Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort

BACKGROUND & AIMS Proprotein convertase 1/3 (PC1/3) deficiency, an autosomal-recessive disorder caused by rare mutations in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities. Common variants in PCSK1 also have been associated with obesity in heterozygotes in several population-based studies. PC1/3 is an endoprotease that processes many prohormones expressed in endocrine and neuronal cells. We investigated clinical and molecular features of PC1/3 deficiency. METHODS We studied the clinical features of 13 children with PC1/3 deficiency and performed sequence analysis of PCSK1. We measured enzymatic activity of recombinant PC1/3 proteins. RESULTS We identified a pattern of endocrinopathies that develop in an age-dependent manner. Eight of the mutations had severe biochemical consequences in vitro. Neonates had severe malabsorptive diarrhea and failure to thrive, required prolonged parenteral nutrition support, and had high mortality. Additional endocrine abnormalities developed as the disease progressed, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism. We identified growth hormone deficiency, central diabetes insipidus, and male hypogonadism as new features of PCSK1 insufficiency. Interestingly, despite early growth abnormalities, moderate obesity, associated with severe polyphagia, generally appears. CONCLUSIONS In a study of 13 children with PC1/3 deficiency caused by disruption of PCSK1, failure of enteroendocrine cells to produce functional hormones resulted in generalized malabsorption. These findings indicate that PC1/3 is involved in the processing of one or more enteric hormones that are required for nutrient absorption.

Home artificial nutrition in Switzerland: an epidemiological survey from 2005 to 2009.

BACKGROUND AND AIMS Home artificial nutrition (HAN), including oral nutritional supplements (ONS) and enteral (HEN) and parenteral (HPN) nutrition, is an established, important treatment for malnourished patients. The aim of this study was to analyze the epidemiological data of patients on HAN in Switzerland. METHODS This retrospective study recorded all new cases of HAN in Switzerland from January 2005 to December 2009. RESULTS A total of 12,917 cases were recorded: 6,731 (52%) males and 6,186 (48%) females, with a mean age of 65.0 ± 17.6 years. The number of patients on ONS was 7,827 (57.4%), on HEN 3,966 (39.4%) and on HPN 433 (3.2%). The most common underlying disease category was neoplasms (6,519, 50.7%). The number of patients on ONS increased from 57.0% (n = 1,252) to 60.8% (n = 2,039), and on HPN from 2.1% (n = 45) to 4.0% (n = 134) between 2005 and 2009. CONCLUSIONS This first analysis of the large-scale Swiss registry of HAN shows that approximately half of the patients received ONS, whereas HPN was rarely delivered. The frequency of ONS and HPN increased from the year 2005 to 2009. In accordance with previous European studies, malignant tumors were by far the most frequent indication for HAN.

The adherence to initial processes of care in elderly patients with acute venous thromboembolism.

BACKGROUND We aimed to assess whether elderly patients with acute venous thromboembolism (VTE) receive recommended initial processes of care and to identify predictors of process adherence. METHODS We prospectively studied in- and outpatients aged ≥65 years with acute symptomatic VTE in a multicenter cohort study from nine Swiss university- and non-university hospitals between September 2009 and March 2011. We systematically assessed whether initial processes of care, which are recommended by the 2008 American College of Chest Physicians guidelines, were performed in each patient. We used multivariable logistic models to identify patient factors independently associated with process adherence. RESULTS Our cohort comprised 950 patients (mean age 76 years). Of these, 86% (645/750) received parenteral anticoagulation for ≥5 days, 54% (405/750) had oral anticoagulation started on the first treatment day, and 37% (274/750) had an international normalized ratio (INR) ≥2 for ≥24 hours before parenteral anticoagulation was discontinued. Overall, 35% (53/153) of patients with cancer received low-molecular-weight heparin monotherapy and 72% (304/423) of patients with symptomatic deep vein thrombosis were prescribed compression stockings. In multivariate analyses, symptomatic pulmonary embolism, hospital-acquired VTE, and concomitant antiplatelet therapy were associated with a significantly lower anticoagulation-related process adherence. CONCLUSIONS Adherence to several recommended processes of care was suboptimal in elderly patients with VTE. Quality of care interventions should particularly focus on processes with low adherence, such as the prescription of continued low-molecular-weight heparin therapy in patients with cancer and the achievement of an INR ≥2 for ≥24 hours before parenteral anticoagulants are stopped.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

BACKGROUND Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is an update of a review first published in February 2012. OBJECTIVES To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis. SEARCH METHODS For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013), CENTRAL (2013, Issue 5), and clinical trials registries (up to June 2013). SELECTION CRITERIA Randomised controlled trials (RCTs) comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS Data were extracted on methodological quality, patients, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. MAIN RESULTS We identified 12 additional RCTs (6323 patients) in the updated search so that this update considered 21 trials with a total of 9861 patients, all evaluating pharmacological interventions and performed mainly in patients with advanced cancer. Overall, the risk of bias varied from low to high. One large trial of 3212 patients found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). LMWH, when compared with inactive control, significantly reduced the incidence of symptomatic VTE (RR 0.53, 95% CI 0.38 to 0.75; no heterogeneity, Tau(2) = 0%) with similar rates of major bleeding events (RR 1.30, 95% CI 0.75 to 2.23). In patients with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE when compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). No major bleeding was observed in the patients treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against inactive control and found an incidence of major bleeding of 1% in both study groups while not reporting on VTE. When compared with placebo, warfarin was associated with a statistically insignificant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE nor major bleeding when compared with inactive control. The new oral factor Xa inhibitor apixaban was evaluated in a phase-II dose finding study that suggested a promising low rate of major bleeding (2.1% versus 3.3%) and symptomatic VTE (1.1% versus 10%) in comparison with placebo. AUTHORS' CONCLUSIONS In this update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin significantly reduced the incidence of symptomatic VTE. However, the broad confidence intervals around the estimates for major bleeding suggest caution in the use of anticoagulation and mandate additional studies to determine the risk to benefit ratio of anticoagulants in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed.

Loss of appetite in acutely ill medical inpatients: physiological response or therapeutic target?

Loss of appetite and ensuing weight loss is a key feature of severe illnesses. Protein-energy malnutrition (PEM) contributes significantly to the adverse outcome of these conditions. Pharmacological interventions to target appetite stimulation have little efficacy but considerable side effects. Therefore nutritional therapy appears to be the logical step to combat inadequate nutrition. However, clinical trial data demonstrating benefits are sparse and there is no current established standard algorithm for use of nutritional support in malnourished, acutely ill medical inpatients. Recent high-quality evidence from critical care demonstrating harmful effects when parenteral nutritional support is used indiscriminately has led to speculation that loss of appetite in the acute phase of illness is indeed an adaptive, protective response that improves cell recycling (autophagy) and detoxification. Outside critical care, there is an important gap in high quality clinical trial data shedding further light on these important issues. The selection, timing, and doses of nutrition should be evaluated as carefully as with any other therapeutic intervention, with the aim of maximising efficacy and minimising adverse effects and costs. In light of the current controversy, a reappraisal of how nutritional support should be used in acutely ill medical inpatients outside critical care is urgently required. The aim of this review is to discuss current pathophysiological concepts of PEM and to review the current evidence for the efficacy of nutritional support regarding patient outcomes when used in an acutely ill medical patient population outside critical care.

Diagnosis and therapy of retained fetal membranes, puerperal metritis and clinical endometritis in cattle: Results of the Online-survey among Swiss practitioners. II. Puerperal metritis and clinical endometritis

The aim of the study was to obtain the diagnostic and therapeutic approach among Swiss practitioners in cows with puerperal metritis and clinical endometritis (part 2). All members of the Association for ruminant health were contacted per email via the newsletter. The survey was completed by 128 veterinarians, partially responded by 140 veterinarians. The following main symptoms of puerperal metritis were stated by the practitioners: purulent vaginal discharge, fever and reduced appetite. A vaginal and rectal examination was performed to diagnose the disease. Usually, an intrauterine treatment with tetracycline or cefapirin was done. Parenteral administration of tetracycline or penicillin was often combined with PGF(2α), NSAIDS or cortisone. Clinical endometritis was also diagnosed by vaginal and rectal examination and the main symptom indicated was purulent vaginal discharge. The therapy consisted of the administration of PGF(2α), uterine infusions predominantly with cefapirin, and rarely with parenteral administration of antibiotics. Further diagnostic tools were not used and normally cows were not rechecked. The success of the therapy of puerperal metritis and clinical endometritis was judged to be satisfactory to excellent.

Diagnosis and therapy of retained fetal membranes, puerperal metritis and clinical endometritis in cattle: Results of the Online-survey among Swiss practitioners. I Retained fetal membranes

The aim of this study was to obtain the diagnostic and therapeutic approach among Swiss practitioners in cows with retained fetal membranes (RFM) (part 1). All members of the Association for ruminant health were contacted per email via the newsletter. The survey was completed by 128 veterinarians, partially responded by 140 veterinarians. The manual removal of the fetal membranes is practiced by 129 of the responding veterinarians. Cows with/without fever are treated usually with intrauterine antibiotics. Cows with RFM with/without fever are most commonly treated parenterally with tetracycline or penicillin. The use of cephalosporins and quinolones in cows with fever is more common than in cows without fever. With the present results of the survey veterinarians should critically question the supposed benefits of the manual removal of the placenta and the use of antibiotics in cows with RFM.

["Not to be taken lightly"].

A 78 year old patient with type 2 diabetes mellitus was hospitalized because of weakness and poor nutritional status. For several years, he suffered from an unintended weight loss and chronic, pulpy diarrhea. On examination, we found a severe loss of muscle and fat tissue as well as difficulty swallowing. An adequate nutritional therapy with combined parenteral and enteral nutrition was implemented under regular monitoring of electrolytes and volume status, under which the state of health improved noticeably, while steatorrhea improved under substitution of pancreatic enzymes.

Treatment for superficial infusion thrombophlebitis of the upper extremity.

BACKGROUND Although superficial thrombophlebitis of the upper extremity represents a frequent complication of intravenous catheters inserted into the peripheral veins of the forearm or hand, no consensus exists on the optimal management of this condition in clinical practice. OBJECTIVES To summarise the evidence from randomised clinical trials (RCTs) concerning the efficacy and safety of (topical, oral or parenteral) medical therapy of superficial thrombophlebitis of the upper extremity. SEARCH METHODS The Cochrane Vascular Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3). Clinical trials registries were searched up to April 2015. SELECTION CRITERIA RCTs comparing any (topical, oral or parenteral) medical treatment to no intervention or placebo, or comparing two different medical interventions (e.g. a different variant scheme or regimen of the same intervention or a different pharmacological type of treatment). DATA COLLECTION AND ANALYSIS We extracted data on methodological quality, patient characteristics, interventions and outcomes, including improvement of signs and symptoms as the primary effectiveness outcome, and number of participants experiencing side effects of the study treatments as the primary safety outcome. MAIN RESULTS We identified 13 studies (917 participants). The evaluated treatment modalities consisted of a topical treatment (11 studies), an oral treatment (2 studies) and a parenteral treatment (2 studies). Seven studies used a placebo or no intervention control group, whereas all others also or solely compared active treatment groups. No study evaluated the effects of ice or the application of cold or hot bandages. Overall, the risk of bias in individual trials was moderate to high, although poor reporting hampered a full appreciation of the risk in most studies. The overall quality of the evidence for each of the outcomes varied from low to moderate mainly due to risk of bias and imprecision, with only single trials contributing to most comparisons. Data on primary outcomes improvement of signs and symptoms and side effects attributed to the study treatment could not be statistically pooled because of the between-study differences in comparisons, outcomes and type of instruments to measure outcomes.An array of topical treatments, such as heparinoid or diclofenac gels, improved pain compared to placebo or no intervention. Compared to placebo, oral non-steroidal anti-inflammatory drugs reduced signs and symptoms intensity. Safety issues were reported sparsely and were not available for some interventions, such as notoginseny creams, parenteral low-molecular-weight heparin or defibrotide. Although several trials reported on adverse events with topical heparinoid creams, Essaven gel or phlebolan versus control, the trials were underpowered to adequately measure any differences between treatment modalities. Where reported, adverse events with topical treatments consisted mainly of local allergic reactions. Only one study of 15 participants assessed thrombus extension and symptomatic venous thromboembolism with either oral non-steroidal anti-inflammatory drugs or low-molecular-weight heparin, and it reported no cases of either. No study reported on the development of suppurative phlebitis, catheter-related bloodstream infections or quality of life. AUTHORS' CONCLUSIONS The evidence about the treatment of acute infusion superficial thrombophlebitis is limited and of low quality. Data appear too preliminary to assess the effectiveness and safety of topical treatments, systemic anticoagulation or oral non-steroidal anti-inflammatory drugs.

Primary prophylaxis for venous thromboembolism in patients undergoing cardiac or thoracic surgery.

BACKGROUND Cardiac and thoracic surgery are associated with an increased risk of venous thromboembolism (VTE). The safety and efficacy of primary thromboprophylaxis in patients undergoing these types of surgery is uncertain. OBJECTIVES To assess the effects of primary thromboprophylaxis on the incidence of symptomatic VTE and major bleeding in patients undergoing cardiac or thoracic surgery. SEARCH METHODS The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2014) and CENTRAL (2014, Issue 4). The authors searched the reference lists of relevant studies, conference proceedings, and clinical trial registries. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. MAIN RESULTS We identified 12 RCTs and one quasi-RCT (6923 participants), six for cardiac surgery (3359 participants) and seven for thoracic surgery (3564 participants). No study evaluated fondaparinux, the new oral direct thrombin, direct factor Xa inhibitors, or caval filters. All studies had major study design flaws and most lacked a placebo or no treatment control group. We typically graded the quality of the overall body of evidence for the various outcomes and comparisons as low, due to imprecise estimates of effect and risk of bias. We could not pool data because of the different comparisons and the lack of data. In cardiac surgery, 71 symptomatic VTEs occurred in 3040 participants from four studies. In a study of 2551 participants, representing 85% of the review population in cardiac surgery, the combination of unfractionated heparin with pneumatic compression stockings was associated with a 61% reduction of symptomatic VTE compared to unfractionated heparin alone (1.5% versus 4.0%; risk ratio (RR) 0.39; 95% confidence interval (CI) 0.23 to 0.64). Major bleeding was only reported in one study, which found a higher incidence with vitamin K antagonists compared to platelet inhibitors (11.3% versus 1.6%, RR 7.06; 95% CI 1.64 to 30.40). In thoracic surgery, 15 symptomatic VTEs occurred in 2890 participants from six studies. In the largest study evaluating unfractionated heparin versus an inactive control the rates of symptomatic VTE were 0.7% versus 0%, respectively, giving a RR of 6.71 (95% CI 0.40 to 112.65). There was insufficient evidence to determine if there was a difference in the risk of major bleeding from two studies evaluating fixed-dose versus weight-adjusted low molecular weight heparin (2.7% versus 8.1%, RR 0.33; 95% CI 0.07 to 1.60) and unfractionated heparin versus low molecular weight heparin (6% and 4%, RR 1.50; 95% CI 0.26 to 8.60). AUTHORS' CONCLUSIONS The evidence regarding the efficacy and safety of thromboprophylaxis in cardiac and thoracic surgery is limited. Data for important outcomes such as pulmonary embolism or major bleeding were often lacking. Given the uncertainties around the benefit-to-risk balance, no conclusions can be drawn and a case-by-case risk evaluation of VTE and bleeding remains preferable.

Anticoagulation Management Practices and Outcomes in Elderly Patients with Acute Venous Thromboembolism: A Clinical Research Study.

Whether anticoagulation management practices are associated with improved outcomes in elderly patients with acute venous thromboembolism (VTE) is uncertain. Thus, we aimed to examine whether practices recommended by the American College of Chest Physicians guidelines are associated with outcomes in elderly patients with VTE. We studied 991 patients aged ≥65 years with acute VTE in a Swiss prospective multicenter cohort study and assessed the adherence to four management practices: parenteral anticoagulation ≥5 days, INR ≥2.0 for ≥24 hours before stopping parenteral anticoagulation, early start with vitamin K antagonists (VKA) ≤24 hours of VTE diagnosis, and the use of low-molecular-weight heparin (LMWH) or fondaparinux. The outcomes were all-cause mortality, VTE recurrence, and major bleeding at 6 months, and the length of hospital stay (LOS). We used Cox regression and lognormal survival models, adjusting for patient characteristics. Overall, 9% of patients died, 3% had VTE recurrence, and 7% major bleeding. Early start with VKA was associated with a lower risk of major bleeding (adjusted hazard ratio 0.37, 95% CI 0.20-0.71). Early start with VKA (adjusted time ratio [TR] 0.77, 95% CI 0.69-0.86) and use of LMWH/fondaparinux (adjusted TR 0.87, 95% CI 0.78-0.97) were associated with a shorter LOS. An INR ≥2.0 for ≥24 hours before stopping parenteral anticoagulants was associated with a longer LOS (adjusted TR 1.2, 95% CI 1.08-1.33). In elderly patients with VTE, the adherence to recommended anticoagulation management practices showed mixed results. In conclusion, only early start with VKA and use of parenteral LMWH/fondaparinux were associated with better outcomes.

Na(+), K(+), Cl(-), acid-base or H2O homeostasis in children with urinary tract infections: a narrative review.

Guidelines on the diagnosis and management of urinary tract infections in childhood do not address the issue of abnormalities in Na(+), K(+), Cl(-) and acid-base balance. We have conducted a narrative review of the literature with the aim to describe the underlying mechanisms of these abnormalities and to suggest therapeutic maneuvers. Abnormalities in Na(+), K(+), Cl(-) and acid-base balance are common in newborns and infants and uncommon in children of more than 3 years of age. Such abnormalities may result from factitious laboratory results, from signs and symptoms (such as excessive sweating, poor fluid intake, vomiting and passage of loose stools) of the infection itself, from a renal dysfunction, from improper parenteral fluid management or from the prescribed antimicrobials. In addition, two transient renal tubular dysfunctions may occur in infants with infectious renal parenchymal involvement: a reduced capacity to concentrate urine and pseudohypoaldosteronism secondary to renal tubular unresponsiveness to aldosterone that presents with hyponatremia, hyperkalemia and acidosis. In addition to antimicrobials, volume resuscitation with an isotonic solution is required in these children. In secondary pseudohypoaldosteronism, isotonic solutions (such as 0.9 % saline or lactated Ringer) correct not only the volume depletion but also the hyperkalemia and acidosis. In conclusion, our review suggests that in infants with infectious renal parenchymal involvement, non-renal and renal causes concur to cause fluid volume depletion and abnormalities in electrolyte and acid-base balance, most frequently hyponatremia.