The Better Operative Outcomes Software Tool (BOOST) Prospective Study: Improving the Quality of Cataract Surgery Outcomes in Low-Resource Settings.

PURPOSE: Post-operative vision impairment is common among patients who have undergone cataract surgery in low-resource settings, impacting quality of clinical outcomes and patient experience. This prospective, multisite, single-armed, pragmatic validation study aimed to assess whether receiving tailored recommendations via the free Better Operative Outcomes Software Tool (BOOST) app improved surgical outcomes, as quantified by post-operative unaided distance visual acuity (UVA) measured 1-3 days after surgery. METHODS: During the baseline data collection round, surgeons in low and middle-income countries recorded clinical characteristics of 60 consecutive cataract cases in BOOST. Additional data on the causes of poor outcomes from 20 consecutive cases with post-operative UVA of <6/60 (4-12 weeks post-surgery) were entered to automatically generate tailored recommendations for improvement, before 60 additional consecutive cases were recorded during the follow-up study round. Average UVA was compared between cases recorded in the baseline study round and those recorded during follow-up. RESULTS: Among 4,233 cataract surgeries performed by 41 surgeons in 18 countries, only 2,002 (47.3%) had post-operative UVA 6/12 or better. Among the 14 surgeons (34.1%) who completed both rounds of the study (1,680 cases total), there was no clinically significant improvement in post-operative average UVA (logMAR units ±SD) between baseline (0.50 ± 0.37) and follow-up (0.47 ± 0.36) rounds (mean improvement 0.03, p = 0.486). CONCLUSIONS: Receiving BOOST-generated recommendations did not result in improved UVA beyond what could be expected from prospective monitoring of surgical outcomes alone. Additional research is required to assess whether targeted support to implement changes could potentiate the uptake of app-generated recommendations and improve outcomes.

Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function.

Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function. We identified a cold-inducible promoter that generates a 5' truncated AC3 mRNA isoform (Adcy3-at), whose expression is driven by a cold-induced, truncated isoform of PPARGC1A (PPARGC1A-AT). Male mice lacking Adcy3-at display increased energy expenditure and are resistant to obesity and ensuing metabolic imbalances. Mouse and human AC3-AT are retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and lack enzymatic activity. AC3-AT interacts with AC3 and sequesters it in the endoplasmic reticulum, reducing the pool of adenylyl cyclases available for G-protein-mediated cAMP synthesis. Thus, AC3-AT acts as a cold-induced rheostat in BAT, limiting adverse consequences of cAMP activity during chronic BAT activation.

Correction: Ivermectin and doxycycline treatments against Onchocerciasis: Adaptations and impact among semi-nomadic population in Massangam Health District, Cameroon.

[This corrects the article DOI: 10.1371/journal.pntd.0011463.].

Comparison of standard and modified human landing catching techniques for blackfly collection.

BACKGROUND: Human landing catches (HLCs) are required to collect blackflies for entomological evaluation to verify onchocerciasis elimination. However, there are ethical concerns regarding exposure of vector collectors to infectious blackflies and safer alternative methods are needed. This study evaluated a modified HLC technique where collectors wore coloured trousers (blue, black or blue-black), protecting them from bites during fly collection, and their performance was compared with the standard. METHODS: The study was conducted in Makouopsap, Cameroon, in the Massangam health district for 4 months. Four collector pairs-one 'standard' (bare-legged) and three modified-were placed 50 m apart along known breeding sites on the Mbam and Nja Rivers. Collections were performed from 07:00 to 17:00 h, 4 d/month. Hourly rates of flies caught were analysed using a negative binomial generalised linear model to explore associations between flies caught and collection techniques and seasons. RESULTS: Overall, 17 246 blackflies were caught. There was no significant statistical difference in the number of blackflies and parous flies caught between black trousers and the standard. Thus there is a strong indication that wearing black trousers is a viable non-inferior alternative to the standard HLC. CONCLUSIONS: Further studies are needed to confirm generalisability in different ecozones and transmission environments and among different blackfly species.

Dihydropyrrole-3-thiones: one-pot synthesis from propargylamines, acyl chlorides and sodium sulfide.

An efficient one-pot synthesis of 1,2,5-trisubstituted-1,2-dihydro-3H-pyrrole-3-thiones (up to 91% yield), representatives of essentially new heterocyclic systems, by the successive treatment of available propargylamines with acyl chlorides (PdCl2/CuI/Ph3P/Et3N, toluene, 40-45 °C, 3 h) and sodium sulfide (Na2S·9H2O, EtOH, 20-25 °C, 7 h) has been developed. The synthesis comprises the addition of sulfide anions to the formed aminoacetylenic ketones followed by dehydrative cyclization of the prototropically rearranged adducts.

Rapid, room-temperature self-organization of polyarylated 1H-pyrroles from acetylenes and nitriles in the KOBut/DMSO system.

We have discovered that three molecules of arylacetylene are rapidly (15 min) assembled with one molecule of nitrile at room temperature in the KOBut/DMSO system to afford 2-aryl-3-arylethynyl-4-aryl-5-benzyl-1H-pyrroles in up to 76% yield. We assume that this unprecedented self-organization process involves the cascade addition of acetylenic carbanions, first to the CN, then to the CC and CC bonds of the intermediates, followed by pyrrole ring closure via the intramolecular nucleophilic addition of the NH functional group to the CC bond of the final intermediates.

Ivermectin and doxycycline treatments against Onchocerciasis: Adaptations and impact among semi-nomadic population in Massangam Health District, Cameroon.

We trialed strategies to reach semi-nomadic population with interventions targeting onchocerciasis including a combination of community knowledge and Geographical Information System (GIS) technology; nomad-specific sensitization; and mobile outreach. The interventions included ivermectin (ivm) mass drug administration (MDA) and treating infected individuals (found upon skin snip microscopy test) with doxycycline for 35 days. Microscopy-negative snips were further tested by Polymerase Chain Reaction (PCR). After 8 months, individuals immigrating or emigrating constituted 47% of the initial population; 59% of individuals not born in the area have immigrated during the last five years; 28% (age>9) reportedly never taken ivm; 72% (compared to 51% previously) of eligible population (age ≥ 5 years) took ivm; and 47% (age > 8, not pregnant, not breastfeeding, not severely ill,) participated in the test. A high prevalence of onchocerciasis,15.1%, was found upon microscopy & PCR test; 9/10 tested by skin snip microscopy and PCR at follow-up were all negative. Microfilaria prevalence and intensity upon skin snip microscopy reduced significantly from baseline following the intervention (8.9% to 4.1%, p = 0.032; 0.18 to 0.16, p = 0.013, respectively). The strategies considerably increased reach to nomadic camps. Treating with doxycycline in combination with ivm is feasible and has led to a significant reduction in infection level within one year among the semi-nomads. Being potentially curative in one intervention round, this combination should be considered for population group faced with challenges of achieving adequate coverage and adhesion to ivm MDA over prolonged period (>10 years).

Acceptability of test and treat with doxycycline against Onchocerciasis in an area of persistent transmission in Massangam Health District, Cameroon.

The main onchocerciasis elimination strategy is annual Community-Directed Treatment with ivermectin (CDTi). However, as a response to persistent high infection prevalence in Massangam Health District in Cameroon, two rounds of alternative treatments including biannual CDTi, ground larviciding and test and treat with doxycycline (TTd) were implemented. This led to a significant prevalence reduction from 35.7% to 12.3% (p<0.001) as reported by Atekem and colleagues. Here we report on the acceptability of TTd component based on qualitative and quantitative data. The TTd involved microscopic examination for microfilaria in skin biopsy and those infected were offered doxycycline 100 mg daily for 35 days by community-directed distributors (CDDs). Participation level was significantly high with 54% of eligible population (age > 8, not pregnant, not breastfeeding, not severely ill,) participating in the test in each round, increasing to 83% over the two rounds. Factors associated with non-participation included mistrust, being female; being younger than 26 years; short stay in the community; and belonging to semi-nomadic sub population due to their remote and disperse settlement, discrimination, their non selection as CDD, and language and cultural barriers. Treatment coverage was high -71% in round 1 and 83% in round 2. People moving away between testing and treatment impacted treatment coverage. Some participants noted mismatch between symptoms and test result; and that ivermectin is better than doxycycline, while others favoured doxycycline. CDD worried about work burden with unmatching compensation. Overall, TTd participation was satisfactory. But can be improved through reinforcing sensitisation, reducing time between test and treatment; combining TTd and CDTi in one outing; augmenting CDDs compensation and/or weekly visit; exploring for frequently excluded populations and adapting strategies to reach them; and use of a sensitive less invasive test.

Concise assembly of 7-ethynyl-6,8-dioxabicyclo[3.2.1]octanes from acetylenes and ketones.

2-Acetyl-3,4-dihydropyrans, assembled from acetylene gas and ketones in a one-pot procedure, are ethynylated with acetylenes (KOBut/DMSO, 15 °C, 2 h) to give acetylenic alcohols, which readily cyclize (TFA, rt, 5 min) to 7-ethynyl-6,8-dioxabicyclo[3.2.1]octanes in up to 92% yield. The ring closure of the above acetylenic alcohols can be performed without their isolation from the reaction mixture. Thus, the synthesis of 7-ethynyl-6,8-dioxabicyclo[3.2.1]octanes can be realized in just two synthetic operations from simple and available starting materials under mild transition-metal-free conditions.

Rule Abstraction Is Facilitated by Auditory Cuing in REM Sleep.

Sleep facilitates abstraction, but the exact mechanisms underpinning this are unknown. Here, we aimed to determine whether triggering reactivation in sleep could facilitate this process. We paired abstraction problems with sounds, then replayed these during either slow-wave sleep (SWS) or rapid eye movement (REM) sleep to trigger memory reactivation in 27 human participants (19 female). This revealed performance improvements on abstraction problems that were cued in REM, but not problems cued in SWS. Interestingly, the cue-related improvement was not significant until a follow-up retest 1 week after the manipulation, suggesting that REM may initiate a sequence of plasticity events that requires more time to be implemented. Furthermore, memory-linked trigger sounds evoked distinct neural responses in REM, but not SWS. Overall, our findings suggest that targeted memory reactivation in REM can facilitate visual rule abstraction, although this effect takes time to unfold.SIGNIFICANCE STATEMENT The ability to abstract rules from a corpus of experiences is a building block of human reasoning. Sleep is known to facilitate rule abstraction, but it remains unclear whether we can manipulate this process actively and which stage of sleep is most important. Targeted memory reactivation (TMR) is a technique that uses re-exposure to learning-related sensory cues during sleep to enhance memory consolidation. Here, we show that TMR, when applied during REM sleep, can facilitate the complex recombining of information needed for rule abstraction. Furthermore, we show that this qualitative REM-related benefit emerges over the course of a week after learning, suggesting that memory integration may require a slower form of plasticity.

Diastereoselective synthesis of tetrahydropyrrolo[1,2-d]oxadiazoles from functionalized Δ1-pyrrolines and in situ generated nitrile oxides.

Tetrahydropyrrolo[1,2-d]oxadiazoles have been synthesized in good-to-excellent yields via the cycloaddition of nitrile oxides (in situ generated from aldoximes) to readily accessible functionalized Δ1-pyrrolines. The reaction proceeds smoothly at room temperature in a two-phase system in the presence of sodium hypochloride as an oxidant to diastereoselectively afford pharmaceutically prospective 1,2,4-oxadiazolines fused with a five-membered ring. The reaction tolerates a broad range of substrates, including those with oxidant-sensitive functional groups and competitive reaction sites.

Trends in the Incidence of Spontaneous Subarachnoid Hemorrhages in the United States, 2007-2017.

BACKGROUND AND OBJECTIVE: To test the hypothesis that age-specific, sex-specific, and race-specific and ethnicity-specific incidence of nontraumatic subarachnoid hemorrhage (SAH) increased in the United States over the last decade. METHODS: In this retrospective cohort study, validated International Classification of Diseases codes were used to identify all new cases of SAH (n = 39,475) in the State Inpatients Databases of New York and Florida (2007-2017). SAH counts were combined with Census data to calculate incidence. Joinpoint regression was used to compute the annual percentage change (APC) in incidence and to compare trends over time between demographic subgroups. RESULTS: Across the study period, the average annual age-standardized/sex-standardized incidence of SAH in cases per 100,000 population was 11.4, but incidence was significantly higher in women (13.1) compared with that in men (9.6), p < 0.001. Incidence also increased with age in both sexes (men aged 20-44 years: 3.6; men aged 65 years or older: 22.0). Age-standardized and sex-standardized incidence was greater in Black patients (15.4) compared with that in non-Hispanic White (NHW) patients (9.9) and other races and ethnicities, p < 0.001. On joinpoint regression, incidence increased over time (APC 0.7%, p < 0.001), but most of this increase occurred in men aged 45-64 years (APC 1.1%, p = 0.006), men aged 65 years or older (APC 2.3%, p < 0.001), and women aged 65 years or older (APC 0.7%, p = 0.009). Incidence in women aged 20-44 years declined (APC -0.7%, p = 0.017), while those in other age/sex groups remained unchanged over time. Incidence increased in Black patients (APC 1.8%, p = 0.014), whereas that in Asian, Hispanic, and NHW patients did not change significantly over time. DISCUSSION: Nontraumatic SAH incidence in the United States increased over the last decade predominantly in middle-aged men and elderly men and women. Incidence is disproportionately higher and increasing in Black patients, whereas that in other races and ethnicities did not change significantly over time.

Evaluating the impact of alternative intervention strategies in accelerating onchocerciasis elimination in an area of persistent transmission in the West Region of Cameroon.

BACKGROUND: Alternative strategies are recommended to accelerate onchocerciasis elimination in problematic areas including areas where annual ivermectin (IVM) distributions are unable to interrupt transmission. The aim of this study was to accelerate progress towards elimination in the Massangam health district, West Region of Cameroon where impact evaluations demonstrated ongoing transmission of onchocerciasis infection and high microfilaria (mf) prevalence despite more than 20 years of annual IVM distribution. METHODOLOGY/PRINCIPAL FINDINGS: Parasitological, entomological, and breeding site surveys were conducted in 2015 delineating a focus of high transmission and identified three communities with high mf prevalence. Individuals in these communities were screened for mf yearly for a period of two years and those positive treated each year with doxycycline 100mg daily for five weeks. In addition, surrounding communities were given biannual IVM. Temephos-based applications were performed once a week for 10 consecutive weeks on Simulium damnosum s.l. breeding sites. Parasitological and entomological assessments were conducted after two years of implementation and findings compared with 2015 baseline. Alternative strategies accelerated progress towards elimination through a significant mf reduction (χ2: 40.1; p<0.001) from 35.7% (95%CI: 29.0-42.8) to 12.3% (95%CI, 9.0-16.4). Reductions were furthermore recorded over a longer period, with a reduction of prevalence of 29.0% under AIS in 2017-2019 compared to 14.6% with IVM in 2011-2015; and by 23.2% following the two years of alternative strategies compared to 20.3% reduction over 15 years of treatment with IVM (1996-2011). Entomological assessment demonstrates that transmission is still ongoing despite the reduction in mf which is expected in an environment with complex breeding sites and open transmission zones, i.e., where migration of flies or humans to and from neighbouring areas is common. CONCLUSION/SIGNIFICANCE: This study provides evidence that alternative strategies are feasible and effective and should be considered in areas where transmission is sustained throughout long term uninterrupted MDA with IVM. However, there is need to consider wider transmission zones, and further explore optimal timing of larviciding with treatment to impact transmission.

Semistabilized Diazatrienyl Anions from Pyridine Imines and Acetylenes: An Access to (Z)-Stilbene/Imidazopyridine Ensembles, Benzyl Imidazopyridines, and Beyond.

Semistabilized diazatrienyl anions are generated by the reaction of 2-pyridylarylimines with arylacetylenes in superbase systems MOtBu (M = Li, Na, K)/DMSO at ambient temperature for 15 min. The initial intermediate N-centered propargyl-1,3-diaza-1,3,5-trienyl anions undergo intermolecular cyclization to benzyl imidazopyridine anions (formally [3 + 2] cycloaddition), further intercepting a second molecule of the starting pyridylimines or a proton of medium to afford (Z)-stilbene/imidazopyridine ensembles and benzyl imidazopyridines. The charge distribution in all intermediate anions and their synthetic evolution are consistent with quantum-chemical analysis (B2PLYPD/6-311+G**//B3LYP/6-31+G*).

Diastereomerically pure rarely functionalized alkenoyl dihydropyrans, 1,6-diketones, and cyclopentanes from acetylene gas and ketones.

Pure (E)-alkenoyl dihydropyrans are stereoselectively assembled from 2-acetyl-3,4-dihydropyrans (products of one-pot self-organization of acetylene gas and ketones) and aromatic aldehydes (52-86% yields). Furthermore, (E)-alkenoyl dihydropyrans undergo ring opening (acid hydrolysis) to afford 5-hydroxy-1,6-diketones (44-67% yields) and acetyl-2-(E)-styryl-2,3-dihydroxycyclopentanes (19-32% yields), both as single diastereomers.

Regio- and stereoselective base-catalyzed assembly of 6-methylene-5-oxaspiro[2.4]heptanones from alkynyl cyclopropyl ketones.

6-Methylene-5-oxaspiro[2.4]heptanones have been synthesized via base-catalyzed dimerization of available alkynyl cyclopropyl ketones. The reaction proceeds effectively in the presence of the t-BuOK/t-BuOH/THF catalytic system at room temperature to afford the desired spirocycles in a regio- and stereoselective manner. A wider synthetic utility of alkynyl cyclopropyl ketones as novel building blocks was demonstrated by the synthesis of diverse spirocyclopropanes.

Synthesis of Pyrrolo[2,1-a]isoquinolinium Salts from 1-Pyrrolines and Alkynes via Rhodium-Catalyzed C-H Functionalization/N-Annulation Tandem Reaction.

A convenient synthesis of pyrrolo[2,1-a]isoquinolinium salts from 1-pyrrolines and alkynes through rhodium-catalyzed C-H functionalization/N-annulation tandem reaction is described. The protocol features a good substrate tolerance, mild reaction conditions, and high yields of target products. Exploration of the alkyne scope unexpectedly revealed a novel labile functional group-promoted rhodium-catalyzed C-H functionalization/C-annulation/elimination cascade reaction of 1-pyrrolines with electron-deficient alkynes.

Measuring equity of access to eye health outreach camps in rural Malawi.

INTRODUCTION: Equity in the access and use of health services is critical if countries are to make progress towards universal health coverage and address the systematic exclusion of the most vulnerable groups. The purpose of this study was to assess if the Co-ordinated Approach To Community Health programme implemented by Sightsavers was successful in reaching the poorest population, women, and people living with disabilities in Kasungu district, Malawi. METHODS: Between April and September 2017, data on socio-economic status, household characteristics and functional disability were collected from patients attending at eye camps in Kasungu district, Malawi. Using asset-based tools to measure household wealth (EquityTool© and Simple Poverty Scorecard©) and the Washington Group Short Set of Questions, individuals were categorised by wealth quintiles, poverty status, and functional disability status and then compared to relevant representative national household surveys. In addition, a follow-up household survey was conducted to check the validity of self-reported household characteristics at eye camps. RESULTS: A total of 1,358 individuals participated in the study. The study shows that self-reported data on household characteristics and assets are reliable and can be collected in clinical settings (instead of relying on direct observations of assets). Individuals attending outreach camps were poorer in terms of relative wealth and absolute poverty rates compared to the rest of the population in Kasungu. It was estimated that 9% of the participants belonged to the poorest quintile compared to 4% for the population in Kasungu (DHS 2015-2016). The ultra-poverty rate was also lower among respondents (13%) compared to 15% for Kasungu district (IHS 2017). The functional disability rate was 27.5% for study participants, and statistically higher than the general population (5.6%, SENTIF 2017). Even though women are more at risks than men, 54% of the participants were men. CONCLUSIONS: Our study shows that existing tools can be reliably used, and combined, if based on recent population data, to assess equity of access to health services for vulnerable groups of the population. The findings suggest that the programme was successful in reaching the poorest people of the Kasungu district population as well as those with disabilities through outreach camps but that more men than women were reach through the programme. Subsequently, our study showed that self-reported household characteristics are a reliable method to measure asset-based wealth of camps' attendee. However, it is essential to use sub-national data (district or regional level) from recent surveys for the purpose of benchmarking in order to produce accurate results.

Primary eye care: opportunities for health system strengthening and improved access to services.

Primary eye care (PEC) is a vital component of primary healthcare (PHC) and is the cornerstone for the progress towards universal eye health coverage. While the concept of PEC is not new, with the increased focus of the global eye-health agenda on equity and people-centred care, it is critical to review experiences of delivering PEC in low- and middle-income countries and to identify common lessons learnt. This commentary builds on the available evidence and focuses specifically on three recently published evaluations of PEC in Sightsavers-supported programmes in Tanzania, Sierra Leone and Pakistan. It argues that systems thinking is critical in the delivery of PEC interventions, as only this approach can ensure that the integration of PEC into PHC is delivered in a comprehensive, coherent and sustainable way.