The durability of oral diabetic medications: Time to A1c baseline and a review of common oral medications used by the primary care provider.

Introduction:Cost of generic medications has risen more in the past few years than any other time in history. While medical insurance covers much of these costs, health care professionals can better provide medications that have the longest duration of action when compared to placebo-treated controls. This will save health care costs and improve prescribing accuracy. Methods:Papers in PubMed were identified with keywords placebo. The study must be at least 2 years in length to evaluate the change in A1c over time. The primary endpoint was time to A1c neutrality (return of A1c to baseline at a maximum dose of single oral agent). A medication would be considered at neutrality if the 95% CI crossed baseline. Time to neutrality was averaged for each medication within the class and each summarized for class effect. Results:Effective therapy for the DPP-4 and sulfonylurea classes of medications are 3-4 years as compared to a 5-year time to A1c neutrality for metformin usage. In comparison, the projected time to A1c neutrality was approximately 6-8 years for rosiglitazone and pioglitazone. While only a few studies have been published in the SGLT-2 class of medication, the time to A1c neutrality was also 6-8 years with Canagliflozin and full dosage of Empagliflozin. Conclusion:Metformin appears to have a 5-year duration of effect before the A1c returns to baseline. The sulfonylureas and DPP-4 inhibitors class of medications have one of the shortest durability which ranges between 3.3 to 4.4 years. In contrast, the SGLT-2 class of medication and the TZD class of medications has a projected time to A1c neutrality from 6-8 years. Diabetic duration of therapy as compared to placebo should be listed with those medications tested so the provider can choose wisely

Development of a constitutive model for the compaction of recovered polyethylene terephthalate packages

[EN] To date, PET (polyethylene terephthalate) is the most widely used plastic in packaging and also one of the most recycled polymers worldwide. However, the high transport costs and stagnated prices of recycled PET undermine recycling process profits. Transport costs can lower through compaction, which is still not a completely wellknown process. Due to heterogeneous designs, the output density of the compaction process varies. This poses problems during equipment design, selection or operation processes as recovery costs sharply increase if the required density is not met. In this manuscript, the authors develop a constitutive model for the compaction of recovered PET packaging. This experimentally validated model, based on the elasto-plastic behaviour of PET packages, allows the output density range to be predicted according to the compression pressure during PET compaction. Unlike other generic compaction models that need more than two parameters, this model uses only one and better correlates with the experimental results. Unlike existing generic models, the model parameters have a physical meaning, which allows the influence of different factors on the compaction process to be assessed. Finally as a result of the model analysis, we provide some tips to enhance compaction equipment efficiency.Funding for open access charge: CRUE-Universitat Politecnica de Valencia.Sanchez-Caballero, S.; Sellés, M.; Peydro, MA.; H.P. Cherukuri (2021). Development of a constitutive model for the compaction of recovered polyethylene terephthalate packages. Waste Management. 133:89-98. https://doi.org/10.1016/j.wasman.2021.07.028S899813

MiR203 Mediates Subversion of Stem Cell Properties During Mammary Epithelial Differentiation via Repression of ΔNP63α and Promotes Mesenchymal-to-Epithelial Transition

During reproductive life, the mammary epithelium undergoes consecutive cycles of proliferation, differentiation and apoptosis. Doing so relies on the retained proliferative capacity, prolonged lifespan and developmental potency of mammary stem cells (MaSCs). ΔNp63α, the predominant TP63 isoform in mammary epithelia, is robustly expressed in MaSCs and is required for preservation of self-renewing capacity in diverse epithelial structures. However, the mechanism(s) underlying subversion of this activity during forfeiture of self-renewing capacity are poorly understood. MicroRNAs (miRNAs) govern critical cellular functions including stem cell maintenance, development, cell cycle regulation and differentiation by disrupting translation of target mRNAs. Data presented here indicate that expression of miR203, a miRNA that targets ΔNp63α and ΔNp63β is activated during luminal epithelial differentiation and that this pattern is observed in the murine mammary hierarchy. In addition, we present evidence that the transcription factor Zeb1 represses miR203 expression, thus enhancing ΔNp63α protein levels. Furthermore, ectopic miR203 suppresses ΔNp63α expression, proliferation and colony formation. The anti-clonogenic effects mediated by miR203 require suppression of ΔNp63α. In addition, ectopic miR203 promotes mesenchymal-to-epithelial transition and disrupts activities associated with epithelial stem cells. These studies support a model in which induction of miR203 mediates forfeiture of self-renewing capacity via suppression of ΔNp63α and may also have anti-tumorigenic activity through its reduction of EMT and cancer stem cell populations

Increased urinary nitrite, a marker of nitric oxide, in active inflammatory bowel disease.

BACKGROUND: Nitric oxide (NO) production is increased in inflammatory bowel disease (IBD), and measurement of NO metabolites may be useful for monitoring disease activity. AIMS AND OBJECTIVES: To characterise urinary nitrite levels, a stable metabolite of NO, in IBD and to evaluate its potential as a marker of disease activity. METHODS: Twelve-hour urinary nitrites were measured by the microplate assay method in 46 patients with IBD (active; n = 32). Urinary samples from 16 healthy individuals served as controls. RESULTS: Increased levels of urinary nitrites were found in patients with active IBD compared with those with inactive IBD. Twenty-eight out of 32 patients (87.5%) with active IBD had detectable levels of nitrite in their urine as compared with 2/14 (14.3%) patients with inactive IBD. None of the 16 healthy controls had detectable urinary nitrite. Twelve-hour urinary nitrite in active compared with inactive IBD: 5 0.7 versus 0.1+/-0.04 micromol (P < 0.05). There was good correlation between urinary nitrite and some markers of disease activity in IBD such as C-reactive protein and microalbuminuria but not with erythrocyte sedimentation rate. Conclusions: Increased levels of nitrite were detected in urine of patients with active IBD, consistent with increased NO synthesis. This simple assay may be exploited as a potential marker of disease activity in IBD

Clinical pharmacokinetics and pharmacodynamics of cerliponase alfa, enzyme replacement therapy for CLN2 disease by intracerebroventricular administration

Cerliponase alfa is recombinant human TPP1 delivered by intracerebroventricular (ICV) infusion for CLN2, a pediatric neurodegenerative disease caused by deficiency in lysosomal enzyme TPP1. We report the PK and PD of cerliponase alfa, the first ICV enzyme replacement therapy, characterized in a Phase 1/2 study. Escalating doses (30-300 mg every two weeks, Q2W) followed by 300 mg Q2W for ≥48 weeks were administered in 24 patients aged ≥3 years. Concentrations peaked in CSF at the end of ~4-hour ICV infusion and 8 hours thereafter in plasma. Plasma exposure was 300-1000 fold lower than in CSF, with no correlation in the magnitude of Cmax or AUC between body sites. There was no apparent accumulation in CSF or plasma exposure with Q2W dosing. Inter- and intra-patient variability of AUC, respectively, were 31-49% and 24% in CSF versus 59-103% and 80% in plasma. PK variability was not explained by baseline demographics, as gender, age, weight, and CLN2 disease severity score did not appear to impact CSF or plasma PK. No apparent correlation was noted between CSF or plasma PK and incidence of adverse events (pyrexia, hypersensitivity, seizure, and epilepsy) or presence of antidrug antibodies in CSF and serum. There was no relationship between magnitude of CSF exposure and efficacy (change in CLN2 score from baseline), indicating maximum benefit was obtained across the range of exposures with 300 mg Q2W. Data from this small trial of ultra-rare disease were leveraged to adequately profile cerliponase alfa and support 300 mg ICV Q2W for CLN2 treatment

Role of Acute and Chronic Glycemic Control on COVID-19 Severity and Length of Hospital Stay in Hospitalized Patients

COVID-19 patients with diabetes have greater morbidity and mortality. Glycated hemoglobin (A1c) indicates chronic glycemic control and is considered a standard of care in the diagnosis and management of diabetes. Whereas, fasting blood glucose (FBG) indicates acute glycemic control and is also recommended option to diagnose diabetes. PURPOSE: The purpose of this study was to determine the effects of acute and chronic glycemic control on severity and length of hospital stay among hospitalized patients with COVID-19. METHODS: This retrospective study used medical records from patients admitted to the University Medical Center, El Paso, TX with COVID-19 (n=364; age 60.0 ± 0.8 years; BMI 30.3 ± 0.4 kg/m²). Chronic and acute glycemia were assessed by A1c and FBG at the time of hospitalization. The severity of the COVID-19 outcome was measured by quick sepsis-related organ failure assessment (qSOFA) and the length of hospitalization was determined by the number of days spent in the hospital. Patients were categorized into 4 groups based on chronic and acute glycemia defining diabetes status. G1: diagnosed no diabetes by both A1c and FBG (A1c\u3c6.5%, FBG\u3c126 mg/dl), G2: diagnosed diabetes by FBG but no diabetes by A1c (A1c\u3c6.5%, FBG≥126 mg/dl), G3: diagnosed diabetes by A1c but no diabetes by FBG (A1c≥6.5%, FBG\u3c126 mg/dl), and G4: diagnosed diabetes by both A1c and FBG (A1c≥6.5%, FBG≥126 mg/dl). One-way ANOVA with posthoc Tucky test was used to determine the statistical differences among groups. RESULTS: Patients diagnosed as diabetes by FBG but not A1c (G2) had a greater COVID-19 severity, measured by qSOFA, compared with the other 3 groups. (G2: 0.61 ± 0.14 vs. G1: 0.24 ± 0.05; P\u3c0.004, G2: 0.61 ± 0.14 vs. G3: 0.16 ± 0.06; P\u3c0.001, and G2: 0.61 ± 0.14 vs. G4: 0.31 ± 0.04; P\u3c0.015). Additionally, this study found a greater length of hospitalization in G2 to compare with G1 (G2: 12.91 ± 1.99 vs. G1: 6.36 ± 0.56 days; P\u3c0.002). CONCLUSION: Patients with acute glycemia represent higher severity and longer length of hospital stay among hospitalized COVID-19 patients. Management of FBG should be considered in the treatment of hospitalized COVID-19 patients

Transitional B cell cytokines predict renal allograft outcomes

Early immunological biomarkers that predict rejection and chronic allograft loss are needed to inform preemptive therapy and improve long-term outcomes. Here, we prospectively examined the ratio of interleukin-10 (IL-10) to tumor necrosis factor–α (TNFα) produced by transitional-1 B cells (T1B) 3 months after transplantation as a predictive biomarker for clinical and subclinical renal allograft rejection and subsequent clinical course. In both Training (n = 162) and Internal Validation (n = 82) Sets, the T1B IL-10/TNFα ratio 3 months after transplantation predicted both clinical and subclinical rejection anytime in the first year. The biomarker also predicted subsequent late rejection with a lead time averaging 8 months. Among biomarker high-risk patients, 60% had early rejection, of which 48% recurred later in the first posttransplant year. Among high-risk patients without early rejection, 74% developed rejection later in the first year. In contrast, only 5% of low-risk patients had early and 5% late rejection. The biomarker also predicted rejection in an External Validation Set (n = 95) and in key patient subgroups, confirming generalizability. Biomarker high-risk patients exhibited progressively worse renal function and decreased 5-year graft survival compared to low-risk patients. Treatment of B cells with anti-TNFα in vitro augmented the IL-10/TNFα ratio, restored regulatory activity, and inhibited plasmablast differentiation. To conclude, the T1B IL-10/TNFα ratio was validated as a strong predictive biomarker of renal allograft outcomes and provides a rationale for preemptive therapeutic intervention with TNF blockade

A primer to common major gastrointestinal post-surgical anatomy on CT—a pictorial review

The post-operative abdomen can be challenging and knowledge of normal post-operative anatomy is important for diagnosing complications. The aim of this pictorial essay is to describe a few selected common, major gastrointestinal surgeries, their clinical indications and depict their normal post-operative computed tomography (CT) appearance. This essay provides some clues to identify the surgeries, which can be helpful especially when surgical history is lacking: recognition of the organ(s) involved, determination of what was resected and familiarity with the type of anastomoses used