Ancient solutions in Lagrangian mean curvature flow

Ancient solutions of Lagrangian mean curvature flow in C^n naturally arise as Type II blow-ups. In this extended note we give structural and classification results for such ancient solutions in terms of their blow-down and, motivated by the Thomas-Yau Conjecture, focus on the almost calibrated case. In particular, we classify Type II blow-ups of almost calibrated Lagrangian mean curvature flow when the blow-down is a pair of transverse planes or, when n=2, a multiplicity two plane. We also show that the Harvey-Lawson Clifford torus cone in C^3 cannot arise as the blow-down of an almost calibrated Type II blow-up.Comment: 30 pages, v2: minor typos corrected, accepted in Ann. Sc. Norm. Super. Pisa Cl. Sc

Immune response to ocular gene therapy with AAV8

1 Introduction Adeno-associated viral (AAV) vectors are commonly used in ocular gene therapy for inherited retinal degenerations. They are known for their excellent efficacy in transducing retinal cells and their benign immune profile. However, the observation that subretinal AAV can lead to ocular inflammation highlights the importance to re-evaluate the immunogenicity of AAV. 2 Methods and material Cynomolgus monkeys (Macaca fascicularis) were treated with subretinal or intravitreal injections of AAV serotype 8. The high dose group received 1x10^12 viral genomes (vg) and the low dose group 1x10^11 vg. The control group received injections with vehicle only (balanced salt solution). Of the 34 animals included in the study, 12 were sacrificed after 28 days and 22 were sacrificed after 90 days. During the observation period, blood was taken at fixed timepoints for ELISA of antibodies directed against AAV capsid epitopes. After the inlife phase of the study, eyes were fixed in 4% PFA, embedded and frozen at -80°C. 20µm cryosections were subsequently used for expression profiling and immunohistochemistry. These data were compared to clinical observations from three patients treated with the same vector subretinally. OCT images were taken and peripheral blood mononuclear cells were isolated from patient blood at defined timepoints to be analysed for AAV specific reactivity. 3 Results The ELISA study of NHP derived blood samples showed an increase in anti-AAV8 titer at day 30 in the intravitreal high dose group but not in the subretinal high or low dose group. No antibody formation was observed in the three patients. Immunohistochemistry showed an inflammation of the NHP retina with activation of IBA1+ microglia and infiltration of CD8+ T cells and CD20+ B cells at 28 days following surgery. Expression analysis of the retinal tissue showed an upregulation of genes related to the innate antiviral immune response and associated with the release of INF-. None of the three patients showed clinically significant inflammation, but one featured hyperreflective foci in OCT images one month after surgery, which disappeared following steroid treatment. PBMC analysis showed changes in the activation pattern of CD8+ T cells one month after surgery in 2 out of 3 patients. 4 Discussion The data presented in this study suggests the activation of the innate and adaptive immune response following AAV administration. This hypothesis is supported by the activation of markers of antiviral immune pathways (Toll like, RIG1 like and NOD like receptor pathways) and the increase of capsid specific antibodies as well as retinal infiltration of cells of the adaptive immune response. Future studies will have to determine the exact dynamics of the infiltrating immune cells and how this immune response can be effectively inhibited

A systematic review of strategies to increase access to health services among children in low and middle income countries.

BACKGROUND: Universal Health Coverage is widely endorsed as the pivotal goal in global health, however substantial barriers to accessing health services for children in low and middle-income countries (LMIC) exist. Failure to access healthcare is an important contributor to child mortality in these settings. Barriers to access have been widely studied, however effective interventions to overcome barriers and increase access to services for children are less well documented. METHODS: We conducted a systematic review of effectiveness of interventions aimed at increasing access to health services for children aged 5 years and below in LMIC. Four databases (EMBASE, Global Health, MEDLINE, and PSYCINFO) were searched in January 2016. Studies were included if they evaluated interventions that aimed to increase: health care utilisation; immunisation uptake; and compliance with medication or referral. Randomised controlled trials and non-randomised controlled study designs were included in the review. A narrative approach was used to synthesise results. RESULTS: Fifty seven studies were included in the review. Approximately half of studies (49%) were conducted in sub-Saharan Africa. Most studies were randomised controlled trials (n = 44; 77%) with the remaining studies employing non-randomised designs. Very few studies were judged as high quality. Studies evaluated a diverse range of interventions and various outcomes. Supply side interventions included: delivery of services at or closer to home and service level improvements (eg. integration of services). Demand side interventions included: educational programmes, text messages, and financial or other incentives. Interventions that delivered services at or closer to home and text messages were in general associated with a significant improvement in relevant outcomes. A consistent pattern was not noted for the remaining studies. CONCLUSIONS: This review fills a gap in the literature by providing evidence of the range and effectiveness of interventions that can be used to increase access for children aged ≤5 years in LMIC. It highlights some intervention areas that seem to show encouraging trends including text message reminders and delivery of services at or close to home. However, given the methodological limitations found in existing studies, the results of this review must be interpreted with caution. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD420160334200

Does parental drinking influence children's drinking? A systematic review of prospective cohort studies.

AIMS: To evaluate evidence of the capacity for causal inference in studies of associations between parental and offspring alcohol consumption in the general population. METHODS: A systematic search for, and narrative analysis of, prospective cohort studies of the consequences of drinking, except where assessed prenatally only, or with clinically derived instruments. Primary outcome measures were alcohol use or related problems in offspring, which were collected at least 3 years after exposure measures of parental drinking. The systematic review included 21 studies comprising 26,354 families or parent-child dyads with quantitative effect measures available for each study. Criteria for capacity of causal inference included (1) theory-driven approach and analysis; (2) analytical rigour; and (3) minimization of sources of bias. RESULTS: Four of the 21 included studies filled several, but not all, criteria and were assessed to have some capacity for causal inference. These four studies found some evidence that parental drinking predicted drinking behaviour in adolescent offspring. The remaining 17 studies had little or no such capacity. CONCLUSIONS: There is a fairly large and consistent literature demonstrating that more parental drinking is associated with more drinking in offspring. Despite this, existing evidence is insufficient to warrant causal inferences at this stage

Transtheoretical model stages of change for dietary and physical exercise modification in weight loss management for overweight and obese adults.

BACKGROUND: Obesity is a global public health threat. The transtheoretical stages of change (TTM SOC) model has long been considered a useful interventional approach in lifestyle modification programmes, but its effectiveness in producing sustainable weight loss in overweight and obese individuals has been found to vary considerably.  OBJECTIVES: To assess the effectiveness of dietary intervention or physical activity interventions, or both, and other interventions based on the transtheoretical model (TTM) stages of change (SOC) to produce sustainable (one year and longer) weight loss in overweight and obese adults. SEARCH METHODS: Studies were obtained from searches of multiple electronic bibliographic databases. We searched The Cochrane Library, MEDLINE, EMBASE and PsycINFO. The date of the last search, for all databases, was 17 December 2013. SELECTION CRITERIA: Trials were included if they fulfilled the criteria of randomised controlled clinical trials (RCTs) using the TTM SOC as a model, that is a theoretical framework or guideline in designing lifestyle modification strategies, mainly dietary and physical activity interventions, versus a comparison intervention of usual care; one of the outcome measures of the study was weight loss, measured as change in weight or body mass index (BMI); participants were overweight or obese adults only; and the intervention was delivered by healthcare professionals or trained lay people at the hospital and community level, including at home. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data, assessed studies for risk of bias and evaluated overall study quality according to GRADE (Grading of Recommendations Assessment, Development and Evaluation). We resolved disagreements by discussion or consultation with a third party. A narrative, descriptive analysis was conducted for the systematic review. MAIN RESULTS: A total of three studies met the inclusion criteria, allocating 2971 participants to the intervention and control groups. The total number of participants randomised to the intervention groups was 1467, whilst 1504 were randomised to the control groups. The length of intervention was 9, 12 and 24 months in the different trials. The use of TTM SOC in combination with diet or physical activity, or both, and other interventions in the included studies produced inconclusive evidence that TTM SOC interventions led to sustained weight loss (the mean difference between intervention and control groups varied from 2.1 kg to 0.2 kg at 24 months; 2971 participants; 3 trials; low quality evidence). Following application of TTM SOC there were improvements in physical activity and dietary habits, such as increased exercise duration and frequency, reduced dietary fat intake and increased fruit and vegetable consumption (very low quality evidence). Weight gain was reported as an adverse event in one of the included trials. None of the trials reported health-related quality of life, morbidity, or economic costs as outcomes. The small number of studies and their variable methodological quality limit the applicability of the findings to clinical practice. The main limitations include inadequate reporting of outcomes and the methods for allocation, randomisation and blinding; extensive use of self-reported measures to estimate the effects of interventions on a number of outcomes, including weight loss, dietary consumption and physical activity levels; and insufficient assessment of sustainability due to lack of post-intervention assessments. AUTHORS' CONCLUSIONS: The evidence to support the use of TTM SOC in weight loss interventions is limited by risk of bias and imprecision, not allowing firm conclusions to be drawn. When combined with diet or physical activity, or both, and other interventions we found very low quality evidence that it might lead to better dietary and physical activity habits. This systematic review highlights the need for well-designed RCTs that apply the principles of the TTM SOC appropriately to produce conclusive evidence about the effect of TTM SOC lifestyle interventions on weight loss and other health outcomes

The effectiveness of M-health technologies for improving health and health services: a systematic review protocol

BACKGROUND: The application of mobile computing and communication technology is rapidly expanding in the fields of health care and public health. This systematic review will summarise the evidence for the effectiveness of mobile technology interventions for improving health and health service outcomes (M-health) around the world. FINDINGS: To be included in the review interventions must aim to improve or promote health or health service use and quality, employing any mobile computing and communication technology. This includes: (1) interventions designed to improve diagnosis, investigation, treatment, monitoring and management of disease; (2) interventions to deliver treatment or disease management programmes to patients, health promotion interventions, and interventions designed to improve treatment compliance; and (3) interventions to improve health care processes e.g. appointment attendance, result notification, vaccination reminders.A comprehensive, electronic search strategy will be used to identify controlled studies, published since 1990, and indexed in MEDLINE, EMBASE, PsycINFO, Global Health, Web of Science, the Cochrane Library, or the UK NHS Health Technology Assessment database. The search strategy will include terms (and synonyms) for the following mobile electronic devices (MEDs) and a range of compatible media: mobile phone; personal digital assistant (PDA); handheld computer (e.g. tablet PC); PDA phone (e.g. BlackBerry, Palm Pilot); Smartphone; enterprise digital assistant; portable media player (i.e. MP3 or MP4 player); handheld video game console. No terms for health or health service outcomes will be included, to ensure that all applications of mobile technology in public health and health services are identified. Bibliographies of primary studies and review articles meeting the inclusion criteria will be searched manually to identify further eligible studies. Data on objective and self-reported outcomes and study quality will be independently extracted by two review authors. Where there are sufficient numbers of similar interventions, we will calculate and report pooled risk ratios or standardised mean differences using meta-analysis. DISCUSSION: This systematic review will provide recommendations on the use of mobile computing and communication technology in health care and public health and will guide future work on intervention development and primary research in this field

Mental health and psychosocial support programmes for adults in humanitarian emergencies: a systematic review and meta-analysis in low and middle-income countries.

BACKGROUND: Humanitarian emergencies are a major global health challenge with the potential to have a profound impact on people's mental and psychological health. Effective interventions in humanitarian settings are needed to support the mental health and psychosocial needs of affected populations. To fill this gap, this systematic review synthesises evidence on the effectiveness of a wide range of mental health and psychosocial support (MHPSS) programmes delivered to adults affected by humanitarian emergencies in low and middle-income countries (LMICs). METHODS: A comprehensive search of 12 electronic databases, key websites and citation checking was undertaken in 2015 and updated in May 2018. We included controlled trials published in English from 1980. We extracted data and assessed risk of bias prior to performing a meta-analysis using random effects models. When meta-analysis was not used, we narratively described individual trial effect sizes using forest plots. RESULTS: Thirty-five studies were included. Overall, MHPSS programmes show benefits in improved functioning and reducing post-traumatic stress disorder. There are also indications from a limited pool of evidence that cognitive-behavioural therapy and narrative exposure therapy may improve mental health conditions. Other psychotherapy modalities also showed a positive trend in favour of MHPSS programmes for improving several mental health outcomes. CONCLUSION: In addition to MHPSS programme for improving mental health outcomes in adults affected by humanitarian emergencies in LMICs, there is also a need to generate robust evidence to identify potential impact on broader social dimensions. Doing so could aid the future development of MHPSS programmes and ensure their effective implementation across different humanitarian contexts in LMICs. Future research on MHPSS programmes which focus on basic services and security, community and family programmes, their cost-effectiveness and mechanisms of impact could also strengthen the MHPSS evidence base to better inform policy and practice decision-making in humanitarian settings. PROTOCOL REGISTRATION NUMBER: CRD42016033578

Oral versus inhaled antibiotics for bronchiectasis

Background Bronchiectasis is a chronic inflammatory disease characterised by a recurrent cycle of respiratory bacterial infections associated with cough, sputum production and impaired quality of life. Antibiotics are the main therapeutic option for managing bronchiectasis exacerbations. Evidence suggests that inhaled antibiotics may be associated with more effective eradication of infective organisms and a lower risk of developing antibiotic resistance when compared with orally administered antibiotics. However, it is currently unclear whether antibiotics are more effective when administered orally or by inhalation. Objectives To determine the comparative efficacy and safety of oral versus inhaled antibiotics in the treatment of adults and children with bronchiectasis. Search methods We identified studies through searches of the Cochrane Airways Group’s Specialised Register (CAGR), which is maintained by the Information Specialist for the group. The Register contains trial reports identified through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts. We also searched ClinicalTrials.gov and the WHO trials portal. We searched all databases in March 2018 and imposed no restrictions on language of publication. Selection criteria We planned to include studies which compared oral antibiotics with inhaled antibiotics. We would have considered short-term use (less than four weeks) for treating acute exacerbations separately from longer-term use as a prophylactic (4 weeks or more). We would have considered both intraclass and interclass comparisons. We planned to exclude studies if the participants received continuous or high-dose antibiotics immediately before the start of the trial, or if they have received a diagnosis of cystic fibrosis (CF), sarcoidosis, active allergic bronchopulmonary aspergillosis or active non-tuberculous Mycobacterial infection. Data collection and analysis Two review authors independently applied study inclusion criteria to the searches and we planned for two authors to independently extract data, assess risk of bias and assess overall quality of the evidence using GRADE criteria. We also planned to obtain missing data from the authors where possible and to report results with 95% confidence intervals (CIs). Main results We identified 313 unique records through database searches and a further 21 records from trial registers. We excluded 307 on the basis of title and abstract alone and a further 27 after examining full-text reports. No studies were identified for inclusion in the review. Authors’ conclusions There is currently no evidence indicating whether orally administered antibiotics are more beneficial compared to inhaled antibiotics. The recent ERS bronchiectasis guidelines provide a practical approach to the use of long-term antibiotics. New research is needed comparing inhaled versus oral antibiotic therapies for bronchiectasis patients with a history of frequent exacerbations, to establish which approach is the most effective in terms of exacerbation prevention, quality of life, treatment burden, and antibiotic resistance

Head-to-head trials of antibiotics for bronchiectasis

Background The diagnosis of bronchiectasis is defined by abnormal dilation of the airways related to a pathological mechanism of progressive airway destruction that is due to a 'vicious cycle' of recurrent bacterial infection, inflammatory mediator release, airway damage, and subsequent further infection. Antibiotics are the main treatment option for reducing bacterial burden in people with exacerbations of bronchiectasis and for longer‐term eradication, but their use is tempered against potential adverse effects and concerns regarding antibiotic resistance. The comparative effectiveness, cost‐effectiveness, and safety of different antibiotics have been highlighted as important issues, but currently little evidence is available to help resolve uncertainty on these questions. Objectives To evaluate the comparative effects of different antibiotics in the treatment of adults and children with bronchiectasis. Search methods We identified randomised controlled trials (RCTs) through searches of the Cochrane Airways Group Register of trials and online trials registries, run 30 April 2018. We augmented these with searches of the reference lists of published studies. Selection criteria We included RCTs reported as full‐text articles, those published as abstracts only, and unpublished data. We included adults and children (younger than 18 years) with a diagnosis of bronchiectasis by bronchography or high‐resolution computed tomography who reported daily signs and symptoms, such as cough, sputum production, or haemoptysis, and those with recurrent episodes of chest infection; we included studies that compared one antibiotic versus another when they were administered by the same delivery method. Data collection and analysis Two review authors independently assessed trial selection, data extraction, and risk of bias. We assessed overall quality of the evidence using GRADE criteria. We made efforts to collect missing data from trial authors. We have presented results with their 95% confidence intervals (CIs) as mean differences (MDs) or odds ratios (ORs). Main results Four randomised trials were eligible for inclusion in this systematic review ‐ two studies with 83 adults comparing fluoroquinolones with β‐lactams and two studies with 55 adults comparing aminoglycosides with polymyxins. None of the included studies reported information on exacerbations ‐ one of our primary outcomes. Included studies reported no serious adverse events ‐ another of our primary outcomes ‐ and no deaths. We graded this evidence as low or very low quality. Included studies did not report quality of life. Comparison between fluoroquinolones and β‐lactams (amoxicillin) showed fewer treatment failures in the fluoroquinolone group than in the amoxicillin group (OR 0.07, 95% CI 0.01 to 0.32; low‐quality evidence) after 7 to 10 days of therapy. Researchers reported that Pseudomonas aeruginosa infection was eradicated in more participants treated with fluoroquinolones (Peto OR 20.09, 95% CI 2.83 to 142.59; low‐quality evidence) but provided no evidence of differences in the numbers of participants showing improvement in sputum purulence (OR 2.35, 95% CI 0.96 to 5.72; very low‐quality evidence). Study authors presented no evidence of benefit in relation to forced expiratory volume in one second (FEV₁). The two studies that compared polymyxins versus aminoglycosides described no clear differences between groups in the proportion of participants with P aeruginosa eradication (OR 1.40. 95% CI 0.36 to 5.35; very low‐quality evidence) or improvement in sputum purulence (OR 0.16, 95% CI 0.01 to 3.85; very low‐quality evidence). The evidence for changes in FEV₁ was inconclusive. Two of three trials reported adverse events but did not report the proportion of participants experiencing one or more adverse events, so we were unable to interpret the information. Authors' conclusions Limited low‐quality evidence favours short‐term oral fluoroquinolones over beta‐lactam antibiotics for patients hospitalised with exacerbations. Very low‐quality evidence suggests no benefit from inhaled aminoglycosides verus polymyxins. RCTs have presented no evidence comparing other modes of delivery for each of these comparisons, and no RCTs have included children. Overall, current evidence from a limited number of head‐to‐head trials in adults or children with bronchiectasis is insufficient to guide the selection of antibiotics for short‐term or long‐term therapy. More research on this topic is needed