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IntroductionData on postoperative bile reflux after one anastomosis gastric bypass (OAGB) is lacking. Bile reflux scintigraphy (BRS) has been shown to be a reliable non-invasive tool to assess bile reflux after OAGB. We set out to study bile reflux after OAGB with BRS and endoscopy in a prospective series (RYSA Trial).MethodsForty patients (29 women) underwent OAGB between November 2016 and December 2018. Symptoms were reported and upper gastrointestinal endoscopy (UGE) was done preoperatively. Six months after OAGB, bile reflux was assessed in UGE findings and as tracer activity found in gastric tube and esophagus in BRS (follow-up rate 95%).ResultsTwenty-six patients (68.4%) had no bile reflux in BRS. Twelve patients (31.6%) had bile reflux in the gastric pouch in BRS and one of them (2.6%) had bile reflux also in the esophagus 6 months postoperatively. Mean bile reflux activity in the gastric pouch was 5.2% (1–21%) of total activity. De novo findings suggestive of bile reflux (esophagitis, stomal ulcer, foveolar inflammation of gastric pouch) were found for 15 patients (39.5%) in postoperative UGE. BRS and UGE findings were significantly associated (P = 0.022). Eight patients experienced de novo reflux symptoms at 6 months, that were significantly associated with BRS and de novo UGE findings postoperatively (P = 0.033 and 0.0005, respectively).ConclusionPostoperative bile reflux in the gastric pouch after OAGB is a common finding in scintigraphy and endoscopy. The long-term effects of bile exposure will be analyzed in future reports after a longer follow-up.Trial registrationClinical Trials Identifier NCT02882685

Introduction There is a lack of prospective studies comparing Roux-en-Y gastric bypass (RYGB) and one-anastomosis gastric bypass (OAGB). Also, the effects of bariatric surgery and weight loss need a deeper understanding through metabolic studies. We describe the trial protocol and interim analysis of a prospective randomized controlled study comparing RYGB and OAGB: the RYSA trial. Materials and methods In total, 120 bariatric patients will be randomized between RYGB and OAGB in two academic centers. All patients will be followed up for 10 years with analysis and measurements of weight, comorbidities, blood tests, body composition and questionnaires. Extensive metabolic analyses (mixed meal tests, energy expenditure, biopsies of muscle and subcutaneous fat, urine, saliva and fecal samples) will be carried out in the Obesity Research Unit, University of Helsinki, for all patients treated at the Helsinki University Hospital (80 patients) at baseline, 6 months and 12 months. Bile reflux will be studied for the OAGB group at the Helsinki University Hospital at 6 months with gastroscopy and scintigraphy. Results At an interim analysis at 3 months (half-way) through recruitment (30 RYGB and 30 OAGB patients) there have been no deaths and no intensive care unit admittances. One patient in both groups required additional gastroscopy, with anastomosis dilatation in the RYGB group but with no additional intervention in the OAGB group. Conclusion The trial can be safely carried out. Recruitment is estimated to be complete by the end of 2019. Trial registration Clinical Trials Identifier NCT02882685 . Registered on August 30th 2016.

Background Bariatric surgery enhances glucose metabolism, yet the detailed postprandial joint glucose and insulin responses, variability in individual outcomes, and differences in surgical approaches remain poorly understood. Methods We used hierarchical multi-output Gaussian process (HMOGP) regression to reveal clinically relevant patterns between persons undergoing two types of bariatric surgery by modeling the individual postprandial glucose and insulin responses and estimating the average response curves from individual data. 44 participants with obesity underwent either Roux-en-Y gastric bypass (RYGB; n  = 24) or One-Anastomosis gastric bypass (OAGB; n  = 20) surgery. The participants were followed up at the 6th and 12th months after the operation, during which they underwent an oral glucose tolerance test (OGTT) and a mixed meal test (MMT). Results A marked reduction in glycemia, an earlier glucose peak, and an increase and sharpening in the postprandial glucose and insulin responses are evident in both metabolic tests post-operation. MMT results in higher postprandial glucose and insulin peaks compared with OGTT. Higher glucose and insulin responses are observed after RYGB compared with OAGB, suggesting differences between the procedures that may influence the clinical practice. Conclusions Computational modeling with HMOGP regression can thus be used to, in detail, predict the combined responses of patient cohorts to ingested glucose or a mixed meal and help in assessing individual metabolic improvement after weight loss. This can lead to new knowledge in personalized metabolic interventions. Plain language summary Bariatric surgery is used to reduce stomach size or nutrient absorption in people with obesity. However, the effects can vary depending on the person and the type of operation performed. This study used a computational model to analyze the amount of sugar and insulin, a hormone that impacts how the body responds to consumption of sugar, in the blood of 44 individuals who underwent two common types of bariatric surgery. The model revealed that while both operations improved people’s ability to process food, they had different impacts on the amounts of sugar and insulin in the blood after consuming a meal. This knowledge could be used to ensure the best strategy to treat obesity is used for each person with obesity. Poyraz, Heinonen et al. model the individual postprandial glucose and insulin responses in people with obesity who underwent either Roux-en-Y gastric bypass or One-Anastomosis gastric bypass surgery. They find differences in postprandial glucose and insulin responses related to the surgery method used.

Background Significant weight-loss and diabetes remission have been reported after mini-gastric bypass (MGB). Concern has been raised regarding postoperative bile reflux (BR), but it has not been demonstrated in previous studies. We set out to find out if BR is evident in hepatobiliary scintigraphy after MGB. Methods Nine consecutive patients, seven with type 2 diabetes, underwent MGB (15 cm gastric tube, 250–275 cm biliary limb) at our institution with a 12-month follow-up, with none lost to follow-up. Then, 10.7 months (8.6–13.0) after MGB, all patients underwent hepatobiliary scintigraphy and a reflux symptom questionnaire (GerdQ) was filled out. A gastroscopy with biopsies was done for all patients with a bile-reflux-positive scintigraphy. Results Mean age at operation was 56 years (41–65) and preoperative BMI 43.1 kg/m 2 (34.2–54.6). Mean %EWL was 83.9 (49.5–128.3) at 12 months. Four patients reached diabetes remission and two became insulin-independent. Hepatobiliary scintigraphy showed a transient BR into the gastric tube for five patients. Bile tracer was found in the gastric tube at 23–58 min after the tracer injection and highest activity was 8% (1–8%) at 58 min. Bile tracer was not found in the esophagus of any of the patients. One patient with a positive scintigraphy in the gastric tube required re-operation. Two patients with reflux symptoms had a negative scintigraphy. Conclusion Our results indicate that transient bile reflux is common after MGB in the gastric tube, but not in the esophagus. The clinical relevance of bile reflux needs further studies.

A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche 1 , 2 . Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor α (PPAR-α) 3 , and lowered PPAR-α activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues. Ageing-associated decline in intestinal stem cell function is mediated by increased Notum, a protein inhibitor of stemness-maintaining Wnt signalling, which is secreted by Paneth cells.

Secondary hyperparathyroidism and renal osteodystrophy are major problems in patients with end-stage renal failure and may result in poor growth in children on dialysis. Whether vitamin D sterols should be given intermittently or daily remains a controversial issue. We studied 16 bilaterally nephrectomised infants with congenital nephrosis of the Finnish type (median age 0.54 years), all on peritoneal dialysis. Nine of them were receiving intermittent 1-alpha calcidol therapy and seven daily 1-alpha calcidol therapy. The target serum parathyroid hormone (PTH) level was 2-3 times the upper limit of normal (ULN). There were no statistically significant differences in PTH values between the groups (1.7-times vs 0.5-times the ULN at 3 months and 3.1-times vs 3.4-times the ULN at 6 months, respectively). The required weekly doses of 1-alpha calcidol were low, and there were no significant differences between the intermittent and daily groups (0.06 microg/kg vs 0.04 microg/kg at 3 months and 0.09 microg/kg vs 0.05 microg/kg at 6 months, respectively). The infants on intermittent 1-alpha calcidol showed significant catch-up growth during dialysis after nephrectomy relative to the infants on daily 1-alpha calcidol (-1.6 SD to -0.7 SD vs -1.4 SD to -1.0 SD, respectively; P < 0.05). Our results indicate that either intermittent or daily vitamin D analogue therapy, if started early, will prevent secondary hyperparathyroidism equally well in children on peritoneal dialysis (PD), but intermittent therapy might be more favourable for growth.

A decline in stem cell function impairs tissue regeneration during aging, but the role of the stem cell supporting niche in aging is not well understood. The small intestine is maintained by actively cycling intestinal stem cells (ISCs) that are regulated by the Paneth cell niche1,2. Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age due to defects in both stem cells and their niche. The functional decline was caused by decrease in stemness maintaining Wnt signalling due to production of an extracellular Wnt-inhibitor, Notum, in aged Paneth cells. Mechanistically, high mTORC1 activity in old Paneth cells inhibits PPARa activity3 and lowered PPARa increased Notum expression. Genetic targeting of Notum or Wnt-supplementation restored function of old intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of old stem cells and promoted recovery from chemotherapy induced damage. Our results reveal an unappreciated role for the stem cell niche in aging and demonstrate that targeting of Notum can promote regeneration of old tissues.

Background Anterior cervical decompression and fusion (ACDF) may necessitate acute and late re-operations. Published long-term follow studies after ACDF are scarce. Objective Our goal was to give a detailed description of early and late re-operations after ACDF in an 11-year follow-up. Methods We retrospectively analyzed all available clinical data, including radiographic imaging for all patients who underwent an ACDF at our institution between 1998 and 1999. ACDF without plating was performed in 327 patients. All re-operations were performed at our institution. Results Forty-nine patients (15 %, CI 12–19 %) underwent a re-operation; 16 (4.9 %, CI 3–8 %) during the first month and 36 (11 %, CI 8–15 %) later during the follow-up. Five early re-operations were due to postoperative hematomas. No anterior transition of cages was detected. Asymptomatic cage subsidence was seen in 21 re-operated patients, but only one (0.3 %, CI 0–2 %) resulted in a re-operation. Adjacent level re-operation was performed for 26 patients (8 %, CI 5–11 %). This was independent of the number of fused levels or the localization of fusion. Plate reinforcement was used in only two patients in addition to ACDF; both of them were re-operations. The outcome was reported good or excellent for 11 (69 %, CI 44–86 %) and 26 (72 %, CI 56–84 %) patients with an early and late re-operation, respectively. Conclusion Fifteen percent of patients underwent a re-operation during the follow-up. The outcome for re-operated patients is similar to patients without a re-operation. A multilevel fusion does not predispose to adjacent level degeneration. A solid fusion can be achieved without plating.

A treatment policy defines when and what treatments are applied to affect some outcome of interest. Data-driven decision-making requires the ability to predict what happens if a policy is changed. Existing methods that predict how the outcome evolves under different scenarios assume that the tentative sequences of future treatments are fixed in advance, while in practice the treatments are determined stochastically by a policy and may depend, for example, on the efficiency of previous treatments. Therefore, the current methods are not applicable if the treatment policy is unknown or a counterfactual analysis is needed. To handle these limitations, we model the treatments and outcomes jointly in continuous time, by combining Gaussian processes and point processes. Our model enables the estimation of a treatment policy from observational sequences of treatments and outcomes, and it can predict the interventional and counterfactual progression of the outcome after an intervention on the treatment policy (in contrast with the causal effect of a single treatment). We show with real-world and semi-synthetic data on blood glucose progression that our method can answer causal queries more accurately than existing alternatives.