Surgical and non-surgical interventions for primary and salvage treatment of growth hormone-secreting pituitary adenomas in adults.

BACKGROUND: Growth hormone (GH)-secreting pituitary adenoma is a severe endocrine disease. Surgery is the currently recommended primary therapy for patients with GH-secreting tumours. However, non-surgical therapy (pharmacological therapy and radiation therapy) may be performed as primary therapy or may improve surgical outcomes. OBJECTIVES: To assess the effects of surgical and non-surgical interventions for primary and salvage treatment of GH-secreting pituitary adenomas in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, WHO ICTRP, and ClinicalTrials.gov. The date of the last search of all databases was 1 August 2022. We did not apply any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of more than 12 weeks' duration, reporting on surgical, pharmacological, radiation, and combination interventions for GH-secreting pituitary adenomas in any healthcare setting. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for relevance, screened for inclusion, completed data extraction, and performed a risk of bias assessment. We assessed studies for overall certainty of the evidence using GRADE. We estimated treatment effects using random-effects meta-analysis. We expressed results as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) for continuous outcomes, or in descriptive format when meta-analysis was not possible. MAIN RESULTS: We included eight RCTs that evaluated 445 adults with GH-secreting pituitary adenomas. Four studies reported that they included participants with macroadenomas, one study included a small number of participants with microadenomas. The remaining studies did not specify tumour subtypes. Studies evaluated surgical therapy alone, pharmacological therapy alone, or combination surgical and pharmacological therapy. Methodological quality varied, with many studies providing insufficient information to compare treatment strategies or accurately judge the risk of bias. We identified two main comparisons, surgery alone versus pharmacological therapy alone, and surgery alone versus pharmacological therapy and surgery combined. Surgical therapy alone versus pharmacological therapy alone Three studies with a total of 164 randomised participants investigated this comparison. Only one study narratively described hyperglycaemia as a disease-related complication. All three studies reported adverse events, yet only one study reported numbers separately for the intervention arms; none of the 11 participants were observed to develop gallbladder stones or sludge on ultrasonography following surgery, while five of 11 participants experienced any biliary problems following pharmacological therapy (RR 0.09, 95% CI 0.01 to 1.47; 1 study, 22 participants; very low-certainty evidence). Health-related quality of life was reported to improve similarly in both intervention arms during follow-up. Surgery alone compared to pharmacological therapy alone may slightly increase the biochemical remission rate from 12 weeks to one year after intervention, but the evidence is very uncertain; 36/78 participants in the surgery-alone group versus 15/66 in the pharmacological therapy group showed biochemical remission. The need for additional surgery or non-surgical therapy for recurrent or persistent disease was described for single study arms only. Surgical therapy alone versus preoperative pharmacological therapy and surgery Five studies with a total of 281 randomised participants provided data for this comparison. Preoperative pharmacological therapy and surgery may have little to no effect on the disease-related complication of a difficult intubation (requiring postponement of surgery) compared to surgery alone, but the evidence is very uncertain (RR 2.00, 95% CI 0.19 to 21.34; 1 study, 98 participants; very low-certainty evidence). Surgery alone may have little to no effect on (transient and persistent) adverse events when compared to preoperative pharmacological therapy and surgery, but again, the evidence is very uncertain (RR 1.23, 95% CI 0.75 to 2.03; 5 studies, 267 participants; very low-certainty evidence). Concerning biochemical remission, surgery alone compared to preoperative pharmacological therapy and surgery may not increase remission rates up until 16 weeks after surgery; 23 of 134 participants in the surgery-alone group versus 51 of 133 in the preoperative pharmacological therapy and surgery group showed biochemical remission. Furthermore, the very low-certainty evidence did not suggest benefit or detriment of preoperative pharmacological therapy and surgery compared to surgery alone for the outcomes 'requiring additional surgery' (RR 0.48, 95% CI 0.05 to 5.06; 1 study, 61 participants; very low-certainty evidence) or 'non-surgical therapy for recurrent or persistent disease' (RR 1.22, 95% CI 0.65 to 2.28; 2 studies, 100 participants; very low-certainty evidence). None of the included studies measured health-related quality of life. None of the eight included studies measured disease recurrence or socioeconomic effects. While three of the eight studies reported no deaths to have occurred, one study mentioned that overall, two participants had died within five years of the start of the study. AUTHORS' CONCLUSIONS: Within the context of GH-secreting pituitary adenomas, patient-relevant outcomes, such as disease-related complications, adverse events and disease recurrence were not, or only sparsely, reported. When reported, we found that surgery may have little or no effect on the outcomes compared to the comparator treatment. The current evidence is limited by the small number of included studies, as well as the unclear risk of bias in most studies. The high uncertainty of evidence significantly limits the applicability of our findings to clinical practice. Detailed reporting on the burden of recurrent disease is an important knowledge gap to be evaluated in future research studies. It is also crucial that future studies in this area are designed to report on outcomes by tumour subtype (that is, macroadenomas versus microadenomas) so that future subgroup analyses can be conducted. More rigorous and larger studies, powered to address these research questions, are required to assess the merits of neoadjuvant pharmacological therapy or first-line pharmacotherapy.

Cost-effectiveness of postoperative imaging surveillance strategies for nonfunctional pituitary adenomas after resection with curative intent.

OBJECTIVE: The aim of this study was to determine an optimal follow-up imaging surveillance strategy in terms of cost-effectiveness after resection of nonfunctioning pituitary adenomas with curative intent. METHODS: An individual-level state-transition microsimulation model was used to simulate costs and outcomes associated with three postoperative imaging strategies over a lifetime time horizon: 1) annual MRI surveillance, 2) tapered MRI surveillance (annual surveillance for 5 years followed by surveillance every 2 years), and 3) personalized surveillance (annual surveillance for 5 years followed by surveillance every 2 years when MRI shows remnant disease/postoperative changes, and surveillance at 7, 10, and 15 years for disease-free MRI). Transition probabilities, utilities, and costs were estimated from recent published data and discounted by 3% annually. Model outcomes included lifetime costs (2022 US dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: Under base case assumptions, annual surveillance yielded higher costs and lower health effects (QALYs) compared with the tapered and personalized surveillance strategies (dominated). Personalized surveillance demonstrated an additional 0.1 QALY at additional cost ($1298) compared with tapered surveillance (7.7 QALYs at a cost of $12,862). The ICER was $11,793/QALY. The optimal decision was most sensitive to the probability of postoperative changes on MRI after surgery and MRI cost. Accounting for parameter uncertainty, personalized surveillance had a higher probability of being a cost-effective surveillance option compared with the alternative strategies at 79%. CONCLUSIONS: Using standard cost-effectiveness thresholds in the US ($100,000/QALY), personalized surveillance that accounted for remnant disease or postoperative changes on MRI was cost-effective compared with alternative surveillance strategies.

Pancreas-derived DPP4 is not essential for glucose homeostasis under metabolic stress.

Mice systemically lacking dipeptidyl peptidase-4 (DPP4) have improved islet health, glucoregulation, and reduced obesity with high-fat diet (HFD) feeding compared to wild-type mice. Some, but not all, of this improvement can be linked to the loss of DPP4 in endothelial cells (ECs), pointing to the contribution of non-EC types. The importance of intra-islet signaling mediated by α to ß cell communication is becoming increasingly clear; thus, our objective was to determine if ß cell DPP4 regulates insulin secretion and glucose tolerance in HFD-fed mice by regulating the local concentrations of insulinotropic peptides. Using ß cell double incretin receptor knockout mice, ß cell- and pancreas-specific Dpp4-/- mice, we reveal that ß cell incretin receptors are necessary for DPP4 inhibitor effects. However, although ß cell DPP4 modestly contributes to high glucose (16.7 mM)-stimulated insulin secretion in isolated islets, it does not regulate whole-body glucose homeostasis.

Post-operative surveillance for somatotroph, lactotroph and non-functional pituitary adenomas after curative resection: a systematic review.

CONTEXT: Pituitary tumors are the third most common brain tumor and yet there is no standardization of the surveillance schedule and assessment modalities after transsphenoidal surgery. EVIDENCE ACQUISITION: OVID, EMBASE and the Cochrane Library databases were systematically screened from database inception to March 5, 2020. Inclusion and exclusion criteria were designed to capture studies examining detection of pituitary adenoma recurrence in patients 18 years of age and older following surgical resection with curative intent. EVIDENCE SYNTHESIS: A total of 7936 abstracts were screened, with 812 articles reviewed in full text and 77 meeting inclusion criteria for data extraction. A pooled analysis demonstrated recurrence rates at 1 year, 5 years and 10 years for non-functioning pituitary adenomas (NFPA; N = 3533 participants) were 1%, 17%, and 33%, for prolactin-secreting adenomas (PSPA; N = 1295) were 6%, 21%, and 28%, and for growth-hormone pituitary adenomas (GHPA; N = 1257) were 3%, 8% and 13%, respectively. Rates of recurrence prior to 1 year were 0% for NFPA, 1-2% for PSPA and 0% for GHPA. The mean time to disease recurrence for NFPA, PSPA and GHPA were 4.25, 2.52 and 4.18 years, respectively. CONCLUSIONS: This comprehensive review of the literature quantified the recurrence rates for commonly observed pituitary adenomas after transsphenoidal surgical resection with curative intent. Our findings suggest that surveillance within 1 year may be of low yield. Further clinical trials and cohort studies investigating cost-effectiveness of surveillance schedules and impact on quality of life of patients under surveillance will provide further insight to optimize follow-up.

Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, modulates glucose production, and when absent influences NAFLD progression.

Elevated circulating dipeptidyl peptidase-4 (DPP4) is a biomarker for liver disease, but its involvement in gluconeogenesis and metabolic associated fatty liver disease progression remains unclear. Here, we identified that DPP4 in hepatocytes but not TEK receptor tyrosine kinase-positive endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4-/-) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of Dpp4-/- mice displayed enrichment for inflammasome, p53, and senescence programs compared with littermate controls. High-fat, high-cholesterol feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling. Moreover, in a lean mouse model of severe nonalcoholic fatty liver disease, phosphatidylethanolamine N-methyltransferase mice, we observed a 4-fold increase in circulating DPP4, in contrast with previous findings connecting DPP4 release and obesity. Last, we evaluated DPP4 levels in patients with hepatitis C infection with dysglycemia (Homeostatic Model Assessment of Insulin Resistance > 2) who underwent direct antiviral treatment (with/without ribavirin). DPP4 protein levels decreased with viral clearance; DPP4 activity levels were reduced at long-term follow-up in ribavirin-treated patients; but metabolic factors did not improve. These data suggest elevations in DPP4 during hepatitis C infection are not primarily regulated by metabolic disturbances.

HCV infection characteristics, treatment uptake and outcomes in patient with diabetes mellitus.

BACKGROUND: The interplay between HCV, DM, and DAA therapy is poorly understood. We compared HCV infection characteristics, treatment uptake, and treatment outcomes in patients with and without DM.  METHODS: A retrospective cohort study was conducted using data from The Ottawa Hospital Viral Hepatitis Program. Statistical comparisons between diabetes and non-diabetes were made using χ2 and t-tests. Logistic regression analyses were performed to assess predictors of DM and SVR. RESULTS: One thousand five hundred eighty-eight HCV patients were included in this analysis; 9.6% had DM. Patients with DM were older and more likely to have cirrhosis. HCC and chronic renal disease were more prevalent in the DM group. Treatment uptake and SVR were comparable between groups. Regression analysis revealed that age and employment were associated with achieving SVR. Post-SVR HCC was higher in DM group. CONCLUSION: The high prevalence of DM in our HCV cohort supports screening. Further assessment is required to determine if targeted, early DAA treatment reduces DM onset, progression to cirrhosis and HCC risk. Further studies are needed to determine if optimization of glycemic control in this population can lead to improved liver outcomes.

Cost-effectiveness of direct surgery versus preoperative octreotide therapy for growth-hormone secreting pituitary adenomas.

PURPOSE: The objective of this study was to compare the cost-effectiveness of preoperative octreotide therapy followed by surgery versus the standard treatment modality for growth-hormone secreting pituitary adenomas, direct surgery (that is, surgery without preoperative treatment) from a public third-party payer perspective. METHODS: We developed an individual-level state-transition microsimulation model to simulate costs and outcomes associated with preoperative octreotide therapy followed by surgery and direct surgery for patients with growth-hormone secreting pituitary adenomas. Transition probabilities, utilities, and costs were estimated from recent published data and discounted by 3% annually over a lifetime time horizon. Model outcomes included lifetime costs [2020 United States (US) Dollars], quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). RESULTS: Under base case assumptions, direct surgery was found to be the dominant strategy as it yielded lower costs and greater health effects (QALYs) compared to preoperative octreotide strategy in the second-order Monte Carlo microsimulation. The ICER was most sensitive to probability of remission following primary therapy and duration of preoperative octreotide therapy. Accounting for joint parameter uncertainty, direct surgery had a higher probability of demonstrating a cost-effective profile compared to preoperative octreotide treatment at 77% compared to 23%, respectively. CONCLUSIONS: Using standard benchmarks for cost-effectiveness in the US ($100,000/QALY), preoperative octreotide therapy followed by surgery may not be cost-effective compared to direct surgery for patients with growth-hormone secreting pituitary adenomas but the result is highly sensitive to initial treatment failure and duration of preoperative treatment.

A Patient-Inspired Quality Improvement Initiative for Pituitary Adenoma Care.

BACKGROUND: Pituitary adenomas (PAs) are common and often require complex multidisciplinary care with multiple specialists. This may result in a healthcare system that is challenging for patients to navigate. Audits of care at our institution revealed opportunities for improvement to better align care with patients' needs. METHODS: A quality improvement initiative that incorporated a patient advisory committee of patients who had received treatment for PA at our center and their family members were used to help identify opportunities for improvement. The patient-identified gaps in care included the need to coordinate and minimize appointments and the desire for better communication and education. Based on this information, changes were implemented to the pituitary program, including increasing access to the Multidisciplinary Clinic and developing a standardized and centralized triage process. RESULTS: A pre- and post-intervention analysis consisting of retrospective chart reviews revealed that these changes had an impact on wait times for first assessment, and a significant shift in the location of this first visit - with a larger proportion of patients being seen in the Multidisciplinary Clinic after an intervention. CONCLUSIONS: We demonstrate that patient involvement, beyond individual patient-physician interactions, can lead to meaningful and observable changes, and can improve the quality of care for PA.

Determinants of Poor Glycemic Control in Patients with Kidney Transplants: A Single-Center Retrospective Cohort Study in Canada.

BACKGROUND: Kidney transplant immunosuppressive medications are known to impair glucose metabolism, causing worsened glycemic control in patients with pre-transplant diabetes mellitus (PrTDM) and new onset of diabetes after transplant (NODAT). OBJECTIVES: To determine the incidence, risk factors, and outcomes of both PrTDM and NODAT patients. DESIGN: This is a single-center retrospective observational cohort study. SETTING: The Ottawa Hospital, Ontario, Canada. PARTICIPANT: A total of 132 adult (>18 years) kidney transplant patients from 2013 to 2015 were retrospectively followed 3 years post-transplant. MEASUREMENTS: Patient characteristics, transplant information, pre- and post-transplant HbA1C and random glucose, follow-up appointments, complications, and readmissions. METHODS: We looked at the prevalence of poor glycemic control (HbA1c >8.5%) in the PrTDM group before and after transplant and compared the prevalence, follow-up appointments, and rate of complications and readmission rates in both the PrTDM and NODAT groups. We determined the risk factors of developing poor glycemic control in PrTDM patients and NODAT. Student t-test was used to compare means, chi-squared test was used to compare percentages, and univariate analysis to determine risk factors was performed by logistical regression. RESULTS: A total of 42 patients (31.8%) had PrTDM and 12 patients (13.3%) developed NODAT. Poor glycemic control (HbA1c >8.5%) was more prevalent in the PrTDM (76.4%) patients compared to those with NODAT (16.7%; P < .01). PrTDM patients were more likely to receive follow-up with an endocrinologist (P < .01) and diabetes nurse (P < .01) compared to those with NODAT. There were no differences in the complication and readmission rates for PrTDM and NODAT patients. Receiving a transplant from a deceased donor was associated with having poor glycemic control, odds ratio (OR) = 3.34, confidence interval (CI = 1.08, 10.4), P = .04. Both patient age, OR = 1.07, CI (1.02, 1.3), P < .01, and peritoneal dialysis prior to transplant, OR = 4.57, CI (1.28, 16.3), P = .02, were associated with NODAT. LIMITATIONS: Our study was limited by our small sample size. We also could not account for any diabetes screening performed outside of our center or follow-up appointments with family physicians or community endocrinologists. CONCLUSION: Poor glycemic control is common in the kidney transplant population. Glycemic targets for patients with PrTDM are not being met in our center and our study highlights the gap in the literature focusing on the prevalence and outcomes of poor glycemic control in these patients. Closer follow-up and attention may be needed for those who are at risk for worse glycemic control, which include older patients, those who received a deceased donor kidney, and/or prior peritoneal dialysis.

CONTEXTE: Les médicaments immunosuppresseurs prescrits à la suite d'une transplantation rénale sont connus pour altérer le métabolisme du glucose, rendant plus difficile le contrôle de la glycémie chez les patients diabétiques avant l'intervention (DbAvT ­ diabétiques avant la transplantation) et chez les patients devenus diabétiques après l'intervention (NDbApT ­ nouveaux diabétiques après la transplantation). OBJECTIF: Déterminer l'incidence d'un contrôle de la glycémie déficient, les facteurs de risque et les résultats chez les patients DbAvT et NDbApT. TYPE D'ÉTUDE: Il s'agit d'une étude de cohorte rétrospective et observationnelle qui s'est tenue dans un seul center. CADRE: L'hôpital d'Ottawa (Ontario), au Canada. SUJETS: Les adultes receveurs d'une greffe rénale entre 2013 et 2015 (n=132) ont été suivis rétrospectivement sur une période de trois ans post-transplantation. MESURES: Les caractéristiques des patients, les informations relatives à la greffe, les taux d'HbA1C et la glycémie pré- et post-transplantation, les rendez-vous de suivi, les complications et les réadmissions. MÉTHODOLOGIE: Nous nous sommes d'abord penchés sur la prévalence d'un contrôle glycémique déficient (HbA1c >8,5 %) dans le groupe DbAvT avant et après la greffe, puis nous avons comparé la prévalence, les rendez-vous de suivi et les taux de complications et de réadmission pour les deux groupes. Nous avons déterminé les facteurs de risque d'un mauvais contrôle glycémique chez les patients DbAvT et NDbApT. Les moyennes ont été comparées à l'aide du test t de Student, et le test du chi carré a servi à comparer les pourcentages. L'analyze univariée pour déterminer les facteurs de risque a été effectuée par régression logistique. RÉSULTATS: Parmi les 132 patients étudiés, 42 (31,8 %) étaient DbAvT et 12 (13,3 %) le sont devenus après l'intervention (NDbApT). La prévalence d'un mauvais contrôle de la glycémie (HbA1c >8,5 %) était plus élevée chez les patients DbAvT que chez les patients NDbApT (76,4 % contre 16,7 %; p<0,01). Les patients DbAvT étaient plus susceptibles d'être suivis par un endocrinologue (p<0.01) et une infirmière spécialisée en diabète (p<0.01) comparativement aux patients NDbApT. Aucune différence n'a été observée entre les deux groupes pour les taux de complications et de réadmission. Un greffon provenant d'un donneur décédé a été associé à un contrôle glycémique déficient (RC=3,34; IC 95 :1,08-10,4; p=0,04). Le développement d'un NDbApT a été associé à la fois à l'âge du patient (RC=1,07 IC 95: 1,02-1,3; p<0,01) et à un traitement de dialyze péritonéale (OR=4,57; IC 95: 1,28-16,3; p=0,02) avant la greffe. LIMITES: Nos résultats sont limités par la faible taille de l'échantillon. Nous n'avons pu rendre compte des dépistages effectués hors de notre center ni des rendez-vous de suivi avec un médecin de famille ou un endocrinologue dans la communauté. CONCLUSION: Un contrôle glycémique déficient est fréquent chez les patients greffés d'un rein. Les cibles glycémiques des patients DbAvT ne sont pas rencontrées dans notre center et notre étude met en lumière les lacunes de la littérature sur la prévalence et les résultats d'un mauvais contrôle glycémique chez ces patients. Un suivi plus étroit et une plus grande attention pourraient être nécessaires pour les patients susceptibles de voir leur contrôle glycémique se détériorer, notamment les personnes âgées, les receveurs d'un rein provenant d'un donneur décédé et les patients traités par dialyze péritonéale avant l'intervention.

Association between hepatitis C antiviral treatment and diabetes mellitus: A case series.

The hepatitis C virus (HCV) infects 185 million people worldwide, and diabetes mellitus (DM) affects 415 million. There has long been a possible association between DM and liver outcomes for patients with HCV infection. We present two cases of worsening glucose resistance and one case of emergent type 1 DM after completion of HCV. The complex interactions between HCV infection and both type 1 and type 2 DM have not yet been elucidated. In addition, consequences and side effects of treatment options for HCV have not been fully studied in the diabetic population. Our case series illustrates a potential complication of HCV treatment, which may warrant additional consideration prior to initiation of therapy as well as monitoring and surveillance post-cure.

Le virus de l'hépatite C (VHC) infecte 185 millions de personnes dans le monde, et le diabète en atteint 415 millions. On sait depuis longtemps qu'il y a une association possible entre le diabète et les affections hépatiques chez les patients infectés par le VHC. Les auteurs présentent deux cas d'aggravation de la résistance au glucose et un cas d'apparition du diabète de type 1 après la fin du traitement du VHC. Les interactions complexes entre l'infection par le VCH et le diabète de type 1 et de type 2 ne sont pas encore établies. De plus, les conséquences et les effets secondaires des possibilités de traitement du VHC n'ont pas fait l'objet d'études approfondies dans la population diabétique. La présente série de cas fait état d'une complication potentielle du traitement du VHC, qui pourrait justifier un examen supplémentaire avant le début du traitement, de même qu'un contrôle et une surveillance par la suite.

Choice of crystalloid fluid in the treatment of hyperglycemic emergencies: a systematic review protocol.

BACKGROUND: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are life-threatening complications of diabetes mellitus which require prompt treatment with large volume crystalloid fluid administration. A variety of crystalloid fluids is currently available for use and differs in their composition and ion concentrations. While there are potential pros and cons for different crystalloid fluids, it remains unknown if any particular fluid confers a clinical outcome benefit over others in the treatment of hyperglycemic emergencies. METHODS: A systematic search of MEDLINE, Embase, and the Cochrane Library of Systematic Reviews will be conducted to identify eligible studies, which will include observational and interventional studies involving adult and pediatric patients admitted to the hospital with either DKA or HHS. The interventions will include intravenous treatment with 0.9% saline versus other buffered (Ringer's lactate, Hartmann's, etc.), and non-buffered (0.45% saline) crystalloid fluids. The primary outcome is mortality at the latest follow-up time point. Secondary outcomes will include mortality at specific time points, length of hospital stay, development of acute kidney injury, requirement for renal replacement therapy, altered level of consciousness, and the time to normalization of several serum biochemical parameters. Where appropriate, meta-analyses will be performed for the outcomes and conducted separately for adult and pediatric patient populations. DISCUSSION: DKA and HHS are dangerous complications of diabetes mellitus and account for significant morbidity and mortality. Given the importance of crystalloid fluid administration in the management of these conditions, a systematic synthesis of the existing evidence base will identify potential evidence gaps and may help guide future clinical practice.

Evaluation of Safety and Effectiveness of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Switch Followed by Ledipasvir/Sofosbuvir HCV Therapy in HIV-HCV Coinfection.

BACKGROUND: We conducted a pilot study assessing the feasibility, efficacy, and safety of a simplified combination HIV antiretroviral and hepatitis C virus (HCV) antiviral regimen in HIV-HCV coinfection. METHODS: Participants on suppressive antiretrovirals and HCV genotype 1 infection were switched to single-tablet daily-dosed elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) and 1 month later initiated single-tablet-regimen daily-dosed ledipasvir-sofosbuvir for 12 weeks. E/C/F/TAF was continued during HCV treatment and for 12 weeks after. RESULTS: Twenty-six individuals were screened, 25 enrolled, and 23 completed all HIV and HCV treatment. Participants were predominantly male, with a mean age (SD) of 55 (7.5) years. The median transient elastography score (interquartile range [IQR]) was 5.9 (5.3 to 7.6) kPa, and the mean CD4 count (SD) was 579 (223) cells/µL. The median adherence to HCV medications, assessed by pill count, was 100% (95% confidence interval [CI], 100%-100%), and HIV ranged from 99% to 100% (100%; 95% CI, 90%-100%) over the 7-month study duration. HIV undetectability was maintained in all but 1 participant enrolled with unsuspected multiclass resistance. Treatment was well tolerated, with no study medication modification due to adverse events and no serious adverse event related to the study drug. All participants achieved sustained virological response. The mean CD4 count (SD) increased to 673 (361) cells/µL, and the fibrosis score (IQR) declined to 5.2 (4.4 to 7.4) kPa by week 12 after HCV treatment. There was no treatment effect on glucose metabolism. Cholesterol increased during and after treatment. CONCLUSIONS: Provision of this 2-tablet daily HIV-HCV regimen is feasible, well tolerated, and safe, avoids drug-drug interactions between HIV and HCV medications, maintains HIV suppression in the absence of drug resistance, and is highly curative of HCV.

Cardiovascular Outcomes in Autonomous Cortisol Secretion and Nonfunctioning Adrenal Adenoma: A Systematic Review.

There is growing evidence that autonomous cortisol secretion (ACS), previously known as subclinical Cushing syndrome, is associated with greater prevalence of cardiovascular (CV) risk factors. However, it is unclear whether ACS is associated with greater prevalence of CV outcomes compared with nonfunctioning adrenal adenomas (NFAAs). The objective of this study is to evaluate CV outcomes and CV risk factors in patients with adrenal adenoma with ACS compared with NFAA. A literature review was performed in Embase, Medline, Cochrane Library, and reference lists within selected articles. The study protocol was registered with PROSPERO. A literature search yielded six studies that met the inclusion criteria. Studies varied in their definitions of ACS and CV outcomes. Two retrospective longitudinal studies further demonstrated higher incidence of new CV events (ACS 16.7% vs NFAA 6.7%, P = 0.04) and higher CV mortality in patients with ACS (ACS 22.6% vs 2.5%, P = 0.02). The prevalence of CV outcomes in ACS was more than three times greater than in patients with NFAA. Three of five studies found that ACS was associated with higher prevalence of diabetes and hypertension. There was no difference in dyslipidemia or body mass index demonstrated in any study. There is heterogeneity among the few studies evaluating the association between ACS and CV outcomes. Although these studies suggest a higher risk of CV outcomes in patients with ACS, many did not adjust for known confounders. Larger, high quality, prospective studies are needed to evaluate this association and to identify modifiable risk factors.

Hepatitis C Direct Acting Antivirals and Ribavirin Modify Lipid but not Glucose Parameters.

Chronic hepatitis C (HCV) infection perturbs lipid and glucose metabolism. The influenceof direct acting antiviral (DAA) treatment and ribavirin on these measures was evaluated.Furthermore, the effect of HCV cure on these parameters was assessed. Participants were allocatedto one of three 12-week treatment groups: non-cirrhotic genotype 1aparitaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) plus ribavirin; non-cirrhotic 1b-PrOD;compensated cirrhotic 1a or 1b-PrOD plus ribavirin. Fasting insulin, glucose, lipid andapolipoprotein measures were assessed at baseline, Treatment Weeks 4 and 12, and 12 and 24 weekspost-dosing. Twenty-three of 24 participants achieved SVR (PP= 23/24, 96% SVR). Overall, totalcholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels all increased intreatment and post-dosing. However, LDL-C levels decreased during treatment in ribavirinrecipients. Fasting glucose, insulin, and HOMA-IR were unchanged during treatment and 12 weekspost-treatment. By 12 weeks post-treatment, controlled attenuation parameter (CAP) scores, ameasure of steatosis, increased from baseline (mean 30.3 ± 63.5, p = 0.05). This regimen was safe andhighly effective and did not influence glucose metabolism. Ribavirin exposure may mitigate someon-treatment lipid changes. Further mechanistic studies are needed to understand how ribavirinimpacts lipid pathways, as there could be therapeutic implications. The metabolic pathophysiologyof increased CAP score with HCV treatment requires explanation.

Improving Glycemic Control in Adults and Children With Type 1 Diabetes With the Use of Smartphone-Based Mobile Applications: A Systematic Review.

OBJECTIVES: Management of type 1 diabetes is often challenging. Smartphone mobile applications (apps) may provide additional support and help to improve glycemic control and clinical outcomes. The objectives of this study were to examine the literature evaluating the use of mobile apps (stand-alone and text messaging/feedback) in type 1 diabetes and to review top-rated mobile apps applicable to type 1 diabetes. METHODS: Medline, Cochrane and Embase databases were systematically searched to identify studies published from inception to February 2018. Top-rated relevant apps from Google Play Store and Apple App Store were reviewed in July 2017. RESULTS: The literature search yielded 3,462 studies. Of these studies, 9 evaluated the stand-alone apps; 3 showed significant improvement in glycated hemoglobin (A1C) levels (0.5%, p<0.05, 0.57%, p<0.05, and 0.58%, p=0.02); 3 demonstrated improved adherence to glucose monitoring; and 1 study demonstrated a reduction in hypoglycemic events (glucose<3.0 mmol/L) in 6 of 10 participants who completed the study. Also, 5 studies evaluated a mobile app plus text-messaging/feedback system. Only 1 showed a significant reduction in severe hypoglycemic events (mobile app+text, IQR 0.33, 95% CI 0.17 to 0.63; vs. control, IQR 2.29, 95% CI 1.80 to 2.91), while another single study demonstrated a reduction in median glycated hemoglobin levels (0.3%; p<0.001). Most top-rated mobile apps logged parameters relevant to diabetes management, and some provided graphic analysis and set reminders. CONCLUSIONS: This study highlights the need for larger and longer studies to explore the efficacy of apps to optimize outcomes in type 1 diabetes, the populations that would benefit most from these tools and the resources needed to support mobile apps plus text-messaging/feedback systems.

Direct-acting antiviral hepatitis C virus treatment perturbation of the metabolic milieu.

OBJECTIVE: Hepatitis C virus (HCV), cirrhosis, and HCV medications including direct-acting antivirals (DAAs) ±ribavirin may all influence the metabolic milieu. While interferon-based regimens improve glucose tolerance, evidence is limited on DAAs. Cases of elevated lactate have recently been reported in patients treated with DAAs, and lactic acidosis is a known complication of antivirals used to treat hepatitis B virus and HIV. PATIENTS AND METHODS: Measures were evaluated at baseline, week 4, end of treatment, and 12-24 weeks after treatment. Mixed-effects modeling was used to determine factors influencing glucose and lactate over time. RESULTS: In total, 442 patients were treated (mean age 56, 65% male, 72% genotype 1, 48% cirrhotic). Glucose did not change on or after DAA treatment from baseline (P=0.51) aside from those with untreated diabetes, which declined (P=0.02). Overall, there was a decline in lactate following HCV treatment (mean 2.4-2.1 mmol/l; P<0.001). Lactate initially increased on treatment and then decreased after treatment completion in male patients treated with ribavirin. This pattern was not observed in other groups. There was no evidence of lactic acidosis with HCV nucleotide use. CONCLUSION: Distinct glucose and lactate trajectories were identified without evidence of DAA metabolic toxicity. HCV treatment does not improve random glucose levels aside from perhaps in untreated diabetic patients.

Antibiotic exposure and risk of weight gain and obesity: protocol for a systematic review.

BACKGROUND: The prevalence of obesity is increasing worldwide, and there is growing interest in better delineating the role of the human gut microbiome in this phenomenon. Obesity-specific gut microbiome features have been observed in both human and animal studies, and these variations appear to play a causative role in increasing body weight. There is evidence that antibiotics can modify the composition and diversity of the gut microbiome and that this may contribute to body weight changes. The primary objective of the proposed systematic review is to evaluate and synthesize the existing evidence evaluating the possible association between antibiotic use, weight gain, and obesity. METHODS: A comprehensive search of the MEDLINE and EMBASE databases will be performed. Both randomized and non-randomized studies (excluding case reports) in neonates, children, adults, and pregnant women will be included. The exposure of interest is antibiotics of any type, duration, and route given for any indication. All included studies must have a comparator group. The primary outcomes are the development of overweight and obesity. Secondary outcomes are percent weight-change from baseline and change in body mass index or waist circumference. Additional secondary outcomes in pregnant women are gestational weight gain, postpartum weight retention, offspring birth weight, childhood weight, and obesity. Risk of bias of included trials will be performed. Two reviewers will screen and perform data extraction independently. DISCUSSION: This systematic review will summarize the existing evidence evaluating the association between antibiotic use, weight gain, and obesity and facilitate the identification of important gaps and uncertainties in the literature. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017069177.

Improving treatment and liver fibrosis outcomes with metformin in HCV-HIV co-infected and HCV mono-infected patients with insulin resistance: study protocol for a randomized controlled trial.

BACKGROUND: Approximately 180 million people worldwide, (3 % of the world's population) are infected with hepatitis C (HCV). Insulin resistance (IR) and type 2 diabetes (T2DM) are common extrahepatic manifestations of chronic HCV infection and associated with poor treatment and liver-related outcomes. The presence of these metabolic complications have been associated with poor response to interferon-based HCV antiviral therapy and increased risk of liver-related outcomes. Metformin, an insulin sensitizer is known to improve HCV treatment response and has been associated with a reduced risk of developing hepatocellular carcinoma (HCC). This study will evaluate the effect of metformin on preventing progression or promoting regression of liver fibrosis, rate of virologic cure (SVR) and other metabolic measures in HCV-HIV co-infected and HCV mono-infected study participants who have IR and are planning on initiating HCV treatment. METHODS: This study is a prospective 48-week single-centre, randomized, open-label, controlled trial of HIV-HCV co-infected and HCV mono-infected patients with IR (HOMA-IR ≥ 2.0) who are planning to initiate HCV antiviral therapy. Sixty participants will be recruited from The Ottawa Hospital Viral Hepatitis Clinic. Participants will be randomized in a 1:1 ratio to either arm 1, metformin 2 g (1 g twice daily) plus lifestyle, or to arm 2, lifestyle alone. The primary outcome will be the change in FibroScan® score (kPa) from baseline to week 12 (start of HCV treatment), the end of HCV treatment (week 24) and 24 weeks post HCV treatment (week 48). Secondary outcomes include changes in liver fibrosis using AST to platelet ratio index, changes in glucose and lipid levels, anthropometric measures, changes in alpha-fetoprotein levels, patient acceptability, and changes in dietary and physical activity parameters. DISCUSSION: This pilot study will be the first to evaluate the role of metformin on liver fibrosis in HCV-HIV co-infected and HCV mono-infected patients with IR receiving DAA HCV treatment. If metformin is effective in reducing liver fibrosis in this patient population, this will represent a well-tolerated, easy-to-administer, inexpensive therapy that will protect against negative HCV outcomes. This study will also be an opportunity to evaluate the impact of insulin resistance and hyperglycemia on viral clearance in HCV-infected patients treated with interferon-free regimens. TRIAL REGISTRATION: ClinicalTrials.gov NCT02306070 version 4.0 (June 29, 2015).

Using a Structured Discharge Letter Template to Improve Communication During the Transition from a Specialized Outpatient Diabetes Clinic to a Primary Care Physician.

OBJECTIVE: Transition from specialists to primary care physicians is dependent on clear communication by means of a discharge letter. Primary care physicians have indicated that letters from specialists rarely contain the details they require. As part of a quality-improvement project to improve the transition from diabetes clinics to primary care physicians, a structured discharge letter template was developed to facilitate the dictation of useful letters by specialists. The objective was to evaluate the content and quality of discharge letters created using a structured discharge letter template as compared to letters completed without the template. METHODS: Retrospective study of patients treated at the Ottawa Hospital and discharged from the outpatient diabetes clinic between November 1, 2009, and December 1, 2010. The letters were reviewed by 2 independent reviewers and were assessed for content, brevity, clarity, management plan, organization and quality. Word count, dictation and transcription times were also compared. RESULTS: Letters completed using the structured discharge letter template were more comprehensive and more likely to contain guidelines on management for glycemic control (51.1% vs. 14.1%; p<0.001); cardiovascular risk factors (65.61% vs. 9.8%; p<0.001); diabetes complications (79.9% vs. 5.9%; p<0.001); and provided re-referral criteria (89.3% vs. 15.7%; p<0.001). Dictation time did not differ between formats. Transcription time (20:65 min vs. 13:45 min; p<0.01) and word count (502 words vs. 292 words; p<0.001) were higher with the template. CONCLUSIONS: The use of a structured discharge letter template improved the content and quality of discharge letters dictated by specialists. Primary care physicians were more consistently provided with valued information and given criteria for re-referral.

Successful Hepatitis C Antiviral Therapy Induces Remission of Type 2 Diabetes: A Case Report.

BACKGROUND: Type 2 diabetes is a well described extra-hepatic manifestation of hepatitis C infection (HCV). Eradication of HCV has led to improvements in insulin resistance but to date has not been shown to induce remission of diabetes. CASE REPORT: We report a case of a 49-year-old man with HCV and a 2-year history of T2DM on oral agents. He was initially treated with peg-interferon/ribavirin (peg-IFN/rib) but did not achieve a HCV treatment response. Four years later he was retreated with peg-IFN/rib plus an HCV protease inhibitor (boceprevir). His HbA1c at the start of treatment was 7.9%. Antiviral response to HCV-therapy correlated with a significant improvement in glucose control without a change in diabetes therapy or improvement in adherence. He achieved a sustained virological response and within a year of completing antiviral therapy he no longer required medical therapy for diabetes. Two years after the completion of HCV treatment, the patient has maintained an HbA1c of 5.8% without any diabetes medications. CONCLUSIONS: This case provides evidence of the important relationship between HCV and diabetes and highlights the potential reversibility of glucose abnormalities with successful eradication of HCV. Increased awareness of this association may improve detection of undiagnosed HCV infection, identify patients with reversible causes of diabetes, guide therapeutic decisions for HCV treatment, and improve outcomes in patients with both diseases.