Prevalence, Management, and Outcomes Related to Preoperative Medical Orders for Life Sustaining Treatment (MOLST) in an Adult Surgical Population: Preoperative MOLST and Code Status Discussions.

OBJECTIVE: To determine prevalence of documented preoperative code status discussions and postoperative outcomes (specifically mortality, readmission, and discharge disposition) of patients with completed MOLST forms before surgery. SUMMARY OF BACKGROUND DATA: A MOLST form documents patient care preference regarding treatment limitations. When considering surgery in these patients, preoperative discussion is necessary to ensure concordance of care. Little is known about prevalence of these discussions and postoperative outcomes. METHODS: A retrospective cohort study was conducted consisting of all patients having surgery during a 1-year period at a tertiary care academic center in Boston, Massachusetts. RESULTS: Among 21,787 surgical patients meeting inclusion criteria, 402 (1.8%) patients had preoperative MOLST. Within the MOLST, 224 (55.7%) patients had chosen to limit cardiopulmonary resuscitation and 214 (53.2%) had chosen to limit intubation and mechanical ventilation. Code status discussion was documented presurgery in 169 (42.0%) patients with MOLST. Surgery was elective or nonurgent for 362 (90%), and median length of stay (Q1, Q3) was 5.1 days (1.9, 9.9). The minority of patients with preoperative MOLST were discharged home [169 (42%), and 103 (25.6%) patients were readmitted within 30 days. Patients with preoperative MOLST had a 30-day mortality of 9.2% (37 patients) and cumulative 90-day mortality of 14.9% (60 patients). CONCLUSIONS: Fewer than half of surgical patients with preoperative MOLST have documented code status discussions before surgery. Given their high risk of postoperative mortality and the diversity of preferences found in MOLST, thoughtful discussion before surgery is critical to ensure concordant perioperative care.

The cytoprotective role of GM1 ganglioside in Huntington disease cells.

BACKGROUND: Huntington disease (HD) is a neurodegenerative disease where a genetic mutation leads to excessive polyglutamine (Q) repeats in the huntingtin protein. The polyglutamine repeats create toxic plaques when the protein is cleaved, leading to neuron death. The glycolipid GM1 ganglioside (GM1) has been shown to be neuroprotective in HD models, as it prevents the cleavage of the mutant huntingtin protein by phosphorylation of serine 13 and 16. Previous studies have tested GM1 in both adult-onset and juvenile-onset HD models, but this study set out to investigate whether GM1 mediated cytoprotection is influenced by the length of polyglutamine repeats. METHOD AND RESULT: This study utilized cell culture to analyze the effect of GM1 on cell viability, directly comparing the response between cells with adult-onset HD and juvenile-onset HD. HEK293 cells expressing either wild-type huntingtin (Htt) (19Q) exon 1, adult-onset HD mutant Htt exon 1 (55Q), or Juvenile HD mutant Htt exon 1 (94Q) were assessed for cell viability using the WST-1 assay. Our results suggested moderate doses of GM1 increased cell viability for all cell lines when compared to untreated cells. When comparing HEK293 55Q and 94Q cells, there was no difference in cell viability within each dose of GM1. CONCLUSION: These data suggest cellular responses to GM1 are independent of polyglutamine repeats in HD cells and provide insight on GM1's application as a therapeutic agent for HD and other diseases.

Gut microbial ß-glucuronidases regulate host luminal proteases and are depleted in irritable bowel syndrome.

Intestinal proteases mediate digestion and immune signalling, while increased gut proteolytic activity disrupts the intestinal barrier and generates visceral hypersensitivity, which is common in irritable bowel syndrome (IBS). However, the mechanisms controlling protease function are unclear. Here we show that members of the gut microbiota suppress intestinal proteolytic activity through production of unconjugated bilirubin. This occurs via microbial ß-glucuronidase-mediated conversion of bilirubin conjugates. Metagenomic analysis of faecal samples from patients with post-infection IBS (n = 52) revealed an altered gut microbiota composition, in particular a reduction in Alistipes taxa, and high gut proteolytic activity driven by specific host serine proteases compared with controls. Germ-free mice showed 10-fold higher proteolytic activity compared with conventional mice. Colonization with microbiota samples from high proteolytic activity IBS patients failed to suppress proteolytic activity in germ-free mice, but suppression of proteolytic activity was achieved with colonization using microbiota from healthy donors. High proteolytic activity mice had higher intestinal permeability, a higher relative abundance of Bacteroides and a reduction in Alistipes taxa compared with low proteolytic activity mice. High proteolytic activity IBS patients had lower fecal ß-glucuronidase activity and end-products of bilirubin deconjugation. Mice treated with unconjugated bilirubin and ß-glucuronidase-overexpressing E. coli significantly reduced proteolytic activity, while inhibitors of microbial ß-glucuronidases increased proteolytic activity. Together, these data define a disease-relevant mechanism of host-microbial interaction that maintains protease homoeostasis in the gut.

Decreased Trabecular Bone Mass in Col22a1-Deficient Mice.

The bone matrix is constantly remodeled by the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. Whereas type I collagen is the most abundant bone matrix protein, there are several other proteins present, some of them specifically produced by osteoblasts. In a genome-wide expression screening for osteoblast differentiation markers we have previously identified two collagen-encoding genes with unknown function in bone remodeling. Here we show that one of them, Col22a1, is predominantly expressed in bone, cultured osteoblasts, but not in osteoclasts. Based on this specific expression pattern we generated a Col22a1-deficient mouse model, which was analyzed for skeletal defects by µCT, undecalcified histology and bone-specific histomorphometry. We observed that Col22a1-deficient mice display trabecular osteopenia, accompanied by significantly increased osteoclast numbers per bone surface. In contrast, cortical bone parameters, osteoblastogenesis or bone formation were unaffected by the absence of Col22a1. Likewise, primary osteoblasts from Col22a1-deficient mice did not display a cell-autonomous defect, and they did not show altered expression of Rankl or Opg, two key regulators of osteoclastogenesis. Taken together, we provide the first evidence for a physiological function of Col22a1 in bone remodeling, although the molecular mechanisms explaining the indirect influence of Col22a1 deficiency on osteoclasts remain to be identified.

Intestinal chemosensitivity in irritable bowel syndrome associates with small intestinal TRPV channel expression.

BACKGROUND: Irritable bowel syndrome (IBS) patients often experience meal-associated symptoms. However, the underlying mechanisms are unclear. AIM: To determine small intestinal mechanisms of lipid-induced symptoms and rectal hypersensitivity in IBS METHODS: We recruited 26 IBS patients (12 IBS-C, 14 IBS-D) and 15 healthy volunteers (HV). In vivo permeability was assessed using saccharide excretion assay. Rectal sensitivity was assessed using a barostat before and after small bowel lipid infusion; symptoms were assessed throughout. Next, an extended upper endoscopy with probe-based confocal laser endomicroscopy (pCLE) was performed with changes induced by lipids. Duodenal and jejunal mucosal biopsies were obtained for transcriptomics. RESULTS: Following lipid infusion, a higher proportion of HV than IBS patients reported no pain, no nausea, no fullness and no urgency (P < 0.05 for all). In a model adjusted for sex and anxiety, IBS-C and IBS-D patients had lower thresholds for first rectal sensation (P = 0.0007) and pain (P = 0.004) than HV. In vivo small intestinal permeability and mean pCLE scores were similar between IBS patients and HV. Post-lipid, pCLE scores were higher than pre-lipid but were not different between groups. Baseline duodenal transient receptor potential vanilloid (TRPV) 1 and 3 expression was increased in IBS-D, and TRPV3 in IBS-C. Duodenal TRPV1 expression correlated with abdominal pain (r = 0.51, FDR = 0.01), and inversely with first rectal sensation (r = -0.48, FDR = 0.01) and pain (r = -0.41, FDR = 0.02) thresholds. CONCLUSION: Lipid infusion elicits a greater symptom response in IBS patients than HV, which is associated with small intestinal expression of TRPV channels. TRPV-mediated small intestinal chemosensitivity may mediate post-meal symptoms in IBS.

Campylobacter jejuni genotypes are associated with post-infection irritable bowel syndrome in humans.

Campylobacter enterocolitis may lead to post-infection irritable bowel syndrome (PI-IBS) and while some C. jejuni strains are more likely than others to cause human disease, genomic and virulence characteristics promoting PI-IBS development remain uncharacterized. We combined pangenome-wide association studies and phenotypic assays to compare C. jejuni isolates from patients who developed PI-IBS with those who did not. We show that variation in bacterial stress response (Cj0145_phoX), adhesion protein (Cj0628_CapA), and core biosynthetic pathway genes (biotin: Cj0308_bioD; purine: Cj0514_purQ; isoprenoid: Cj0894c_ispH) were associated with PI-IBS development. In vitro assays demonstrated greater adhesion, invasion, IL-8 and TNFα secretion on colonocytes with PI-IBS compared to PI-no-IBS strains. A risk-score for PI-IBS development was generated using 22 genomic markers, four of which were from Cj1631c, a putative heme oxidase gene linked to virulence. Our finding that specific Campylobacter genotypes confer greater in vitro virulence and increased risk of PI-IBS has potential to improve understanding of the complex host-pathogen interactions underlying this condition.

Intestinal barrier dysfunction in irritable bowel syndrome: a systematic review.

BACKGROUND AND AIM: Irritable bowel syndrome (IBS) is a complex and heterogeneous disorder. Sensory, motor and barrier dysfunctions are the key physiological endophenotypes of IBS. Our aim is to review studies evaluating barrier dysfunction in adults and children with IBS, as well as to link those changes with IBS symptomatology and quality of life. METHODS: A comprehensive and systematic review of multiple databases was performed up to March 2020 to identify studies comparing intestinal permeability in IBS patients with healthy controls. Both in vivo and in vitro studies were considered. RESULTS: We identified 66 studies, of which 27 used intestinal probes to quantify barrier function. The prevalence of barrier dysfunction differed between PI-IBS (17-50%), IBS-D (37-62%) and IBS-C (4-25%). At a group level, permeability was increased compared with healthy controls in IBS-D (9/13 studies) and PI-IBS (4/4 studies), but only a minority of IBS-C (2/7 studies) and not in the only IBS-M study. All four studies in children with IBS demonstrated loss of barrier function. A heterogeneous set of tight junction genes were found to be altered in small and large intestines of adults with IBS, but these have not been evaluated in children. Positive associations were identified between barrier dysfunction and bowel disturbances (6/9 studies), abdominal pain (9/13 studies), overall symptom severity (1/6 studies), depression and anxiety (1/1 study) and quality of life (1/4 studies). Fecal slurry or supernatants of IBS patients were found to induce barrier disruption in animal models (5/6 studies). CONCLUSIONS: Barrier dysfunction is present in a significant proportion of adult and all pediatric IBS studies, especially in the IBS-D and PI-IBS subtype. The majority of studies indicated a positive association between loss of barrier function and symptoms such as abdominal pain and changes in the bowel function.

Interprofessional learning during SARS-CoV-2 (COVID-19) pandemic conditions: the learning project I-reCovEr as a substitute for a rotation on an interprofessional training ward.

The COVID-19 pandemic has led to massive and aprupt changes in the training of health care professionals. Especially hands-on training can no longer take place in the usual form in everyday clinical practice. Rotations on the interprofessional training ward in Pediatrics (IPAPAED) at the University Medical Center Freiburg, had to be suspended starting March 2020. This report presents the interprofessional Covid-19 Replacement Program (I-reCovEr) as an alternative learning format for a rotation on the IPAPAED at the Center for Pediatric and Adolescent Medicine. I-reCovEr offers opportunities for pediatric nursing trainees (n=6) and medical students (n=9) to learn together, taking hygienic and distancing measures into account. Based on a case study, selected learning aspects regarding interprofessional cooperation and communication are targeted. The participants report increased knowledge about the work of the other professional group in the evaluation using the Interprofessional Socialization and Valuing Scale (ISVS) -9A. In comparison to participants of the IPAPAED, however, the self-evaluation did not reveal any self-perceived acquisition of other interprofessional skills or competences. I-reCovEr can therefore serve as an introduction to interprofessional training, but it cannot replace interprofessional learning and working on an interprofessional training ward.

Duodenal mucosal secretory disturbances in functional dyspepsia.

BACKGROUND: There is increased recognition of duodenal disturbances (inflammation, altered mucosal protein expression, and chemosensitivity) in functional dyspepsia (FD). Besides sensorimotor functions, enteric submucosal neurons also regulate epithelial ion transport. We hypothesized that duodenal mucosal ion transport and expression of associated genes are altered in FD. METHODS: Duodenal mucosal ion transport (basal and acetylcholine- and glucose-evoked changes in short-circuit current [Isc]) and expression of associated genes and regulatory miRNAs were evaluated in 40 FD patients and 24 healthy controls. RESULTS: Basal Isc (FD: 88.2 [52.6] µA/cm2 vs healthy: 20.3 [50.2] µA/cm2 ; P ≤ .0001), acetylcholine-evoked Isc (FD: Emax 50.4 [35.8] µA/cm2 vs healthy: 16.6 [15] µA/cm2 ; P ≤ .001), and glucose-evoked Isc responses (FD: Emax 69.8 [42.1] µA/cm2 vs healthy: 40.3 [24.6] µA/cm2 ; P = .02) were greater in FD than in controls. The Emax for glucose was greater in FD patients on selective serotonin reuptake inhibitors. In FD, the mRNA expression of SLC4A7 and SLC4A4, which transport bicarbonate into cells at the basolateral surface, and the apical anion exchanger SLC26A3 were reduced (false discovery rate <0.05), the serotonin receptor HTR4 was increased, and the serotonin transporter SLC6A4 was decreased. Selected miRNAs (hsa-miR-590-3p, hsa-miR-32-5p) that target genes associated with ionic transport were upregulated in FD. CONCLUSIONS: Compared to controls, FD patients had greater baseline and agonist-evoked duodenal mucosal secretory responses. These findings may be explained by reduced gene expression, which would be anticipated to reduce luminal bicarbonate secretion. The upregulated miRNAs may partly explain the downregulation of these genes in FD.

Protecting children across borders - child protection in an international context (Germany/Switzerland) as an interprofessional teaching unit.

Introduction: Interprofessional collaboration (IPC) in everyday clinical practice is a prerequisite for good patient care but currently this is not sufficiently anchored in the education of health care professionals. Project description: A course on child protection in the interprofessional and international domain was established at the Medical School, University of Freiburg. In this course, students of medicine, nursing science and social work acquire skills for successful interprofessional cooperation. Its participants learn across professional and national borders, not only with but also from and about each other. In this way, they deepen their insights into international IPC through a key topic that is relevant to many disciplines. The course is run as a one-day campus day. This paper presents the course setup and evaluation results. Methods: The evaluation was carried out online and in writing in a before and after format using the Freiburg Questionnaire for Interprofessional Learning Evaluation (FILE) in addition to oral feedback. Learning objectives for IPC and child protection were formulated and the participants were asked about their subjective achievements. Results: From summer semester (SuSe) 2017 to SuSe 2018, 39 participants took part in the course. It was rated as m=1.5 (using German school grades where 1=very good, 6=unsatisfactory). In 18 of the 26 FILE items, participants report a self-assessed increase in knowledge or skills/abilities. This growth in learning coincides with the learning objectives set. Discussion & conclusion: From the perspective of the participants, the course teaches interprofessional competencies in an international setting and is seen as an informative course offer. The continuation or expansion of such courses as a supplement to purely single-country interprofessional courses is desirable.

Association of obesity with postoperative outcomes after proctectomy.

BACKGROUND: Prior efforts evaluating obesity as a risk factor for postoperative complications following proctectomy have been limited by sample size and uniform outcome classification. METHODS: The ACS NSQIP was queried for patients with non-metastatic rectal adenocarcinoma who underwent elective proctectomy. After stratification by BMI classification, multivariable modeling was used to identify the effect of BMI class on adjusted risk of 30-day outcomes controlling for patient, procedure, and tumor factors. RESULTS: Of 2241 patients identified, 33.4% had a normal BMI, 33.5% were overweight, 21.1% were obese, and 12.0% were morbidly obese. Increased risk of superficial surgical site infection (SSI) was observed in obese (OR 2.42, 95%CI:[1.36-4.29]) and morbidly obese (OR 3.29, 95%CI:[1.77-6.11]) patients when compared to normal BMI. Morbid obesity was associated with increased risk of any complication (OR 1.44, 95%CI:[1.05-1.96]). BMI class was not associated with risk adjusted odds of anastomotic leak. CONCLUSIONS: Morbid obesity is independently associated with an increased composite odds risk of short-term morbidity following elective proctectomy for cancer primarily due to increased risk of superficial SSI.

Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS.

OBJECTIVE: The intestinal lumen contains several proteases. Our aim was to determine the role of faecal proteases in mediating barrier dysfunction and symptoms in IBS. DESIGN: 39 patients with IBS and 25 healthy volunteers completed questionnaires, assessments of in vivo permeability, ex vivo colonic barrier function in Ussing chambers, tight junction (TJ) proteins, ultrastructural morphology and 16 s sequencing of faecal microbiota rRNA. A casein-based assay was used to measure proteolytic activity (PA) in faecal supernatants (FSNs). Colonic barrier function was determined in mice (ex-germ free) humanised with microbial communities associated with different human PA states. RESULTS: Patients with IBS had higher faecal PA than healthy volunteers. 8/20 postinfection IBS (PI-IBS) and 3/19 constipation- predominant IBS had high PA (>95th percentile). High-PA patients had more and looser bowel movements, greater symptom severity and higher in vivo and ex vivo colonic permeability. High-PA FSNs increased paracellular permeability, decreased occludin and increased phosphorylated myosin light chain (pMLC) expression. Serine but not cysteine protease inhibitor significantly blocked high-PA FSN effects on barrier. The effects on barrier were diminished by pharmacological or siRNA inhibition of protease activated receptor-2 (PAR-2). Patients with high-PA IBS had lower occludin expression, wider TJs on biopsies and reduced microbial diversity than patients with low PA. Mice humanised with high-PA IBS microbiota had greater in vivo permeability than those with low-PA microbiota. CONCLUSION: A subset of patients with IBS, especially in PI-IBS, has substantially high faecal PA, greater symptoms, impaired barrier and reduced microbial diversity. Commensal microbiota affects luminal PA that can influence host barrier function.

Revealing Novel IDEAS: A Fiduciary Framework for Team-Based Prescribing.

The importance of safe, effective, and cost-effective prescribing habits can hardly be overstated in the current pay-for-value environment. The prescribing process taught in most medical curricula focuses primarily on accurate medical indications. While this may be of utmost importance from the clinician's perspective, it falls short of addressing the other key elements of highly effective prescribing. These other elements are often paramount in the minds of patients. A patient-centric framework that associates and incorporates the necessary components of optimal prescribing is overdue. Building this framework into medical curricula will foster increased teamwork among providers and enhance shared decision making between patients and clinicians. In addition to establishing accurate medical indications, prescribing teams need to assure every prescribed medication is desired, effective, affordable, and safe for patients who receive them. Prescription writing is an honorable prerogative, and doing so safely, effectively, and cost-effectively requires both teamwork and technology. Highly effective prescribing teams can implement the IDEAS (Indicated, Desired, Effective, Affordable, Safe) framework through appropriate and deliberate delegation. By empowering members of the care team to support and educate patients, this framework will allow physicians to focus on ensuring appropriate indications and real-world effectiveness. This novel IDEAS framework serves as an important mental model for medical trainees and reinforces sound prescribing habits among seasoned clinicians. High-touch and high-tech partnerships have the potential to maximize the triple aim (i.e., improving the patient's experience of care, improving the health of populations, and reducing the per capita cost of health care). In an era when costs overwhelm quality, providing a fiduciary framework to instill responsibility for optimal prescribing, especially among young physician-leaders, is invaluable.

Prevention of Pressure Ulcers in a Pediatric Cardiac Intensive Care Unit.

BACKGROUND: Pressure ulcer (PU) is an injury to skin or underlying tissue as a result of pressure or pressure with shear stress. We classify PUs by the level of tissue injury: stage I-IV, unstageable, suspected deep tissue injury. This quality project was aimed to reduce the incidence of PUs > stage II in the cardiothoracic intensive care unit. METHODS: We reviewed PUs > stage II from March 2010 to December 2017. Interventions included: PU bundle (April 2010, revised January 2013); multidisciplinary huddles for PUs > stage II (October 2011); multidisciplinary weekly skin rounds (March 2010, revised August 2012); unit specific workgroup (October 2012); caregiver input form (December 2012). The PU bundle included diaper barrier cream, pulse oximeter probe rotation, turning schedule, pressure reduction surfaces, heel pressure release, head of the bed elevation. RESULTS: Between 2010 and 2014, PUs decreased from 15.7 events per 1,000 patient days to a new baseline of 2.9 events per 1,000 patient days. We have sustained this rate for 3 years. PUs related to immobility decreased from 35 in 2010-2011 to 4 in 2016-2017. PU related to medical devices decreased from 34 in 2010-2011 to 15 in 2016-2017. CONCLUSIONS: Institution of PU bundle, multidisciplinary weekly skin rounds, and huddles for PUs > stage II reduced PUs related to immobility, allowed for earlier identification of stage II PUs and reduced stage III PUs. Challenges remain in reducing PUs related to medical devices. Importantly, we sustained this improvement over the past 3 years.

Temperature sensitivity of mineral-enzyme interactions on the hydrolysis of cellobiose and indican by ß-glucosidase.

Extracellular enzymes are mainly responsible for depolymerizing soil organic matter (SOM) in terrestrial ecosystems, and soil minerals are known to affect enzyme activity. However, the mechanisms and the effects of mineral-enzyme interactions on enzymatic degradation of organic matter remain poorly understood. In this study, we examined the adsorption of fungal ß-glucosidase enzyme on minerals and time-dependent changes of enzymatic reactivity, measured by the degradation of two organic substrates (i.e., cellobiose and indican) under both cold (4 °C) and warm (20 and 30 °C) conditions. Hematite, kaolinite, and montmorillonite were used, to represent three common soil minerals with distinctly different surface charges and characteristics. ß-glucosidase was found to sorb more strongly onto hematite and kaolinite than montmorillonite. All three minerals inhibited enzyme degradation of cellobiose and indican, likely due to the inactivation or hindrance of enzyme active sites. The mineral-bound ß-glucosidase retained its specificity for organic substrate degradation, and increasing temperature from 4 to 30 °C enhanced the degradation rates by 2-4 fold for indican and 5-9 fold for cellobiose. These results indicate that enzyme adsorption, mineral type, temperature, and organic substrate specificity are important factors influencing enzymatic reactivity and thus have important implications in further understanding and modeling complex enzyme-facilitated SOM transformations in terrestrial ecosystems.

Osteoblast-specific expression of Panx3 is dispensable for postnatal bone remodeling.

Since cost-effective osteoanabolic treatment options remain to be established, it is relevant to identify specific molecules physiologically regulating osteoblast differentiation and/or activity that are principally accessible as drug targets. Specific or predominant gene expression in a given cell type often predicts a relevant function in the respective tissue. Thus, we aimed to identify genes encoding membrane-associated proteins with selective expression in differentiated osteoblasts. We therefore applied an unbiased approach, i.e. Affymetrix Gene Chip hybridization, to compare global gene expression in primary murine osteoblasts at two stages of differentiation. For the most strongly induced genes we analyzed their expression pattern in different tissues, which led us to identify known and unknown osteoblast differentiation markers with predominant expression in bone. One of these genes was Panx3, encoding a transmembrane hemichannel with ill-defined function in skeletal remodeling. To decipher the role of Panx3 in osteoblasts we first generated Panx3-fl/fl mice carrying a Runx2-Cre transgene. Using undecalcified histology followed by bone-specific histomorphometry we did not observe any significant difference between 24 weeks old Cre-negative and Cre-positive littermates. We additionally generated and analyzed mice with ubiquitous Panx3 deletion, where a delay of endochondral ossification did not translate into a detectable skeletal phenotype after weaning, possibly explained by compensatory induction of Panx1. Of note, newborn Panx3-deficient mice displayed significantly reduced serum glucose levels, which was not the case in older animals. Our findings demonstrate that Panx3 expression in osteoblasts is not required for postnatal bone remodeling, which essentially rules out its suitability as a target protein for osteoanabolic medication.

Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders.

Small intestinal bacterial overgrowth (SIBO) has been implicated in symptoms associated with functional gastrointestinal disorders (FGIDs), though mechanisms remain poorly defined and treatment involves non-specific antibiotics. Here we show that SIBO based on duodenal aspirate culture reflects an overgrowth of anaerobes, does not correspond with patient symptoms, and may be a result of dietary preferences. Small intestinal microbial composition, on the other hand, is significantly altered in symptomatic patients and does not correspond with aspirate culture results. In a pilot interventional study we found that switching from a high fiber diet to a low fiber, high simple sugar diet triggered FGID-related symptoms and decreased small intestinal microbial diversity while increasing small intestinal permeability. Our findings demonstrate that characterizing small intestinal microbiomes in patients with gastrointestinal symptoms may allow a more targeted antibacterial or a diet-based approach to treatment.

Systems Delivery Innovation for Alzheimer Disease.

OBJECTIVE: The authors describe a comprehensive care model for Alzheimer disease (AD) that improves value within 1-3 years after implementation by leveraging targeted outpatient chronic care management, cognitively protective acute care, and timely caregiver support. METHODS: Using current best evidence, expert opinion, and macroeconomic modeling, the authors designed a comprehensive care model for AD that improves the quality of care while reducing total per capita healthcare spending by more than 15%. Cost savings were measured as reduced spending by payers. Cost estimates were derived from medical literature and national databases, including both public and private U.S. payers. All estimates reflect the value in 2015 dollars using a consumer price index inflation calculator. Outcome estimates were determined at year 2, accounting for implementation and steady-state intervention costs. RESULTS: After accounting for implementation and recurring operating costs of approximately $9.5 billion, estimated net cost savings of between $13 and $41 billion can be accomplished concurrently with improvements in quality and experience of coordinated chronic care ($0.01-$6.8 billion), cognitively protective acute care ($8.7-$26.6 billion), timely caregiver support ($4.3-$7.5 billion), and caregiver efficiency ($4.1-$7.2 billion). CONCLUSION: A high-value care model for AD may improve the experience of patients with AD while significantly lowering costs.

Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand.

WNT1 mutations in humans are associated with a new form of osteogenesis imperfecta and with early-onset osteoporosis, suggesting a key role of WNT1 in bone mass regulation. However, the general mode of action and the therapeutic potential of Wnt1 in clinically relevant situations such as aging remain to be established. Here, we report the high prevalence of heterozygous WNT1 mutations in patients with early-onset osteoporosis. We show that inactivation of Wnt1 in osteoblasts causes severe osteoporosis and spontaneous bone fractures in mice. In contrast, conditional Wnt1 expression in osteoblasts promoted rapid bone mass increase in developing young, adult, and aged mice by rapidly increasing osteoblast numbers and function. Contrary to current mechanistic models, loss of Lrp5, the co-receptor thought to transmit extracellular WNT signals during bone mass regulation, did not reduce the bone-anabolic effect of Wnt1, providing direct evidence that Wnt1 function does not require the LRP5 co-receptor. The identification of Wnt1 as a regulator of bone formation and remodeling provides the basis for development of Wnt1-targeting drugs for the treatment of osteoporosis.