Cork University Hospital

PURPOSE: Screening tool of older people's prescriptions (STOPP) and screening tool to alert to right treatment (START) criteria were first published in 2008. Due to an expanding therapeutics evidence base, updating of the criteria was required. METHODS: We reviewed the 2008 STOPP/START criteria to add new evidence-based criteria and remove any obsolete criteria. A thorough literature review was performed to reassess the evidence base of the 2008 criteria and the proposed new criteria. Nineteen experts from 13 European countries reviewed a new draft of STOPP & START criteria including proposed new criteria. These experts were also asked to propose additional criteria they considered important to include in the revised STOPP & START criteria and to highlight any criteria from the 2008 list they considered less important or lacking an evidence base. The revised list of criteria was then validated using the Delphi consensus methodology. RESULTS: The expert panel agreed a final list of 114 criteria after two Delphi validation rounds, i.e. 80 STOPP criteria and 34 START criteria. This represents an overall 31% increase in STOPP/START criteria compared with version 1. Several new STOPP categories were created in version 2, namely antiplatelet/anticoagulant drugs, drugs affecting, or affected by, renal function and drugs that increase anticholinergic burden; new START categories include urogenital system drugs, analgesics and vaccines. CONCLUSION: STOPP/START version 2 criteria have been expanded and updated for the purpose of minimizing inappropriate prescribing in older people. These criteria are based on an up-to-date literature review and consensus validation among a European panel of experts.

Alterations in the human intestinal microbiota are linked to conditions including inflammatory bowel disease, irritable bowel syndrome, and obesity. The microbiota also undergoes substantial changes at the extremes of life, in infants and older people, the ramifications of which are still being explored. We applied pyrosequencing of over 40,000 16S rRNA gene V4 region amplicons per subject to characterize the fecal microbiota in 161 subjects aged 65 y and older and 9 younger control subjects. The microbiota of each individual subject constituted a unique profile that was separable from all others. In 68% of the individuals, the microbiota was dominated by phylum Bacteroides, with an average proportion of 57% across all 161 baseline samples. Phylum Firmicutes had an average proportion of 40%. The proportions of some phyla and genera associated with disease or health also varied dramatically, including Proteobacteria, Actinobacteria, and Faecalibacteria. The core microbiota of elderly subjects was distinct from that previously established for younger adults, with a greater proportion of Bacteroides spp. and distinct abundance patterns of Clostridium groups. Analyses of 26 fecal microbiota datasets from 3-month follow-up samples indicated that in 85% of the subjects, the microbiota composition was more like the corresponding time-0 sample than any other dataset. We conclude that the fecal microbiota of the elderly shows temporal stability over limited time in the majority of subjects but is characterized by unusual phylum proportions and extreme variability.

OBJECTIVE: Older people experience more concurrent illnesses, are prescribed more medications and suffer more adverse drug events than younger people. Many drugs predispose older people to adverse events such as falls and cognitive impairment, thus increasing morbidity and health resource utilization. At the same time, older people are often denied potentially beneficial, clinically indicated medications without a valid reason. We aimed to validate a new screening tool of older persons' prescriptions incorporating criteria for potentially inappropriate drugs called STOPP (Screening Tool of Older Persons' Prescriptions) and criteria for potentially appropriate, indicated drugs called START (Screening Tool to Alert doctors to Right, i.e. appropriate, indicated Treatment). METHODS: A Delphi consensus technique was used to establish the content validity of STOPP/START. An 18-member expert panel from academic centers in Ireland and the United Kingdom completed two rounds of the Delphi process by mail survey. Inter-rater reliability was assessed by determining the kappa-statistic for measure of agreement on 100 data-sets. RESULTS: STOPP is comprised of 65 clinically significant criteria for potentially inappropriate prescribing in older people. Each criterion is accompanied by a concise explanation as to why the prescribing practice is potentially inappropriate. START consists of 22 evidence-based prescribing indicators for commonly encountered diseases in older people. Inter-rater reliability is favorable with a kappa-coefficient of 0.75 for STOPP and 0.68 for START. CONCLUSION: STOPP/START is a valid, reliable and comprehensive screening tool that enables the prescribing physician to appraise an older patient's prescription drugs in the context of his/her concurrent diagnoses.

OBJECTIVE: The commensal microbiota, host immunity and metabolism participate in a signalling network, with diet influencing each component of this triad. In addition to diet, many elements of a modern lifestyle influence the gut microbiota but the degree to which exercise affects this population is unclear. Therefore, we explored exercise and diet for their impact on the gut microbiota. DESIGN: Since extremes of exercise often accompany extremes of diet, we addressed the issue by studying professional athletes from an international rugby union squad. Two groups were included to control for physical size, age and gender. Compositional analysis of the microbiota was explored by 16S rRNA amplicon sequencing. Each participant completed a detailed food frequency questionnaire. RESULTS: As expected, athletes and controls differed significantly with respect to plasma creatine kinase (a marker of extreme exercise), and inflammatory and metabolic markers. More importantly, athletes had a higher diversity of gut micro-organisms, representing 22 distinct phyla, which in turn positively correlated with protein consumption and creatine kinase. CONCLUSIONS: The results provide evidence for a beneficial impact of exercise on gut microbiota diversity but also indicate that the relationship is complex and is related to accompanying dietary extremes.

BACKGROUND: It is increasingly recognized that the impact of disease on quality of life should be taken into account when assessing health status. It is likely that tooth loss, in most cases being a consequence of oral diseases, affects Oral Health-Related Quality of Life (OHRQoL). The aim of the present study is to systematically review the literature and to analyse the relationship between the number and location of missing teeth and oral health-related quality of life (OHRQoL). It was hypothesized that tooth loss is associated with an impairment of OHRQoL. Secondly, it was hypothesized that location and distribution of remaining teeth play an important role in this. METHODS: Relevant databases were searched for papers in English, published from 1990 to July 2009 following a broad search strategy. Relevant papers were selected by two independent readers using predefined exclusion criteria, firstly on the basis of abstracts, secondly by assessing full-text papers. Selected studies were grouped on the basis of OHRQoL instruments used and assessed for feasibility for quantitative synthesis. Comparable outcomes were subjected to meta-analysis; remaining outcomes were subjected to a qualitative synthesis only. RESULTS: From a total of 924 references, 35 were eligible for synthesis (inter-reader agreement abstracts κ = 0.84 ± 0.03; full-texts: κ = 0.68 ± 0.06). Meta-analysis was feasible for 10 studies reporting on 13 different samples, resulting in 6 separate analyses. All studies showed that tooth loss is associated with unfavourable OHRQoL scores, independent of study location and OHRQoL instrument used. Qualitative synthesis showed that all 9 studies investigating a possible relationship between number of occluding pairs of teeth present and OHRQoL reported significant positive correlations. Five studies presented separate data regarding OHRQoL and location of tooth loss (anterior tooth loss vs. posterior tooth loss). Four of these reported highest impact for anterior tooth loss; one study indicated a similar impact for both locations of tooth loss. CONCLUSIONS: This study provides fairly strong evidence that tooth loss is associated with impairment of OHRQoL and location and distribution of tooth loss affect the severity of the impairment. This association seems to be independent from the OHRQoL instrument used and context of the included samples.

BACKGROUND AND METHODS: In February 1994, batches of anti-D immune globulin used in Ireland during 1977 and 1978 to prevent Rh isoimmunization were found to be contaminated with hepatitis C virus (HCV) from a single infected donor. In March 1994, a national screening program was initiated for all women who had received anti-D immune globulin between 1970 and 1994. Of the 62,667 women who had been screened when this study began, 704 (1.1 percent) had evidence of past or current HCV infection, and 390 of those 704 (55 percent) had positive tests for serum HCV RNA on reverse-transcription-polymerase-chain-reaction analysis. All 390 were offered a referral for clinical assessment and therapy. We evaluated 376 of these 390 women (96 percent); the other 14 were not seen at one of the designated treatment centers. RESULTS: The mean (+/-SD) age of the 376 women was 45+/-6 years at the time of screening. They had been infected with hepatitis C for about 17 years. A total of 304 women (81 percent) reported symptoms, most commonly fatigue (248 [66 percent]). Serum alanine aminotransferase concentrations were slightly elevated (40 to 99 U per liter) in 176 of 371 women (47 percent), and the concentrations were 100 U per liter or higher in 31 (8 percent). Liver biopsies showed inflammation in 356 of 363 women (98 percent); in most cases the inflammation was slight (41 percent) or moderate (52 percent). Although the biopsy samples from 186 of the 363 women (51 percent) showed evidence of fibrosis, only 7 women (2 percent) had probable or definite cirrhosis. Two of the seven reported excessive alcohol consumption. CONCLUSIONS: Most of the women with HCV infection 17 years after receiving HCV-contaminated anti-D immune globulin had evidence of slight or moderate hepatic inflammation on liver biopsy, about half had fibrosis, and 2 percent had probable or definite cirrhosis.

The Academic Research Consortium (ARC)-2 initiative revisited the clinical and angiographic end point definitions in coronary device trials, proposed in 2007, to make them more suitable for use in clinical trials that include increasingly complex lesion and patient populations and incorporate novel devices such as bioresorbable vascular scaffolds. In addition, recommendations for the incorporation of patient-related outcomes in clinical trials are proposed. Academic Research Consortium-2 is a collaborative effort between academic research organizations in the United States and Europe, device manufacturers, and European, US, and Asian regulatory bodies. Several in-person meetings were held to discuss the changes that have occurred in the device landscape and in clinical trials and regulatory pathways in the last decade. The consensus-based end point definitions in this document are endorsed by the stakeholders of this document and strongly advocated for clinical trial purposes. This Academic Research Consortium-2 document provides further standardization of end point definitions for coronary device trials, incorporating advances in technology and knowledge. Their use will aid interpretation of trial outcomes and comparison among studies, thus facilitating the evaluation of the safety and effectiveness of these devices.

The study of biological systems in a holistic manner (systems biology) is increasingly being viewed as a necessity to provide qualitative and quantitative descriptions of the emergent properties of the complete system. Systems biology performs studies focussed on the complex interactions of system components; emphasising the whole system rather than the individual parts. Many perturbations to mammalian systems (diet, disease, drugs) are multi-factorial and the study of small parts of the system is insufficient to understand the complete phenotypic changes induced. Metabolomics is one functional level tool being employed to investigate the complex interactions of metabolites with other metabolites (metabolism) but also the regulatory role metabolites provide through interaction with genes, transcripts and proteins (e.g. allosteric regulation). Technological developments are the driving force behind advances in scientific knowledge. Recent advances in the two analytical platforms of mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy have driven forward the discipline of metabolomics. In this critical review, an introduction to metabolites, metabolomes, metabolomics and the role of MS and NMR spectroscopy will be provided. The applications of metabolomics in mammalian systems biology for the study of the health-disease continuum, drug efficacy and toxicity and dietary effects on mammalian health will be reviewed. The current limitations and future goals of metabolomics in systems biology will also be discussed (374 references).

Abstract The diffuse neuroendocrine system consists of specialised endocrine cells and peptidergic nerves and is present in all organs of the body. Substance P (SP) is secreted by nerves and inflammatory cells such as macrophages, eosinophils, lymphocytes, and dendritic cells and acts by binding to the neurokinin‐1 receptor (NK‐1R). SP has proinflammatory effects in immune and epithelial cells and participates in inflammatory diseases of the respiratory, gastrointestinal, and musculoskeletal systems. Many substances induce neuropeptide release from sensory nerves in the lung, including allergen, histamine, prostaglandins, and leukotrienes. Patients with asthma are hyperresponsive to SP and NK‐1R expression is increased in their bronchi. Neurogenic inflammation also participates in virus‐associated respiratory infection, non‐productive cough, allergic rhinitis, and sarcoidosis. SP regulates smooth muscle contractility, epithelial ion transport, vascular permeability, and immune function in the gastrointestinal tract. Elevated levels of SP and upregulated NK‐1R expression have been reported in the rectum and colon of patients with inflammatory bowel disease (IBD), and correlate with disease activity. Increased levels of SP are found in the synovial fluid and serum of patients with rheumatoid arthritis (RA) and NK‐1R mRNA is upregulated in RA synoviocytes. Glucocorticoids may attenuate neurogenic inflammation by decreasing NK‐1R expression in epithelial and inflammatory cells and increasing production of neutral endopeptidase (NEP), an enzyme that degrades SP. Preventing the proinflammatory effects of SP using tachykinin receptor antagonists may have therapeutic potential in inflammatory diseases such as asthma, sarcoidosis, chronic bronchitis, IBD, and RA. In this paper, we review the role that SP plays in inflammatory disease. J. Cell. Physiol. 201: 167–180, 2004. © 2004 Wiley‐Liss, Inc.

INTRODUCTION: STOPP (Screening Tool of Older Persons' potentially inappropriate Prescriptions) is a new, systems-defined medicine review tool. We compared the performance of STOPP to that of established Beers' criteria in detecting potentially inappropriate medicines (PIMs) and related adverse drug events (ADEs) in older patients presenting for hospital admission. METHODS: we prospectively studied 715 consecutive acute admissions to a university teaching hospital. Diagnoses, reason for admission and concurrent medications were recorded. STOPP and Beers' criteria were applied. PIMs with clear causal connection or contribution to the principal reason for admission were determined. RESULTS: median patient age (interquartile range) was 77 (72-82) years. Median number of prescription medicines was 6 (range 0-21). STOPP identified 336 PIMs affecting 247 patients (35%), of whom one-third (n = 82) presented with an associated ADE. Beers' criteria identified 226 PIMs affecting 177 patients (25%), of whom 43 presented with an associated ADE. STOPP-related PIMs contributed to 11.5% of all admissions. Beers' criteria-related PIMs contributed to significantly fewer admissions (6%). CONCLUSION: STOPP criteria identified a significantly higher proportion of patients requiring hospitalisation as a result of PIM-related adverse events than Beers' criteria. This finding has significant implications for hospital geriatric practice.

PURPOSE BRCA1 or BRCA2 ( BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study. METHODS We enrolled patients who progressed after one to two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate. RESULTS Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients). CONCLUSION Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.

BACKGROUND: Although Wernicke encephalopathy (WE) is a preventable and treatable disease it still often remains undiagnosed during life. OBJECTIVES: To create practical guidelines for diagnosis, management and prevention of the disease. METHODS: We searched MEDLINE, EMBASE, LILACS, Cochrane Library. CONCLUSIONS AND RECOMMENDATIONS: 1 The clinical diagnosis of WE should take into account the different presentations of clinical signs between alcoholics and non alcoholics (Recommendation Level C); although prevalence is higher in alcoholics, WE should be suspected in all clinical conditions which could lead to thiamine deficiency (good practice point - GPP). 2 The clinical diagnosis of WE in alcoholics requires two of the following four signs; (i) dietary deficiencies (ii) eye signs, (iii) cerebellar dysfunction, and (iv) either an altered mental state or mild memory impairment (Level B). 3 Total thiamine in blood sample should be measured immediately before its administration (GPP). 4 MRI should be used to support the diagnosis of acute WE both in alcoholics and non alcoholics (Level B). 5 Thiamine is indicated for the treatment of suspected or manifest WE. It should be given, before any carbohydrate, 200 mg thrice daily, preferably intravenously (Level C). 6 The overall safety of thiamine is very good (Level B). 7 After bariatric surgery we recommend follow-up of thiamine status for at least 6 months (Level B) and parenteral thiamine supplementation (GPP). 8 Parenteral thiamine should be given to all at-risk subjects admitted to the Emergency Room (GPP). 9 Patients dying from symptoms suggesting WE should have an autopsy (GPP).

PURPOSE: STOPP/START is a physiological systems-based explicit set of criteria that attempts to define the clinically important prescribing problems relating to potentially inappropriate medications (PIMs-STOPP criteria) and potential prescribing omissions (PPOs-START criteria). The previous two versions of STOPP/START criteria were published in 2008 and 2015. The present study describes the revised and updated third version of the criteria. METHODS: A detailed system-by-system review of the published literature from April 2014 to March 2022 was undertaken with the aim of including clinically important new explicit PIM and PPO criteria and removing any criteria considered to be no longer correct or outdated. A panel of 11 academic physicians with recognized expertise in geriatric pharmacotherapy from 8 European countries participated in a Delphi panel with the task of validating the draft criteria. The panel was presented with the draft new criteria using the SurveyMonkey® on-line platform in which panelists were asked to indicate their level of agreement on a five-point Likert scale. RESULTS: Two hundred and four evidence-based draft criteria (one hundred and forty-five STOPP criteria, fifty-nine START criteria) were presented to panelists for assessment using the Delphi validation method. Over the course of four rounds of Delphi validation, the panel achieved consensus on 133 STOPP criteria and 57 START criteria, i.e., 190 STOPP/START criteria in total representing a 66.7% increase in the number of criteria compared to STOPP/START version 2 published in 2015. CONCLUSION: A fully revised and updated version of STOPP/START criteria has been validated by a European expert panel using the Delphi consensus process.

BACKGROUND: Chronic pain is common in Europe and elsewhere and its under treatment confers a substantial burden on individuals, employers, healthcare systems and society in general. Indeed, the personal and socioeconomic impact of chronic pain is as great as, or greater, than that of other established healthcare priorities. In light of review of recently published data confirming its clinical and socioeconomic impact, this paper argues that chronic pain should be ranked alongside other conditions of established priority in Europe. We outline strategies to help overcome barriers to effective pain care resulting in particular from deficiencies in education and access to interdisciplinary pain management services. We also address the confusion that exists between proper clinical and scientific uses of opioid medications and their potential for misuse and diversion, as reflected in international variations in the access to, and availability of, these agents. DISCUSSION: As the economic costs are driven in part by the costs of lost productivity, absenteeism and early retirement, pain management should aim to fully rehabilitate patients, rather than merely to relieve pain. Accredited education of physicians and allied health professionals regarding state-of-the-art pain management is crucial. Some progress has been made in this area, but further provision and incentivization is required. We support a tiered approach to pain management, whereby patients with pain uncontrolled by non-specialists are able to consult a physician with a pain competency or a specialist in pain medicine, who in turn can recruit the services of other professionals on a case-by-case basis. A fully integrated interdisciplinary pain service should ideally be available to patients with refractory pain. Governments and healthcare systems should ensure that their policies on controlled medications are balanced, safeguarding public health without undue restrictions that compromise patient care, and that physician education programmes support these aims. SUMMARY: Strategic prioritization and co-ordinated actions are required nationally and internationally to address the unacceptable and unnecessary burden of uncontrolled chronic pain that plagues European communities and economies. An appreciation of the 'return on investment' in pain management services will require policymakers to adopt a long-term, cross-budgetary approach.

IMPORTANCE: A critical decision in the management of metastatic castration-resistant prostate cancer (mCRPC) is when to administer an androgen receptor signaling (ARS) inhibitor or a taxane. OBJECTIVE: To determine if pretherapy nuclear androgen-receptor splice variant 7 (AR-V7) protein expression and localization on circulating tumor cells (CTCs) is a treatment-specific marker for response and outcomes between ARS inhibitors and taxanes. DESIGN, SETTING, AND PARTICIPANTS: For this cross-sectional cohort study at Memorial Sloan Kettering Cancer Center, 265 men with progressive mCRPC undergoing a change in treatment were considered; 86 were excluded because they were not initiating ARS or taxane therapy; and 18 were excluded for processing time constraints, leaving 161 patients for analysis. Between December 2012 and March 2015, blood was collected and processed from patients with progressive mCRPC immediately prior to new line of systemic therapy. Patients were followed up to 3 years. MAIN OUTCOMES AND MEASURES: Prostate-specific antigen (PSA) response, time receiving therapy, radiographic progression-free survival (rPFS), and overall survival (OS). RESULTS: Overall, of 193 prospectively collected blood samples from 161 men with mCRPC, 191 were evaluable (128 pre-ARS inhibitor and 63 pretaxane). AR-V7-positive CTCs were found in 34 samples (18%), including 3% of first-line, 18% of second-line, and 31% of third- or greater line samples. Patients whose samples had AR-V7-positive CTCs before ARS inhibition had resistant posttherapy PSA changes (PTPC), shorter rPFS, shorter time on therapy, and shorter OS than those without AR-V7-positive CTCs. Overall, resistant PTPC were seen in 65 of 112 samples (58%) without detectable AR-V7-positive CTCs prior to ARS inhibition. There were statistically significant differences in OS but not in PTPC, time on therapy, or rPFS for patients with or without pretherapy AR-V7-positive CTCs treated with a taxane. A multivariable model adjusting for baseline factors associated with survival showed superior OS with taxanes relative to ARS inhibitors when AR-V7-positive CTCs were detected pretherapy (hazard ratio, 0.24; 95% CI, 0.10-0.57; P = .035). CONCLUSIONS AND RELEVANCE: The results validate CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker that is associated with superior survival on taxane therapy over ARS-directed therapy in a clinical practice setting. Continued examination of this biomarker in prospective studies will further aid clinical utility.

BACKGROUND AND METHODS: In some patients who are hospitalized for acute illness, we have noted a reversible syndrome of headache, altered mental functioning, seizures, and loss of vision associated with findings indicating predominantly posterior leukoencephalopathy on imaging studies. To elucidate this syndrome, we searched the log books listing computed tomographic (CT) and magnetic resonance imaging (MRI) studies performed at the New England Medical Center in Boston and Hôpital Sainte Anne in Paris; we found 15 such patients who were evaluated from 1988 through 1994. RESULTS: Of the 15 patients, 7 were receiving immunosuppressive therapy after transplantation or as treatment for aplastic anemia, 1 was receiving interferon for melanoma, 3 had eclampsia, and 4 had acute hypertensive encephalopathy associated with renal disease (2 with lupus nephritis, 1 with acute glomerulonephritis, and 1 with acetaminophen-induced hepatorenal failure). Altogether, 12 patients had abrupt increases in blood pressure, and 8 had some impairment of renal function. The clinical findings included headaches, vomiting, confusion, seizures, cortical blindness and other visual abnormalities, and motor signs. CT and MRI studies showed extensive bilateral white-matter abnormalities suggestive of edema in the posterior regions of the cerebral hemispheres, but the changes often involved other cerebral areas, the brain stem, or the cerebellum. The patients were treated with antihypertensive medications, and immunosuppressive therapy was withdrawn or the dose was reduced. In all 15 patients, the neurologic deficits resolved within two weeks. CONCLUSIONS: Reversible, predominantly posterior leukoencephalopathy may develop in patients who have renal insufficiency or hypertension or who are immunosuppressed. The findings on neuroimaging are characteristic of subcortical edema without infarction.

Background: Recent decades have witnessed an increase in mean maternal age at childbirth in most high-resourced countries. Advanced maternal age has been associated with several adverse maternal and perinatal outcomes. Although there are many studies on this topic, data from large contemporary population-based cohorts that controls for demographic variables known to influence perinatal outcomes is limited.

Human breast milk is considered the optimum feeding regime for newborn infants due to its ability to provide complete nutrition and many bioactive health factors. Breast feeding is associated with improved infant health and immune development, less incidences of gastrointestinal disease and lower mortality rates than formula fed infants. As well as providing fundamental nutrients to the growing infant, breast milk is a source of commensal bacteria which further enhance infant health by preventing pathogen adhesion and promoting gut colonisation of beneficial microbes. While breast milk was initially considered a sterile fluid and microbes isolated were considered contaminants, it is now widely accepted that breast milk is home to its own unique microbiome. The origins of bacteria in breast milk have been subject to much debate, however, the possibility of an entero-mammary pathway allowing for transfer of microbes from maternal gut to the mammary gland is one potential pathway. Human milk derived strains can be regarded as potential probiotics; therefore, many studies have focused on isolating strains from milk for subsequent use in infant health and nutrition markets. This review aims to discuss mammary gland development in preparation for lactation as well as explore the microbial composition and origins of the human milk microbiota with a focus on probiotic development.

OBJECTIVE: To assess the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact. DESIGN: Individual participant data meta-analysis of 39 cohorts. SETTING: Europe, North America, and Oceania. POPULATION: 265 270 births. METHODS: Information on maternal pre-pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used. MAIN OUTCOME MEASURES: Gestational hypertension, pre-eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth. RESULTS: Higher maternal pre-pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31- 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain. CONCLUSIONS: Maternal pre-pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre-pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity. TWEETABLE ABSTRACT: Promoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

OBJECTIVE: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder. Evidence for treatment of the condition with antidepressants and psychological therapies is conflicting. DESIGN: Systematic review and meta-analysis of randomised controlled trials (RCTs). MEDLINE, EMBASE and the Cochrane Controlled Trials Register were searched (up to May 2008). SETTING: RCTs based in primary, secondary and tertiary care. PATIENTS: Adults with IBS. INTERVENTIONS: Antidepressants versus placebo, and psychological therapies versus control therapy or "usual management". MAIN OUTCOME MEASURES: Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference. RESULTS: The search strategy identified 571 citations. Thirty-two RCTs were eligible for inclusion: 19 compared psychological therapies with control therapy or "usual management", 12 compared antidepressants with placebo, and one compared both psychological therapy and antidepressants with placebo. Study quality was generally good for antidepressant but poor for psychological therapy trials. The RR of IBS symptoms persisting with antidepressants versus placebo was 0.66 (95% CI, 0.57 to 0.78), with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors. The RR of symptoms persisting with psychological therapies was 0.67 (95% CI, 0.57 to 0.79). The NNT was 4 for both interventions. CONCLUSIONS: Antidepressants are effective in the treatment of IBS. There is less high-quality evidence for routine use of psychological therapies in IBS, but available data suggest these may be of comparable efficacy.