Rates of sexual partner acquisition from nationally representative surveys: variation between countries and by age, sex, wealth, partner and HIV status.

BACKGROUND: Knowing levels and determinants of partnership acquisition will help inform interventions that try to reduce transmission of sexually transmitted infections (STIs) including HIV. METHODS: We used population-based, cross-sectional data from 47 Demographic and Health Surveys to calculate rates of partner acquisition among men and women (15-49years), and identified socio-demographic correlates for partner acquisition. Partner acquisition rates were estimated as the total number of acquisitions divided by the person-time in the period covered by the survey. For each survey and by sex, we estimated age-specific partner acquisition rates and used age-adjusted piecewise exponential survival models to explore whether there was any association between wealth, HIV status and partner status with partner acquisition rates. RESULTS: Across countries, the median partner acquisition rates were 30/100 person-years for men (interquartile range 21-45) and 13/100 person-years for women (interquartile range 6-18). There were substantial variations in partner acquisition rates by age. Associations between wealth and partner acquisition rates varied across countries. People with a cohabiting partner were less likely to acquire a new one, and this effect was stronger for women than men and varied substantially between countries. Women living with HIV had higher partner acquisition rates than HIV-negative women but this association was less apparent for men. At a population level, partner acquisition rates were correlated with HIV incidence. CONCLUSIONS: Partner acquisition rates are variable and are associated with important correlates of STIs and thus could be used to identify groups at high risk of STIs.

In vivo synthesis of bacterial amyloid curli contributes to joint inflammation during S. Typhimurium infection.

Reactive arthritis, an autoimmune disorder, occurs following gastrointestinal infection with invasive enteric pathogens, such as Salmonella enterica. Curli, an extracellular, bacterial amyloid with cross beta-sheet structure can trigger inflammatory responses by stimulating pattern recognition receptors. Here we show that S. Typhimurium produces curli amyloids in the cecum and colon of mice after natural oral infection, in both acute and chronic infection models. Production of curli was associated with an increase in anti-dsDNA autoantibodies and joint inflammation in infected mice. The negative impacts on the host appeared to be dependent on invasive systemic exposure of curli to immune cells. We hypothesize that in vivo synthesis of curli contributes to known complications of enteric infections and suggest that cross-seeding interactions can occur between pathogen-produced amyloids and amyloidogenic proteins of the host.

A dynamic and collaborative approach to trial recruitment in safetxt, a UK sexual health randomised controlled trial.

BACKGROUND/AIMS: Recruiting to target in randomised controlled trials is crucial for providing reliable results, yet many trials struggle to achieve their target sample size. Many trials do not report sufficient, if any, details of their recruitment strategy for others to adapt for their own trials. Furthermore, much of the available evidence describes strategies to improve recruitment aimed at participants, as opposed to strategies aimed at engaging and motivating recruiting staff who are deemed essential for recruitment success. The safetxt trial aimed to recruit 6250 participants, aged 16-24 years, who had either tested positive, or received treatment, for chlamydia/gonorrhoea/non-specific urethritis in the last 2 weeks, from across the United Kingdom into a randomised controlled trial investigating a text message intervention to improve sexual health outcomes. In this article, we describe in detail the recruitment strategies we employed that were primarily aimed at recruiters. METHODS: Recruitment began in April 2016. We built on our recruitment methods established in the pilot trial and developed several strategies to increase recruitment as the trial progressed including optimising site set-up, monitoring recruitment progress and identifying issues, facilitating shared learning, tailored recruitment materials, sustaining motivation, and communication. We describe these strategies in detail and provide practical examples for each. RESULTS: We combine our strategies for increasing recruitment into one cyclical approach whereby progress is continuously monitored, and interventions to improve recruitment are implemented. The site initiation visits were used to develop a clear recruitment plan and establish good relationships with local site staff. Screening logs were particularly helpful for monitoring recruitment challenges. We facilitated shared learning by organising meetings with recruiting sites and conducting site visits. Tailored recruitment materials helped to promote the trial in clinic environments, and rewards and goals helped sustain motivation among recruiting staff. Finally, at the centre of the approach is good communication which ensured we maintained good relationships with local site staff. CONCLUSION: We conducted a large, multi-centre trial and successfully recruited to target. Our dynamic collaborative approach to recruitment described in this paper builds upon previous research by combining suggested good practice into one cyclical approach to recruitment, and providing detailed examples of each strategy. It is not possible to attribute a causal link between our approach and recruitment success overall, or with specific sites or recruiting staff. Nonetheless we describe the processes we used to build a good relationship with recruiting staff and sites, and maintain recruitment of large numbers of participants over the 32 months of the trial. Other researchers can use our approach and adapt our examples for their own trials.

Achieving proportional representation in a reproductive health survey through social media: process and recommendations.

BACKGROUND: The narrative surrounding women's reproductive health has shifted from a medical model to an emphasis on reproductive well-being over different life-stages. We developed and piloted a tracker survey for monitoring women's reproductive health and well-being in England, recruiting respondents online. This paper reports on the success of the online recruitment strategies in achieving a sample proportionally representative of the England general population. METHODS: Recruitment was through Facebook and Instagram advertisements and dissemination through Twitter and a blog. At the end week one, the sample was reviewed and compared to the 2011 Census England population. From week two, recruitment targeted under-represented groups. Key data were compared with prevalence estimates from the Third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). RESULTS: Between 1 July-17 August 2021, 13,962 people initiated the online survey, with 11,578 completing it. Numbers were low initially, but peaked at 1700 survey initiations per day after increasing the daily advertisement budget on day seven. At the end of week one, minority ethnic groups and people without a degree or equivalent were under-represented. From week two, we altered the advertisement settings to show to people whose profile indicated they were a 'high school leaver' had 'up to some high school', worked in industries that do not typically require a degree or lived in local authorities with a high proportion of ethnic minority residents. This had a modest effect, with the final sample short of proportional representation in terms of ethnicity and education but close in terms of region and age. Compared to Natsal-3, we found consistency in the proportion of respondents reporting an abortion and a live birth in the last year, however, the proportion of our sample reporting ever having experienced infertility was significantly higher than in Natsal-3, as was the proportion of 'planned' pregnancies in the last year. CONCLUSIONS: It is possible to recruit large numbers of respondents online, relatively quickly, to complete a reproductive health survey. This will be valuable to track reproductive health and well-being at a national level over time. More work is needed to understand reasons for non-response among under-represented groups.

Parallel evolution leading to impaired biofilm formation in invasive Salmonella strains.

Pathogenic Salmonella strains that cause gastroenteritis are able to colonize and replicate within the intestines of multiple host species. In general, these strains have retained an ability to form the rdar morphotype, a resistant biofilm physiology hypothesized to be important for Salmonella transmission. In contrast, Salmonella strains that are host-adapted or even host-restricted like Salmonella enterica serovar Typhi, tend to cause systemic infections and have lost the ability to form the rdar morphotype. Here, we investigated the rdar morphotype and CsgD-regulated biofilm formation in two non-typhoidal Salmonella (NTS) strains that caused invasive disease in Malawian children, S. Typhimurium D23580 and S. Enteritidis D7795, and compared them to a panel of NTS strains associated with gastroenteritis, as well as S. Typhi strains. Sequence comparisons combined with luciferase reporter technology identified key SNPs in the promoter region of csgD that either shut off biofilm formation completely (D7795) or reduced transcription of this key biofilm regulator (D23580). Phylogenetic analysis showed that these SNPs are conserved throughout the African clades of invasive isolates, dating as far back as 80 years ago. S. Typhi isolates were negative for the rdar morphotype due to truncation of eight amino acids from the C-terminus of CsgD. We present new evidence in support of parallel evolution between lineages of nontyphoidal Salmonella associated with invasive disease in Africa and the archetypal host-restricted invasive serovar; S. Typhi. We hypothesize that the African invasive isolates are becoming human-adapted and 'niche specialized' with less reliance on environmental survival, as compared to gastroenteritis-causing isolates.

A SNP in the Cache 1 Signaling Domain of Diguanylate Cyclase STM1987 Leads to Increased In Vivo Fitness of Invasive Salmonella Strains.

Nontyphoidal Salmonella (NTS) strains are associated with gastroenteritis worldwide but are also the leading cause of bacterial bloodstream infections in sub-Saharan Africa. The invasive NTS (iNTS) strains that cause bloodstream infections differ from standard gastroenteritis-causing strains by >700 single-nucleotide polymorphisms (SNPs). These SNPs are known to alter metabolic pathways and biofilm formation and to contribute to serum resistance and are thought to signify iNTS strains becoming human adapted, similar to typhoid fever-causing Salmonella strains. Identifying SNPs that contribute to invasion or increased virulence has been more elusive. In this study, we identified a SNP in the cache 1 signaling domain of diguanylate cyclase STM1987 in the invasive Salmonella enterica serovar Typhimurium type strain D23580. This SNP was conserved in 118 other iNTS strains analyzed and was comparatively absent in global S Typhimurium isolates associated with gastroenteritis. STM1987 catalyzes the formation of bis-(3',5')-cyclic dimeric GMP (c-di-GMP) and is proposed to stimulate production of cellulose independent of the master biofilm regulator CsgD. We show that the amino acid change in STM1987 leads to a 10-fold drop in cellulose production and increased fitness in a mouse model of acute infection. Reduced cellulose production due to the SNP led to enhanced survival in both murine and human macrophage cell lines. In contrast, loss of CsgD-dependent cellulose production did not lead to any measurable change in in vivo fitness. We hypothesize that the SNP in stm1987 represents a pathoadaptive mutation for iNTS strains.

Sexual health interventions delivered to participants by mobile technology: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The use of mobile technologies to prevent STIs is recognised as a promising approach worldwide; however, evidence has been inconclusive, and the field has developed rapidly. With about 1 million new STIs a day globally, up-to-date evidence is urgently needed. OBJECTIVE: To assess the effectiveness of mobile health interventions delivered to participants for preventing STIs and promoting preventive behaviour. METHODS: We searched seven databases and reference lists of 49 related reviews (January 1990-February 2020) and contacted experts in the field. We included randomised controlled trials of mobile interventions delivered to adolescents and adults to prevent sexual transmission of STIs. We conducted meta-analyses and assessed risk of bias and certainty of evidence following Cochrane guidance. RESULTS: After double screening 6683 records, we included 22 trials into the systematic review and 20 into meta-analyses; 18 trials used text messages, 3 used smartphone applications and 1 used Facebook messages as delivery modes. The certainty of evidence regarding intervention effects on STI/HIV occurrence and adverse events was low or very low. There was moderate certainty of evidence that in the short/medium-term text messaging interventions had little or no effect on condom use (standardised mean differences (SMD) 0.02, 95% CI -0.09 to 0.14, nine trials), but increased STI/HIV testing (OR 1.83, 95% CI 1.41 to 2.36, seven trials), although not if the standard-of-care control already contained an active text messaging component (OR 1.00, 95% CI 0.68 to 1.47, two trials). Smartphone application messages also increased STI/HIV testing (risk ratio 1.40, 95% CI 1.22 to 1.60, subgroup analysis, two trials). The effects on other outcomes or of social media or blended interventions is uncertain due to low or very low certainty evidence. CONCLUSIONS: Text messaging interventions probably increase STI/HIV testing but not condom use in the short/medium term. Ongoing trials will report the effects on biological and other outcomes.

Mobile phone-based interventions for improving adherence to medication prescribed for the primary prevention of cardiovascular disease in adults.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of disability and mortality globally. Premature fatal and non-fatal CVD is considered to be largely preventable through the control of risk factors by lifestyle modifications and preventive medication. Lipid-lowering and antihypertensive drug therapies for primary prevention are cost-effective in reducing CVD morbidity and mortality among high-risk people and are recommended by international guidelines. However, adherence to medication prescribed for the prevention of CVD can be poor. Approximately 9% of CVD cases in the EU are attributed to poor adherence to vascular medications. Low-cost, scalable interventions to improve adherence to medications for the primary prevention of CVD have potential to reduce morbidity, mortality and healthcare costs associated with CVD. OBJECTIVES: To establish the effectiveness of interventions delivered by mobile phone to improve adherence to medication prescribed for the primary prevention of CVD in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two other databases on 7 January 2020. We also searched two clinical trials registers on 5 February 2020. We searched reference lists of relevant papers. We applied no language or date restrictions. SELECTION CRITERIA: We included randomised controlled trials investigating interventions delivered wholly or partly by mobile phones to improve adherence to cardiovascular medications prescribed for the primary prevention of CVD. We only included trials with a minimum of one-year follow-up in order that the outcome measures related to longer-term, sustained medication adherence behaviours and outcomes. Eligible comparators were usual care or control groups receiving no mobile phone-delivered component of the intervention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The main outcomes of interest were objective measures of medication adherence (blood pressure (BP) and cholesterol), CVD events, and adverse events. We contacted study authors for further information when this was not reported. MAIN RESULTS: We included 14 trials with 25,633 randomised participants. Participants were recruited from community-based primary and tertiary care or outpatient clinics. The interventions varied widely from those delivered solely through short messaging service (SMS) to those involving a combination of modes of delivery, such as SMS in addition to healthcare worker training, face-to-face counselling, electronic pillboxes, written materials, and home blood pressure monitors. Some interventions only targeted medication adherence, while others additionally targeted lifestyle changes such as diet and exercise. Due to heterogeneity in the nature and delivery of the interventions and study populations, we reported most results narratively, with the exception of two trials which were similar enough to meaningfully pool in meta-analyses. The body of evidence for the effect of mobile phone-based interventions on objective outcomes of adherence (BP and cholesterol) was of low certainty, due to most trials being at high risk of bias, and inconsistency in outcome effects. Two trials were at low risk of bias. Among five trials (total study enrolment: 5441 participants) recording low-density lipoprotein cholesterol (LDL-C), two studies found evidence for a small beneficial intervention effect on reducing LDL-C (-5.30 mg/dL, 95% confidence interval (CI) -8.30 to -2.30; and -9.20 mg/dL, 95% CI -17.70 to -0.70). The other three studies found results varying from a small reduction (-7.7 mg/dL) to a small increase in LDL-C (0.77 mg/dL). All of which had wide confidence intervals that included no effect. Across 13 studies (25,166 participants) measuring systolic blood pressure, effect estimates ranged from a large reduction (MD -12.45 mmHg, 95% CI -15.02 to -9.88) to a small increase (MD 2.80 mmHg, 95% CI 0.30 to 5.30). We found a similar range of effect estimates for diastolic BP, ranging from -12.23 mmHg (95% CI 14.03 to -10.43) to 1.64 mmHg (95% CI -0.55 to 3.83) (11 trials, 19,716 participants). Four trials showed intervention benefits for systolic and diastolic BP with confidence intervals excluding no effect, and among these were all three of the trials evaluating self-monitoring of blood pressure with mobile phone-based telemedicine. The fourth trial included SMS and provider support (with additional varied features). Seven studies (19,185 participants) reported 'controlled' BP as an outcome, and intervention effect estimates varied from negligible effects (odds ratio (OR) 1.01, 95% CI 0.76 to 1.34) to large improvements in BP control (OR 2.41, 95% CI: 1.57 to 3.68). The three trials of clinician training or decision support combined with SMS (with additional varied features) had confidence intervals encompassing benefits and harms, with point estimates close to zero. Pooled analyses of the two trials of interventions solely delivered through SMS were indicative of little or no beneficial intervention effect on systolic BP (MD -1.55 mmHg, 95% CI -3.36 to 0.25; I2 = 0%) and small increases in controlled BP (OR 1.32, 95% CI 1.06 to 1.65; I2 = 0%). Based on four studies (12,439 participants), there was very low-certainty evidence (downgraded twice for imprecision and once for risk of bias) relating to the intervention effect on combined (fatal and non-fatal) CVD events. Two studies (2535 participants) provided low-certainty evidence for the effect of the intervention on cognitive outcomes, with little or no difference between trial arms for perceived quality of care and satisfaction with treatment. There was moderate-certainty evidence (downgraded due to risk of bias) that the interventions did not cause harm, based on six studies (8285 participants). Three studies reported no adverse events attributable to the intervention. One study reported no difference between groups in experience of adverse effects of statins, and that no participants reported intervention-related adverse events. One study stated that potential side effects were similar between groups. One study reported a similar number of deaths in each arm, but did not provide further information relating to potential adverse events. AUTHORS' CONCLUSIONS: There is low-certainty evidence on the effects of mobile phone-delivered interventions to increase adherence to medication prescribed for the primary prevention of CVD. Trials of BP self-monitoring with mobile-phone telemedicine support reported modest benefits. One trial at low risk of bias reported modest reductions in LDL cholesterol but no benefits for BP. There is moderate-certainty evidence that these interventions do not result in harm. Further trials of these interventions are warranted.

Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study.

BACKGROUND & AIMS: Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that has been hypothesized to improve non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic bile acid production. We studied the safety, tolerability and efficacy of volixibat in patients with NASH. METHODS: In this double-blind, phase II dose-finding study, adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive volixibat (5, 10 or 20 mg) or placebo once daily for 48 weeks. The endpoints of a predefined interim analysis (n = 80), at week 24, were: ≥5% reduction in MRI-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was a ≥2-point reduction in non-alcoholic fatty liver disease activity score without worsening fibrosis at week 48. RESULTS: Volixibat did not meet either interim endpoint; the study was terminated owing to lack of efficacy. In participants receiving any volixibat dose, mean serum 7-alpha-hydroxy-4-cholesten-3-one (C4; a biomarker of bile acid synthesis) increased from baseline to week 24 (+38.5 ng/ml [SD 53.18]), with concomitant decreases in serum total cholesterol (-14.5 mg/dl [SD 28.32]) and low-density lipoprotein cholesterol (-16.1 mg/dl [SD 25.31]). These changes were generally dose-dependent. On histological analysis, a greater proportion of participants receiving placebo (38.5%, n = 5/13) than volixibat (30.0%, n = 9/30) met the primary endpoint. Treatment-emergent adverse events (TEAEs) were mainly mild or moderate. No serious TEAEs were related to volixibat. Diarrhoea was the most common TEAE overall and the most common TEAE leading to discontinuation. CONCLUSIONS: Increased serum C4 and decreased serum cholesterol levels provide evidence of target engagement. However, inhibition of ASBT by volixibat did not elicit a liver-related therapeutic benefit in adults with NASH. LAY SUMMARY: A medicine called volixibat has previously been shown to reduce cholesterol levels in the blood. This study investigated whether volixibat could reduce the amount of fat in the liver and reduce liver injury in adults with an advanced form of non-alcoholic fatty liver disease. Volixibat did not reduce the amount of fat in the liver, nor did it have any other beneficial effect on liver injury. Participants in the study generally tolerated the side effects of volixibat and, as in previous studies, the main side effect was diarrhoea. These results show that volixibat is not an effective treatment for people with fatty liver disease. CLINICAL TRIAL IDENTIFIER: NCT02787304.

Nivolumab in Combination with Irinotecan and 5-Fluorouracil (FOLFIRI) for Refractory Advanced Gastroesophageal Cancer.

INTRODUCTION: Advanced unresectable gastroesophageal cancers continue to confer a dismal patient prognosis. Limited options remain once the cancer is refractory to cytotoxics/biologics (like irinotecan, taxane, and ramucirumab). Recently, anti-programmed death-1 (anti-PD-1) inhibitors have been used with limited efficacy in select patients with adenocarcinoma. Similarly, irinotecan-based therapy has marginal efficacy. We combined irinotecan plus a fluoropyrimidine with an anti-PD-1 antibody, nivolumab, with hopes of having a higher advantage for patients. OBJECTIVES: Primary objective was to assess safety judged by toxicities, dose delays, or dose reductions. Secondary endpoints included the assessment of response, overall survival (OS), and progression-free survival (PFS). METHODS: We treated 15 patients with this combination during July 2017 to April 2019. Patients were included if they had follow-up at our institution. RESULTS: Median doses given were nivolumab 240 mg + irinotecan 120 mg/m2 + 5-FU 2,000 mg/m2 over 46-48 h (or capecitabine 1,250 mg/m2/day; 7 days on, 7 days off) given every 2 weeks. Median age of the patients was 55 years, and all patients had an ECOG performance status of 0-1. The patients had a median of 1 prior therapy. Slightly over half of the patients had PD-L1 expression. The median number of cycles was 7. Five patients (33%) had a dose delay or dose adjustment. The most common reason for dose delay or adjustment was grade 2 fatigue. Disease control (response or stability) on first scan was 73.3% (n = 11). Median PFS and OS for the entire group was 7 and 13.3 months, respectively. CONCLUSION: In this small cohort of patients, we conclude that this combination is quite feasible and resulted in prolonged stability in some patients. Further development of this regimen is warranted.

Targeted client communication via mobile devices for improving maternal, neonatal, and child health.

BACKGROUND: The global burden of poor maternal, neonatal, and child health (MNCH) accounts for more than a quarter of healthy years of life lost worldwide. Targeted client communication (TCC) via mobile devices (MD) (TCCMD) may be a useful strategy to improve MNCH. OBJECTIVES: To assess the effects of TCC via MD on health behaviour, service use, health, and well-being for MNCH. SEARCH METHODS: In July/August 2017, we searched five databases including The Cochrane Central Register of Controlled Trials, MEDLINE and Embase. We also searched two trial registries. A search update was carried out in July 2019 and potentially relevant studies are awaiting classification. SELECTION CRITERIA: We included randomised controlled trials that assessed TCC via MD to improve MNCH behaviour, service use, health, and well-being. Eligible comparators were usual care/no intervention, non-digital TCC, and digital non-targeted client communication. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane, although data extraction and risk of bias assessments were carried out by one person only and cross-checked by a second. MAIN RESULTS: We included 27 trials (17,463 participants). Trial populations were: pregnant and postpartum women (11 trials conducted in low-, middle- or high-income countries (LMHIC); pregnant and postpartum women living with HIV (three trials carried out in one lower middle-income country); and parents of children under the age of five years (13 trials conducted in LMHIC). Most interventions (18) were delivered via text messages alone, one was delivered through voice calls only, and the rest were delivered through combinations of different communication channels, such as multimedia messages and voice calls. Pregnant and postpartum women TCCMD versus standard care For behaviours, TCCMD may increase exclusive breastfeeding in settings where rates of exclusive breastfeeding are less common (risk ratio (RR) 1.30, 95% confidence intervals (CI) 1.06 to 1.59; low-certainty evidence), but have little or no effect in settings where almost all women breastfeed (low-certainty evidence). For use of health services, TCCMD may increase antenatal appointment attendance (odds ratio (OR) 1.54, 95% CI 0.80 to 2.96; low-certainty evidence); however, the CI encompasses both benefit and harm. The intervention may increase skilled attendants at birth in settings where a lack of skilled attendants at birth is common (though this differed by urban/rural residence), but may make no difference in settings where almost all women already have a skilled attendant at birth (OR 1.00, 95% CI 0.34 to 2.94; low-certainty evidence). There were uncertain effects on maternal and neonatal mortality and morbidity because the certainty of the evidence was assessed as very low. TCCMD versus non-digital TCC (e.g. pamphlets) TCCMD may have little or no effect on exclusive breastfeeding (RR 0.92, 95% CI 0.79 to 1.07; low-certainty evidence). TCCMD may reduce 'any maternal health problem' (RR 0.19, 95% CI 0.04 to 0.79) and 'any newborn health problem' (RR 0.52, 95% CI 0.25 to 1.06) reported up to 10 days postpartum (low-certainty evidence), though the CI for the latter includes benefit and harm. The effect on health service use is unknown due to a lack of studies. TCCMD versus digital non-targeted communication No studies reported behavioural, health, or well-being outcomes for this comparison. For use of health services, there are uncertain effects for the presence of a skilled attendant at birth due to very low-certainty evidence, and the intervention may make little or no difference to attendance for antenatal influenza vaccination (RR 1.05, 95% CI 0.71 to 1.58), though the CI encompasses both benefit and harm (low-certainty evidence). Pregnant and postpartum women living with HIV TCCMD versus standard care For behaviours, TCCMD may make little or no difference to maternal and infant adherence to antiretroviral (ARV) therapy (low-certainty evidence). For health service use, TCC mobile telephone reminders may increase use of antenatal care slightly (mean difference (MD) 1.5, 95% CI -0.36 to 3.36; low-certainty evidence). The effect on the proportion of births occurring in a health facility is uncertain due to very low-certainty evidence. For health and well-being outcomes, there was an uncertain intervention effect on neonatal death or stillbirth, and infant HIV due to very low-certainty evidence. No studies reported on maternal mortality or morbidity. TCCMD versus non-digital TCC The effect is unknown due to lack of studies reporting this comparison. TCCMD versus digital non-targeted communication TCCMD may increase infant ARV/prevention of mother-to-child transmission treatment adherence (RR 1.26, 95% CI 1.07 to 1.48; low-certainty evidence). The effect on other outcomes is unknown due to lack of studies. Parents of children aged less than five years No studies reported on correct treatment, nutritional, or health outcomes. TCCMD versus standard care Based on 10 trials, TCCMD may modestly increase health service use (vaccinations and HIV care) (RR 1.21, 95% CI 1.08 to 1.34; low-certainty evidence); however, the effect estimates varied widely between studies. TCCMD versus non-digital TCC TCCMD may increase attendance for vaccinations (RR 1.13, 95% CI 1.00 to 1.28; low-certainty evidence), and may make little or no difference to oral hygiene practices (low-certainty evidence). TCCMD versus digital non-targeted communication TCCMD may reduce attendance for vaccinations, but the CI encompasses both benefit and harm (RR 0.63, 95% CI 0.33 to 1.20; low-certainty evidence). No trials in any population reported data on unintended consequences. AUTHORS' CONCLUSIONS: The effect of TCCMD for most outcomes is uncertain. There may be improvements for some outcomes using targeted communication but these findings were of low certainty. High-quality, adequately powered trials and cost-effectiveness analyses are required to reliably ascertain the effects and relative benefits of TCCMD. Future studies should measure potential unintended consequences, such as partner violence or breaches of confidentiality.

Targeted client communication via mobile devices for improving sexual and reproductive health.

BACKGROUND: The burden of poor sexual and reproductive health (SRH) worldwide is substantial, disproportionately affecting those living in low- and middle-income countries. Targeted client communication (TCC) delivered via mobile devices (MD) (TCCMD) may improve the health behaviours and service use important for sexual and reproductive health. OBJECTIVES: To assess the effects of TCC via MD on adolescents' knowledge, and on adolescents' and adults' sexual and reproductive health behaviour, health service use, and health and well-being. SEARCH METHODS: In July/August 2017, we searched five databases including The Cochrane Central Register of Controlled Trials, MEDLINE and Embase. We also searched two trial registries. A search update was carried out in July 2019 and potentially relevant studies are awaiting classification. SELECTION CRITERIA: We included randomised controlled trials of TCC via MD to improve sexual and reproductive health behaviour, health service use, and health and well-being. Eligible comparators were standard care or no intervention, non-digital TCC, and digital non-targeted communication. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane, although data extraction and risk of bias assessments were carried out by one person only and cross-checked by a second. We have presented results separately for adult and adolescent populations, and for each comparison. MAIN RESULTS: We included 40 trials (27 among adult populations and 13 among adolescent populations) with a total of 26,854 participants. All but one of the trials among adolescent populations were conducted in high-income countries. Trials among adult populations were conducted in a range of high- to low-income countries. Among adolescents, nine interventions were delivered solely through text messages; four interventions tested text messages in combination with another communication channel, such as emails, multimedia messaging, or voice calls; and one intervention used voice calls alone. Among adults, 20 interventions were delivered through text messages; two through a combination of text messages and voice calls; and the rest were delivered through other channels such as voice calls, multimedia messaging, interactive voice response, and instant messaging services. Adolescent populations TCCMD versus standard care TCCMD may increase sexual health knowledge (risk ratio (RR) 1.45, 95% confidence interval (CI) 1.23 to 1.71; low-certainty evidence). TCCMD may modestly increase contraception use (RR 1.19, 95% CI 1.05 to 1.35; low-certainty evidence). The effects on condom use, antiretroviral therapy (ART) adherence, and health service use are uncertain due to very low-certainty evidence. The effects on abortion and STI rates are unknown due to lack of studies. TCCMD versus non-digital TCC (e.g. pamphlets) The effects of TCCMD on behaviour (contraception use, condom use, ART adherence), service use, health and wellbeing (abortion and STI rates) are unknown due to lack of studies for this comparison. TCCMD versus digital non-targeted communication The effects on sexual health knowledge, condom and contraceptive use are uncertain due to very low-certainty evidence. Interventions may increase health service use (attendance for STI/HIV testing, RR 1.61, 95% CI 1.08 to 2.40; low-certainty evidence). The intervention may be beneficial for reducing STI rates (RR 0.61, 95% CI 0.28 to 1.33; low-certainty evidence), but the confidence interval encompasses both benefit and harm. The effects on abortion rates and on ART adherence are unknown due to lack of studies. We are uncertain whether TCCMD results in unintended consequences due to lack of evidence. Adult populations TCCMD versus standard care For health behaviours, TCCMD may modestly increase contraception use at 12 months (RR 1.17, 95% CI 0.92 to 1.48) and may reduce repeat abortion (RR 0.68 95% CI 0.28 to 1.66), though the confidence interval encompasses benefit and harm (low-certainty evidence). The effect on condom use is uncertain. No study measured the impact of this intervention on STI rates. TCCMD may modestly increase ART adherence (RR 1.13, 95% CI 0.97 to 1.32, low-certainty evidence, and standardised mean difference 0.44, 95% CI -0.14 to 1.02, low-certainty evidence). TCCMD may modestly increase health service utilisation (RR 1.17, 95% CI 1.04 to 1.31; low-certainty evidence), but there was substantial heterogeneity (I2 = 85%), with mixed results according to type of service utilisation (i.e. attendance for STI testing; HIV treatment; voluntary male medical circumcision (VMMC); VMMC post-operative visit; post-abortion care). For health and well-being outcomes, there may be little or no effect on CD4 count (mean difference 13.99, 95% CI -8.65 to 36.63; low-certainty evidence) and a slight reduction in virological failure (RR 0.86, 95% CI 0.73 to 1.01; low-certainty evidence). TCCMD versus non-digital TCC No studies reported STI rates, condom use, ART adherence, abortion rates, or contraceptive use as outcomes for this comparison. TCCMD may modestly increase in service attendance overall (RR: 1.12, 95% CI 0.92-1.35, low certainty evidence), however the confidence interval encompasses benefit and harm. TCCMD versus digital non-targeted communication No studies reported STI rates, condom use, ART adherence, abortion rates, or contraceptive use as outcomes for this comparison. TCCMD may increase service utilisation overall (RR: 1.71, 95% CI 0.67-4.38, low certainty evidence), however the confidence interval encompasses benefit and harm and there was considerable heterogeneity (I2 = 72%), with mixed results according to type of service utilisation (STI/HIV testing, and VMMC). Few studies reported on unintended consequences. One study reported that a participant withdrew from the intervention as they felt it compromised their undisclosed HIV status. AUTHORS' CONCLUSIONS: TCCMD may improve some outcomes but the evidence is of low certainty. The effect on most outcomes is uncertain/unknown due to very low certainty evidence or lack of evidence. High quality, adequately powered trials and cost effectiveness analyses are required to reliably ascertain the effects and relative benefits of TCC delivered by mobile devices. Given the sensitivity and stigma associated with sexual and reproductive health future studies should measure unintended consequences, such as partner violence or breaches of confidentiality.

An Intervention Delivered by Mobile Phone Instant Messaging to Increase Acceptability and Use of Effective Contraception Among Young Women in Bolivia: Randomized Controlled Trial.

BACKGROUND: Although the most effective methods of contraception are available in Bolivia, unmet need for contraception among women aged 15 to 19 years is estimated to be 38% (2008), and the adolescent fertility rate is 71 per 1000 women (2016). Mobile phones are a popular mode to deliver health behavior support. We developed a contraceptive behavioral intervention for young Bolivian women delivered by mobile phone and guided by behavioral science. The intervention consists of short instant messages sent through an app over 4 months. OBJECTIVE: This trial aimed to evaluate the effect of the intervention on young Bolivian women's use of and attitudes toward the effective contraceptive methods available in Bolivia. METHODS: This was a parallel group, individually randomized superiority trial with a 1:1 allocation ratio. Women were eligible if they were aged 16 to 24 years, owned a personal Android mobile phone, lived in La Paz or El Alto, reported an unmet need for contraception, and could read Spanish. The target sample size was 1310 participants. Participants allocated to the intervention had access to an app with standard family planning information and intervention messages. Participants allocated to the control group had access to the same app and control messages. Coprimary outcomes were use of effective contraception and acceptability of at least one method of effective contraception at 4 months. Secondary outcomes were use of effective contraception during the study, acceptability of the individual methods, service uptake, unintended pregnancy, and abortion. Process outcomes included knowledge, perceived norms, personal agency, and intention. Outcomes were analyzed using logistic and linear regression. We also asked participants about physical violence. RESULTS: A total of 640 participants were enrolled, and 67.0% (429) of them contributed follow-up data for the coprimary outcome, the use of effective contraception. There was no evidence that use differed between the groups (33% control vs 37% intervention; adjusted odds ratio [OR] 1.19, 95% CI 0.80 to 1.77; P=.40). There was a borderline significant effect regarding acceptability (63% control vs 72% intervention; adjusted OR 1.49, 95% CI 0.98 to 2.28; P=.06). There were no statistically significant differences in any of the secondary or process outcomes. The intervention dose received was low. In the control group, 2.8% (6/207) reported experiencing physical violence compared with 1.9% (4/202) in the intervention group (Fisher exact test P=.75). CONCLUSIONS: This trial was unable to provide definitive conclusions regarding the effect of the intervention on use and acceptability of effective contraception because of under recruitment. Although we cannot strongly recommend implementation, the results suggest that it would be safe and may increase the acceptability of effective contraception if the intervention messages were offered alongside the download of the app. TRIAL REGISTRATION: ClinicalTrials.gov NCT02905526; https://clinicaltrials.gov/ct2/show/NCT02905526.

Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial.

BACKGROUND: Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). METHODS: Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). RESULTS: Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6-3.2 times higher in HVs (643.73-1239.3 µmol/24 h) and ~8 times higher in T2DM (1786.0 µmol/24 h) than with placebo (HVs: 386.93 µmol/24 h; T2DM: 220.00 µmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3-5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. CONCLUSIONS: Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013).

Mobile phone-based interventions for improving adherence to medication prescribed for the primary prevention of cardiovascular disease in adults.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of disability and mortality globally. Premature fatal and non-fatal CVD is considered to be largely preventable through the control of risk factors via lifestyle modifications and preventive medication. Lipid-lowering and antihypertensive drug therapies for primary prevention are cost-effective in reducing CVD morbidity and mortality among high-risk people and are recommended by international guidelines. However, adherence to medication prescribed for the prevention of CVD can be poor. Approximately 9% of CVD cases in the EU are attributed to poor adherence to vascular medications. Low-cost, scalable interventions to improve adherence to medications for the primary prevention of CVD have potential to reduce morbidity, mortality and healthcare costs associated with CVD. OBJECTIVES: To establish the effectiveness of interventions delivered by mobile phone to improve adherence to medication prescribed for the primary prevention of CVD in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two other databases on 21 June 2017 and two clinical trial registries on 14 July 2017. We searched reference lists of relevant papers. We applied no language or date restrictions. SELECTION CRITERIA: We included randomised controlled trials investigating interventions delivered wholly or partly by mobile phones to improve adherence to cardiovascular medications prescribed for the primary prevention of CVD. We only included trials with a minimum of one-year follow-up in order that the outcome measures related to longer-term, sustained medication adherence behaviours and outcomes. Eligible comparators were usual care or control groups receiving no mobile phone-delivered component of the intervention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. We contacted study authors for disaggregated data when trials included a subset of eligible participants. MAIN RESULTS: We included four trials with 2429 randomised participants. Participants were recruited from community-based primary care or outpatient clinics in high-income (Canada, Spain) and upper- to middle-income countries (South Africa, China). The interventions received varied widely; one trial evaluated an intervention focused on blood pressure medication adherence delivered solely through short messaging service (SMS), and one intervention involved blood pressure monitoring combined with feedback delivered via smartphone. Two trials involved interventions which targeted a combination of lifestyle modifications, alongside CVD medication adherence, one of which was delivered through text messages, written information pamphlets and self-completion cards for participants, and the other through a multi-component intervention comprising of text messages, a computerised CVD risk evaluation and face-to-face counselling. Due to heterogeneity in the nature and delivery of the interventions, we did not conduct a meta-analysis, and therefore reported results narratively.We judged the body of evidence for the effect of mobile phone-based interventions on objective outcomes (blood pressure and cholesterol) of low quality due to all included trials being at high risk of bias, and inconsistency in outcome effects. Of two trials targeting medication adherence alongside other lifestyle modifications, one reported a small beneficial intervention effect in reducing low-density lipoprotein cholesterol (mean difference (MD) -9.2 mg/dL, 95% confidence interval (CI) -17.70 to -0.70; 304 participants), and the other found no benefit (MD 0.77 mg/dL, 95% CI -4.64 to 6.18; 589 participants). One trial (1372 participants) of a text messaging-based intervention targeting adherence showed a small reduction in systolic blood pressure (SBP) for the intervention arm which delivered information-only text messages (MD -2.2 mmHg, 95% CI -4.4 to -0.04), but uncertain evidence of benefit for the second intervention arm that provided additional interactivity (MD -1.6 mmHg, 95% CI -3.7 to 0.5). One study examined the effect of blood pressure monitoring combined with smartphone messaging, and reported moderate intervention benefits on SBP and diastolic blood pressure (DBP) (SBP: MD -7.10 mmHg, 95% CI -11.61 to -2.59; DBP: -3.90 mmHg, 95% CI -6.45 to -1.35; 105 participants). There was mixed evidence from trials targeting medication adherence alongside lifestyle advice using multi-component interventions. One trial found large benefits for SBP and DBP (SBP: MD -12.45 mmHg, 95% CI -15.02 to -9.88; DBP: MD -12.23 mmHg, 95% CI -14.03 to -10.43; 589 participants), whereas the other trial demonstrated no beneficial effects on SBP or DBP (SBP: MD 0.83 mmHg, 95% CI -2.67 to 4.33; DBP: MD 1.64 mmHg, 95% CI -0.55 to 3.83; 304 participants).Two trials reported on adverse events and provided low-quality evidence that the interventions did not cause harm. One study provided low-quality evidence that there was no intervention effect on reported satisfaction with treatment.Two trials were conducted in high-income countries, and two in upper- to middle-income countries. The interventions evaluated employed between three and 16 behaviour change techniques according to coding using Michie's taxonomic method. Two trials evaluated interventions that involved potential users in their development. AUTHORS' CONCLUSIONS: There is low-quality evidence relating to the effects of mobile phone-delivered interventions to increase adherence to medication prescribed for the primary prevention of CVD; some trials reported small benefits while others found no effect. There is low-quality evidence that these interventions do not result in harm. On the basis of this review, there is currently uncertainty around the effectiveness of these interventions. We identified six ongoing trials being conducted in a range of contexts including low-income settings with potential to generate more precise estimates of the effect of primary prevention medication adherence interventions delivered by mobile phone.

A randomized controlled trial of an intervention delivered by mobile phone app instant messaging to increase the acceptability of effective contraception among young people in Tajikistan.

BACKGROUND: Unintended pregnancy is associated with poorer health outcomes for women and their families. In Tajikistan, around 26% of married 15-24 year old women have an unmet need for contraception. There is some evidence that interventions delivered by mobile phone can affect contraceptive-related behaviour and knowledge. We developed an intervention delivered by mobile phone app instant messaging to improve acceptability of effective contraceptive methods among young people in Tajikistan. METHODS: This was a randomized controlled trial among Tajik people aged 16-24. Participants allocated to the intervention arm had access to an app plus intervention messages. Participants allocated to the control arm had access to the app plus control messages. The primary outcome was acceptability of at least one method of effective contraception at 4 months. Secondary outcomes were use of effective contraception at 4 months and during the study, acceptability of individual methods, service uptake, unintended pregnancy and induced abortion. Process outcomes were knowledge, perceived norms, personal agency and intention. Outcomes were analysed using logistic and linear regression. We conducted a pre-specified subgroup analysis and a post-hoc analysis of change in acceptability from baseline to follow-up. RESULTS: Five hundred and seventy-three participants were enrolled. Intervention content was included on the app, causing contamination. Four hundred and seventy-two (82%) completed follow-up for the primary outcome. There was no evidence of a difference in acceptability of effective contraception between the groups (66% in the intervention arm vs 64% in the control arm, adjusted OR 1.21, 95% CI .80-1.83, p = 0.36). There were no differences in the secondary or process outcomes between groups. There was some evidence that the effect of the intervention was greater among women compared to men (interaction test p = 0.03). There was an increase in acceptability of effective contraception from baseline to follow-up (2% to 65%, p < 0.001). CONCLUSIONS: The whole intervention delivered by instant messaging provided no additional benefit over a portion of the intervention delivered by app pages. The important increase in contraceptive acceptability from baseline to follow-up suggests that the intervention content included on the app may influence attitudes. Further research is needed to establish the effect of the intervention on attitudes towards and use of effective contraception among married/sexually active young people. TRIAL REGISTRATION: Clinicaltrial.gov NCT02905513 . Date of registration: 14 September 2016.

Correction to: A randomized controlled trial of an intervention delivered by mobile phone app instant messaging to increase the acceptability of effective contraception among young people in Tajikistan.

After publication of the original article [1], it came to the authors' attention that there is a typo in the Results section.

Internet-accessed sexually transmitted infection (e-STI) testing and results service: A randomised, single-blind, controlled trial.

BACKGROUND: Internet-accessed sexually transmitted infection testing (e-STI testing) is increasingly available as an alternative to testing in clinics. Typically this testing modality enables users to order a test kit from a virtual service (via a website or app), collect their own samples, return test samples to a laboratory, and be notified of their results by short message service (SMS) or telephone. e-STI testing is assumed to increase access to testing in comparison with face-to-face services, but the evidence is unclear. We conducted a randomised controlled trial to assess the effectiveness of an e-STI testing and results service (chlamydia, gonorrhoea, HIV, and syphilis) on STI testing uptake and STI cases diagnosed. METHODS AND FINDINGS: The study took place in the London boroughs of Lambeth and Southwark. Between 24 November 2014 and 31 August 2015, we recruited 2,072 participants, aged 16-30 years, who were resident in these boroughs, had at least 1 sexual partner in the last 12 months, stated willingness to take an STI test, and had access to the internet. Those unable to provide consent and unable to read English were excluded. Participants were randomly allocated to receive 1 text message with the web link of an e-STI testing and results service (intervention group) or to receive 1 text message with the web link of a bespoke website listing the locations, contact details, and websites of 7 local sexual health clinics (control group). Participants were free to use any other services or interventions during the study period. The primary outcomes were self-reported STI testing at 6 weeks, verified by patient record checks, and self-reported STI diagnosis at 6 weeks, verified by patient record checks. Secondary outcomes were the proportion of participants prescribed treatment for an STI, time from randomisation to completion of an STI test, and time from randomisation to treatment of an STI. Participants were sent a £10 cash incentive on submission of self-reported data. We completed all follow-up, including patient record checks, by 17 June 2016. Uptake of STI testing was increased in the intervention group at 6 weeks (50.0% versus 26.6%, relative risk [RR] 1.87, 95% CI 1.63 to 2.15, P < 0.001). The proportion of participants diagnosed was 2.8% in the intervention group versus 1.4% in the control group (RR 2.10, 95% CI 0.94 to 4.70, P = 0.079). No evidence of heterogeneity was observed for any of the pre-specified subgroup analyses. The proportion of participants treated was 1.1% in the intervention group versus 0.7% in the control group (RR 1.72, 95% CI 0.71 to 4.16, P = 0.231). Time to test, was shorter in the intervention group compared to the control group (28.8 days versus 36.5 days, P < 0.001, test for difference in restricted mean survival time [RMST]), but no differences were observed for time to treatment (83.2 days versus 83.5 days, P = 0.51, test for difference in RMST). We were unable to recruit the planned 3,000 participants and therefore lacked power for the analyses of STI diagnoses and STI cases treated. CONCLUSIONS: The e-STI testing service increased uptake of STI testing for all groups including high-risk groups. The intervention required people to attend clinic for treatment and did not reduce time to treatment. Service innovations to improve treatment rates for those diagnosed online are required and could include e-treatment and postal treatment services. e-STI testing services require long-term monitoring and evaluation. TRIAL REGISTRATION: ISRCTN Registry ISRCTN13354298.

Changes in conceptions in women younger than 18 years and the circumstances of young mothers in England in 2000-12: an observational study.

BACKGROUND: In 2000, a 10-year Teenage Pregnancy Strategy was launched in England to reduce conceptions in women younger than 18 years and social exclusion in young parents. We used routinely collected data and data from Britain's National Surveys of Sexual Attitudes and Lifestyles (Natsal) to examine progress towards these goals. METHODS: In this observational study, we used random-effects meta-regression to analyse the change in conception rates from 1994-98 to 2009-13 by top-tier local authorities in England, in relation to Teenage Pregnancy Strategy-related expenditure per head, socioeconomic deprivation, and region. Data from similar probability sample surveys: Natsal-1 (1990-91), Natsal-2 (1999-2001), and Natsal-3 (2010-12) were used to assess the prevalence of risk factors and their association with conception in women younger than 18 years in women aged 18-24 years; and the prevalence of participation in education, work, and training in young mothers. FINDINGS: Conception rates in women younger than 18 years declined steadily from their peak in 1996-98 and more rapidly from 2007 onwards. More deprived areas and those receiving greater Teenage Pregnancy Strategy-related investment had higher rates of conception in 1994-98 and had greater declines to 2009-13. Regression analyses assessing the association between Teenage Pregnancy Strategy funding and decline in conception rates in women younger than 18 years showed an estimated reduction in the conception rate of 11.4 conceptions (95% CI 9.6-13.2; p<0.0001) per 1000 women aged 15-17 years for every £100 Teenage Pregnancy Strategy spend per head and a reduction of 8.2 conceptions (5.8-10.5; p<0.0001) after adjustment for socioeconomic deprivation and region. The association between conception in women younger than 18 years and lower socioeconomic status weakened slightly between Natsal-2 and Natsal-3. The prevalence of participation in education, work, or training among young women with a child conceived before age 18 years was low, but the odds of them doing so doubled between Natsal-2 and Natsal-3 (odds ratio 1.99, 95% CI 0.99-4.00). INTERPRETATION: A sustained, multifaceted policy intervention involving health and education agencies, alongside other social and educational changes, has probably contributed to a substantial and accelerating decline in conceptions in women younger than 18 years in England since the late 1990s. FUNDING: Medical Research Council, Wellcome Trust, Economic and Social Research Council, and Department of Health.

Performance tuning non-uniform sampling for sensitivity enhancement of signal-limited biological NMR.

Non-uniform sampling (NUS) has been established as a route to obtaining true sensitivity enhancements when recording indirect dimensions of decaying signals in the same total experimental time as traditional uniform incrementation of the indirect evolution period. Theory and experiments have shown that NUS can yield up to two-fold improvements in the intrinsic signal-to-noise ratio (SNR) of each dimension, while even conservative protocols can yield 20-40% improvements in the intrinsic SNR of NMR data. Applications of biological NMR that can benefit from these improvements are emerging, and in this work we develop some practical aspects of applying NUS nD-NMR to studies that approach the traditional detection limit of nD-NMR spectroscopy. Conditions for obtaining high NUS sensitivity enhancements are considered here in the context of enabling (1)H,(15)N-HSQC experiments on natural abundance protein samples and (1)H,(13)C-HMBC experiments on a challenging natural product. Through systematic studies we arrive at more precise guidelines to contrast sensitivity enhancements with reduced line shape constraints, and report an alternative sampling density based on a quarter-wave sinusoidal distribution that returns the highest fidelity we have seen to date in line shapes obtained by maximum entropy processing of non-uniformly sampled data.