephrine may be used for patients with septic shock with the intent of rapidly achieving mean arterial pressure (MAP) goals. However, the clinical effectiveness and safety of this approach are unclear.

In patients with septic shock, is administration of a phenylephrine push before norepinephrine initiation associated with a higher incidence of hemodynamic stability?

This retrospective, multicenter cohort study included adult patients with septic shock initiated on norepinephrine. Propensity scores for initial phenylephrine push receipt were generated, and patients receiving an initial phenylephrine push were propensity score-matched 12 to those not receiving an initial phenylephrine push. The primary outcome was achievement of hemodynamic stability (defined as maintaining MAP of≥ 65mmHg for at least 6h without an increase in continuous infusion vasoactive agent dosage) within 3 and 12h of norepinephrine initiation.

Of 1,317 included patients, 181 received an initial phenylephrine pusindependently with higher ICU mortality. Caution is warranted when clinicians are considering the use of phenylephrine pushes in patients with septic shock.

OSA is common in chronic kidney disease (CKD) and may accelerate a decline in kidney function. It is not clear whether treatment of OSA with CPAP improves kidney function.

Does treatment with CPAP improve kidney function in patients with CKD and coexisting OSA?

A randomized, controlled, nonblinded, parallel clinical trial was performed of patients with stages 3 and 4 CKD and coexisting OSA comparing the effect of CPAP vsusual care on the estimated glomerular filtration rate (eGFR) and the urine albumin to creatinine ratio (ACR) over 12months.

Fifty-seven patients were enrolled and 30 were randomized to CPAP. They had moderately severe CKD (eGFR, 38.4 ± 1.5mL/min/1.73 m

) and significant OSA and nocturnal hypoxemia (oxygen desaturation index 23.9 events/h; interquartile range [IQR], 20.3 events/h; mean peripheral capillary oxygen saturation 89.5%; IQR, 1.7%); 60%had baseline albuminuria (ACR, > 3mg/mmol). No significant difference was found between CPAP and usual care in the change in eGFR and ACR over 12months.