Mortality risk factors in community-dwelling, subjectively healthy, Swiss older adults: update after 8-years follow-up.

BACKGROUND: Worldwide population is ageing, but little is known regarding risk factors associated with increased mortality in subjectively healthy, community-dwelling older adults. We present the updated results of the longest follow-up carried out on Swiss pensioners and we provide results on potential risk factors associated with mortality before the onset of the COVID-19 pandemic. MATERIALS AND METHODS: Within the SENIORLAB study, we collected demographic data, anthropometric measures, medical history, and laboratory parameters of 1467 subjectively healthy, community-dwelling, Swiss adults aged ≥ 60 years over a median follow-up of 8.79 years. The variables considered in the multivariable Cox-proportional hazard model for mortality during follow-up were selected based on prior knowledge. Two separate models for males and females were calculated; moreover, we fitted the old model obtained in 2018 to the complete follow-up data to highlight differences and similarities. RESULTS: The population sample included 680 males and 787 females. Age of participants ranged between 60 and 99 years. We experienced 208 deaths throughout the entire follow-up period; no patients were lost at follow-up. The Cox-proportional hazard regression model included female gender, age, albumin levels, smoking status, hypertension, osteoporosis and history of cancer within predictors of mortality over the follow-up period. Consistent findings were obtained also after gender stratification. After fitting the old model, female gender, hypertension, and osteoporosis still showed statistically significant independent associations with all-cause mortality. CONCLUSIONS: Understanding the predictors of a healthy survival can improve the overall quality of life of the ageing population and simultaneously reduce their global economic burden. TRIAL REGISTRATION: The present study was registered in the International Standard Randomized Controlled Trial Number registry: https://www.isrctn.com/ISRCTN53778569 (registration date: 27/05/2015).

Perianastomotic Irrigation With Passive Drainage Dramatically Decreases POPF Rate After High-risk Pancreaticoduodenectomy.

Objective: To assess whether prophylactic irrigation and passive drainage of pancreatico-jejunal anastomosis could reduce leak and mortality rates after high-risk pancreaticoduodenectomies. Background: Postoperative pancreatic fistula (POPF) is a life-threatening complication following pancreaticoduodenectomy. Several risk factors have been proposed likewise potential mitigation strategies. Regarding the latter, surgical drain policy remains a "hot topic." We propose an innovative approach to mitigate POPF and POPF-related mortality following high-risk pancreaticoduodenectomies. Methods: One hundred fifty-seven patients undergoing pancreaticoduodenectomy between January 2012 and November 2021 were included in the study. Subjects with main pancreatic duct ≤ 3 mm and soft parenchyma were classified as high-risk for POPF development. Since August 2015, high-risk patients received prophylactic irrigation and drainage of the perianastomotic area. These patients were compared with risk-matched historical controls. Results: We identified 73 high-risk patients. Of these, the 47 subjects receiving prophylactic perianastomotic irrigation showed significantly lower POPF rates (12.7% vs 69.2%, P < 0.001). Multivariate regression analysis confirmed the significant association between irrigation drainages and POPF (odds ratio 0.014, P = 0.01). Although not significant, mortality was lower in the irrigation group (4.2% vs 13.0%, P = 0.340). However, none of the fatalities in the irrigation-drainage group were POPF-related. No significant difference in length of hospital stay was observed between the 2 groups (18.0 vs 21.0 days, P = 0.091). Conclusions: Irrigation and drainage of the perianastomotic area represents a powerful approach to reduce POPF and, potentially, mortality after high-risk pancreaticoduodenectomies.

Osteoporosis, diabetes, and hypertension are major risk factors for mortality in older adults: an intermediate report on a prospective survey of 1467 community-dwelling elderly healthy pensioners in Switzerland.

BACKGROUND: Osteoporosis is an important morbidity factor for ageing populations in developed countries. However, compared to the amount of information available on diabetes and cardiovascular disease, little is known about the direct impact of osteoporosis on general mortality in older age. METHODS: We obtained data from a prospective population-based cohort of pensioners from the SENIORLAB study who were subjectively healthy. The inclusion criteria were an age of at least 60 years and Swiss residence. We assessed and analysed clinical measures, voluntary reports, and laboratory values. RESULTS: In total, 1467 subjects were included in the cohort. The mean follow-up time was 3.68 years (95% confidence interval, 3.64-3.71). The ages of the included participants ranged from 60 to 99 years. At follow-up, there were 1401 survivors, and 66 participants had died. According to the multivariate analysis (Cox regression), osteoporosis was the most important risk factor for all-cause mortality (hazard ratio, 4.46; 95% confidence interval, 1.82-10.91), followed by diabetes (hazard ratio, 2.17; 95% confidence interval, 1.04-4.52) and hypertension (hazard ratio, 1.81; 95% confidence interval, 1.09-3.03). CONCLUSIONS: Osteoporosis is a major risk factor for all-cause mortality in a subjectively healthy senior population, followed by type 2 diabetes mellitus and hypertension. Osteoporosis should be more actively diagnosed in healthy pensioners before they develop osteoporosis-associated health incidents. TRIAL REGISTRATION: The present study was registered in the International Standard Randomized Controlled Trial Number registry: ISRCTN53778569 .

Effect of a test meal on meal responses of satiation hormones and their association to insulin resistance in obese adolescents.

OBJECTIVE: The role of gastrointestinal (GI) hormones in the pathophysiology of obesity is unclear, although they are involved in the regulation of satiation and glucose metabolism. To (i) examine glucagon-like peptide 1 (GLP-1), amylin, ghrelin, and glucagon responses to a meal in obese adolescents and to (ii) test which GI peptides are associated with insulin resistance are presented. METHODS: A total of 16 obese (body mass index (BMI) ≥ 97th percentile for age and gender) and 14 control (BMI between 25th and 75th percentiles) adolescents were included. Subjects were instructed to eat a test meal (490 kcal). Plasma samples were collected for hormone and glucose analysis. RESULTS: Obese adolescents were insulin resistant as expressed by the Homeostasis Model Assessment (HOMA) index and had significantly increased fasting glucagon and amylin levels compared to the control group (P = 0.003 and 0.044, respectively). In response to the meal, the increase in GLP-1 levels was reduced in obese adolescents (P < 0.001). In contrast, amylin secretion was significantly increased in the obese population compared to the control group (P < 0.005). CONCLUSIONS: Obese adolescents have increased fasting glucagon and amylin levels and attenuated post-prandial GLP-1 concentrations compared with the control group. These factors could contribute to the metabolic syndrome.

Glucocorticoid treatment, immobility, and constipation are associated with nutritional risk.

PURPOSE: The hypothesis of this clinical study was to determine whether glucocorticoid use and immobility were associated with in-hospital nutritional risk. METHODS: One hundred and one patients consecutively admitted to the medical wards were enrolled. Current medical conditions, symptoms, medical history, eating and drinking habits, diagnosis, laboratory findings, medications, and anthropometrics were recorded. The Nutrition Risk Score 2002 (NRS-2002) was used as a screening instrument to identify nutritional risk. RESULTS: The results confirmed that glucocorticoid use and immobility are independently associated with nutritional risk determined by the NRS-2002. Constipation could be determined as an additional cofactor independently associated with nutritional risk. CONCLUSIONS: Glucocorticoid treatment, immobility, and constipation are associated with nutritional risk in a mixed hospitalized population. The presence of long-time glucocorticoid use, immobility, or constipation should alert the clinician to check for nutritional status, which is an important factor in mortality and morbidity.

Primary care emergency services utilization in German-speaking Switzerland: a population-based cross-sectional study.

BACKGROUND: Traditionally, emergency consultations have been done by a general practitioner (GP) in Switzerland. Over the last years, there seems to have been a shift between general practice to hospital emergency ward utilisation. There are several local initiatives of general practitioners and hospitals to change the organisation of emergency care. To plan a new organisation form of emergency care, delivery should be based on population based data. OBJECTIVE: The aim of the study was to investigate the epidemiology and distribution of emergency consultations of primary care in a hospital and in a practice of general practitioners. In addition, factors of clinical performance in emergency consultations are of great public health interest. METHODS: For this survey, all emergency patient contacts of general practitioners from the catchment area of Bülach, serving 27 088 inhabitants, were assessed by a questionnaire during the fourth quarter of 2006. Sex, age, time, duration of the contact and triage diagnosis were assessed. In addition, all patients seen by the emergency ward at the local hospital were assessed. Contact rates and hospitalisation rates per 100 000 inhabitants were determined. In addition, a multiple linear regression model was performed to determine factors associated with consultation time as a marker for clinical performance. RESULTS: Between October 1th and December 31th 2006, 1001 patient contacts were registered at the same time period in the hospital and general practice. The patient contact rate was 94.8 contacts per 100 000 inhabitants per day, and the hospitalisation rate was 9.1 patient per 100 000 inhabitants. Patients seen at the hospital were older than in general practice (41.2 ± 22.8 vs. 32.6 ± 26.3 years) and consultation and waiting time was longer in the hospital than consultation time with the GP (144.8 ± 106.5 vs. 19.6 ± 17.6 minutes). CONCLUSION: Nearly 1 out of 1000 inhabitants were looking for emergency primary care help, and 10% of the patients were seen urgently by general practitioners and hospital staff and were hospitalised. These numbers are important information for planning emergency primary care facilities. The most prevalent triage diagnoses in practice are infections, traumatological reasons and ENT-problems, whereas in hospital the most frequent triage diagnosis is a traumatological disorder, followed by thoracic pain and infections. In addition, GP's treat patients more rapidly than a hospital does and treat patients in shorter time intervals.

Glucagon-like peptide-1 is involved in sodium and water homeostasis in humans.

UNLABELLED: In previous studies with glucagon-like peptide-1 (GLP-1) we have observed that this peptide modulates fluid intake and increases renal sodium excretion in healthy volunteers and in patients with diabetes mellitus type 2. The effect of GLP-1 on thirst, water intake and on osmoregulation has, however, not been examined in detail in humans. METHODS: Seventeen healthy male subjects were enrolled in two double-blind, placebo-controlled studies. In study part A, 8 volunteers participated in a protocol with an intravenous salt load of 26.7 +/- 0.9 g comparing the effect of an infusion of GLP-1 (1.5 pmol/kg x min) to isotonic saline (placebo). Sodium excretion and water intake were measured. In part B, 9 volunteers were challenged with an oral salt load of 27.7 +/- 0.5 g; sodium excretion and water intake were determined comparing an infusion of GLP-1 (1.5 pmol/kg x min) to isotonic saline (placebo). In part C, intestinal biopsies along the gastrointestinal tract were obtained from 14 healthy subjects. Expression of human GLP-1 receptor mRNA was measured by real-time polymerase chain reaction. RESULTS: In study part A, an increase in renal sodium excretion was demonstrated: FeNa rose from 1.6 +/- 0.3 (placebo) to 2.7 +/- 0.2% (GLP-1; p = 0.0005). There was no difference in water consumption between the two treatments: 1,291 +/- 69 (saline) vs. 1,228 +/- 74 ml (GLP-1; p = 0.49). In part B, an oral salt challenge of 27.7 +/- 0.5 g led to an increased renal excretion of sodium during GLP-1: FeNa increased from 1.6 +/- 0.2% (placebo) to 2.0 +/- 0.2% (GLP-1; p = 0.012). In contrast to part A, oral water intake was reduced by 36% under GLP-1 treatment: 1,848 +/- 331 ml (placebo) vs. 1,181 +/- 177 ml (GLP-1; p = 0.0414). Three subjects in part B did not finish treatment with GLP-1 because of diarrhea. Human GLP-1 receptor mRNA expression was highest in the proximal human small intestine compared to terminal ileum and colon (p < 0.02). CONCLUSIONS: GLP-1 acts on renal tissue reducing sodium absorption, probably via similar sodium transporters, which also may be localized in the gastrointestinal tract. This hypothesis needs to be confirmed by further studies.

Mapping of multidrug resistance gene 1 and multidrug resistance-associated protein isoform 1 to 5 mRNA expression along the human intestinal tract.

Efflux transporters such as P-glycoprotein and multidrug resistance-associated proteins (MRPs) in the intestinal wall restrict intestinal drug transport. To overcome this limitation for enteral drug absorption, galenical targeting approaches have been proposed for site-specific luminal drug release in segments of the gut, where expression of the respective absorption-limiting transporter is minimal. Therefore, expression of multidrug resistance gene 1 (MDR1) and MRP1-5 was systematically investigated in 10 healthy subjects. Biopsies were taken from different segments of the gastrointestinal tract (from duodenum and terminal ileum, as well as ascending, transverse, descending, and sigmoid colon). Gene expression was investigated by quantitative real-time PCR (TaqMan). MRP3 appeared to be the most abundantly expressed transporter in investigated parts of the human intestine, except for the terminal ileum, where MDR1 showed the highest expression. The ranking of transporter gene expression in the duodenum was MRP3 >> MDR1 > MRP2 > MRP5 > MRP4 > MRP1. In the terminal ileum, the ranking order was as follows: MDR1 > MRP3 >> MRP1 approximately MRP5 approximately MRP4 > MRP2. In all segments of the colon (ascending, transverse, descending, and sigmoid colon), the transporter gene expression showed the following order: MRP3 >> MDR1 > MRP4 approximately MRP5 > MRP1 >> MRP2. We have shown, for the first time, systematic site-specific expression of MDR1 and MRP mRNA along the gastrointestinal tract in humans. All transporters showed alterations in their expression levels from the duodenum to sigmoid colon. The most pronounced changes were observed for MRP2, with high levels in the small intestine and hardly any expression in colonic segments. This knowledge may be useful to develop new targeting strategies for enteral drug delivery.

Glucagon-like peptide 1 (GLP-1) and eating.

New information regarding gastrointestinal mechanisms that participate in the control of food intake has extended our understanding of appetite control. Although each new signaling pathway discovered in the gut is a potential target for drug development in the treatment of obesity, the growing number of such signaling molecules indicates that a highly complex process controls food intake. The present summary focuses on the role of glucagon-like peptide 1 (GLP-1) in this regulatory process. The different biological effects of GLP-1 (glucose-lowering properties, inhibition of appetite and food intake) provide a powerful impetus for development of GLP-1-based new drugs.

Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men.

Glucagon-like peptide-1-(7-36)-amide (GLP-1) is involved in satiety control and glucose homeostasis. Animal studies suggest a physiological role for GLP-1 in water and salt homeostasis. This study's aim was to define the effects of GLP-1 on water and sodium excretion in both healthy and obese men. Fifteen healthy subjects and 16 obese men (mean body mass index, 36 kg/m2) were examined in a double-blind, placebo-controlled, crossover study to demonstrate the effects of a 3-h infusion of GLP-1 on urinary sodium excretion, urinary output, and the glomerular filtration rate after an i.v. 9.9-g salt load. Infusion of GLP-1 evoked a dose-dependent increase in urinary sodium excretion in healthy subjects (from 74 +/- 8 to 143 +/- 18 mmol/180 min, P = 0.0013). In obese men, there was a significant increase in urinary sodium excretion (from 59 to 96 mmol/180 min, P = 0.015), a decrease in urinary H+ secretion (from 1.1 to 0.3 pmol/180 min, P = 0.013), and a 6% decrease in the glomerular filtration rate (from 151 +/- 8 to 142 +/- 8 ml/min, P = 0.022). Intravenous infusions of GLP-1 enhance sodium excretion, reduce H+ secretion, and reduce glomerular hyperfiltration in obese men. These findings suggest an action at the proximal renal tubule and a potential renoprotective effect.

Interaction between GLP-1 and CCK-33 in inhibiting food intake and appetite in men.

Glucagon-like peptide-1 (GLP-1) and CCK-33 were intravenously infused alone or in combination into normal weight men for 60 min before they were served a lunch of ham sandwiches, chocolate mousse, and orange juice. Infusion of GLP-1 (dose: 0.9 pmol x kg(-1) x min(-1)) or CCK-33 (dose: 0.2 pmol x kg(-1) x min(-1)) each reduced calorie intake of the test meal. However, simultaneous infusion of these peptide doses reduced calorie intake less than the sum of the peptides' individual effects. Infusions of the same doses of GLP-1 plus CCK-33 had neither individual nor interactive effects on meal size or calorie consumption. The combination of GLP-1 plus CCK-33 induced, however, a significant reduction in hunger feelings in the premeal period (P = 0.036 vs. all other treatments). In summary, intravenous infusion of near physiological doses of CCK-33 and GLP-1 produced specific inhibitions of hunger feeling in men; the simultaneous infusion resulted in an infra-additive reduction in calorie consumption, rejecting thereby the hypothesis that the two peptides exert a positive synergistic effect on food intake compared with the effects observed with infusion of individual peptides. In conclusion, CCK and GLP-1 are meal-related satiety signals that are released from the gastrointestinal tract during food intake.

Estimating phosphate removal in haemodialysis: an additional tool to quantify dialysis dose.

BACKGROUND: Half of the dialysis population suffers from hyperphosphataemia, which is now recognized as a major factor of haemodialysis (HD) morbidity and mortality. Current control is focussed on reducing dietary phosphate intake and diminishing absorption using phosphate binders, whereas control and quantification of phosphate removal by HD is undervalued. The aim of this prospective study was to develop a simple, bedside formula to estimate dialytic phosphate removal in stable HD patients. METHODS: This was a prospective, randomized trial. Phosphate and urea elimination were assessed in a representative group of patients at two dialysis centres using randomly different dialysers (1.3-2.4 m(2)). Quantification was performed by partial dialysate collection, concentration measurements in blood and effluent dialysate spot samples, and Kt/V(urea) during standard high-flux HD. Multiple linear regression analyses were used in 77% of all data sets to generate an equation to predict phosphate removal. The formula was validated in the remaining 23% of data sets, in the same group of patients using a large capillary filter, and in diabetic patients treated with a small dialyser at different blood flows (200, 250, and 300 ml/min). RESULTS: A formula allowing quantification of phosphate removal within one HD session was developed in 18 of 74 patients during 41 treatments (137 out of 177 data sets) and was determined as: M(PO4pred)=0.1t -17+50c(ds60)+11c(b60), where t is treatment time in min, c(ds60) and c(b60) are phosphate concentrations in dialysate and plasma measured 60 min into HD in mmol/l, and M(PO4pred) is estimated phosphate removed in mmol. The precision was remarkable (r(2)=0.92-0.94). The comparison of phosphate and Kt/V(urea) showed a significant association (r(2)=0.28), albeit with remarkable scatter. CONCLUSIONS: We present the first approach to quantify phosphate removal during high-flux HD by a bedside formula. Only 28% of the variation in phosphate removal was explained by Kt/V(urea). It appears that other factors not adequately accounted for by Kt/V(urea) affect phosphate removal. Therefore, we propose an individual control and quantification of phosphate removal in HD.