Serological evidence of zoonotic filovirus exposure among bushmeat hunters in Guinea.

Human Ebola virus (EBOV) outbreaks caused by persistent EBOV infection raises questions on the role of zoonotic spillover in filovirus epidemiology. To characterise filovirus zoonotic exposure, we collected cross-sectional serum samples from bushmeat hunters (n = 498) in Macenta Prefecture Guinea, adjacent to the index site of the 2013 EBOV-Makona spillover event. We identified distinct immune signatures (20/498, 4.0%) to multiple EBOV antigens (GP, NP, VP40) using stepwise ELISA and Western blot analysis and, live EBOV neutralisation (5/20; 25%). Using comparative serological data from PCR-confirmed survivors of the 2013-2016 EBOV outbreak, we demonstrated that most signatures (15/20) were not plausibly explained by prior EBOV-Makona exposure. Subsequent data-driven modelling of EBOV immunological outcomes to remote-sensing environmental data also revealed consistent associations with intact closed canopy forest. Together our findings suggest exposure to other closely related filoviruses prior to the 2013-2016 West Africa epidemic and highlight future surveillance priorities.

Quantifying Population Burden and Effectiveness of Decentralized Surveillance Strategies for Skin-Presenting Neglected Tropical Diseases, Liberia.

We evaluated programmatic approaches for skin neglected tropical disease (NTD) surveillance and completed a robust estimation of the burden of skin NTDs endemic to West Africa (Buruli ulcer, leprosy, lymphatic filariasis morbidity, and yaws). In Maryland, Liberia, exhaustive case finding by community health workers of 56,285 persons across 92 clusters identified 3,241 suspected cases. A total of 236 skin NTDs (34.0 [95% CI 29.1-38.9]/10,000 persons) were confirmed by midlevel healthcare workers trained using a tailored program. Cases showed a focal and spatially heterogeneous distribution. This community health worker‒led approach showed a higher skin NTD burden than prevailing surveillance mechanisms, but also showed high (95.1%) and equitable population coverage. Specialized training and task-shifting of diagnoses to midlevel health workers led to reliable identification of skin NTDs, but reliability of individual diagnoses varied. This multifaceted evaluation of skin NTD surveillance strategies quantifies benefits and limitations of key approaches promoted by the 2030 NTD roadmap of the World Health Organization.

Methods and Approaches for Buruli Ulcer Surveillance in Africa: Lessons Learnt and Future Directions.

Over 95% of the global burden of Buruli ulcer disease (BU) caused by Mycobacterium ulcerans occurs in equatorial Africa. National and sub-national programs have implemented various approaches to improve detection and reporting of incident cases over recent decades. Regional incidence rates are currently in decline; however, surveillance targets outlined in 2012 by WHO have been missed and detection bias may contribute to these trends. In light of the new 2030 NTD roadmap and disease-specific targets, BU programs are required to strengthen case detection and begin a transition towards integration with other skin-NTDs. This transition comes with new opportunities to enhance existing BU surveillance systems and develop novel approaches for implementation and evaluation.In this review, we present a breakdown and assessment of the methods and approaches that have been the pillars of BU surveillance systems in Africa: (1) Passive case detection, (2) Data systems, (3) Clinical training, (4) Active case finding, (5) Burden estimation, and (6) Laboratory confirmation pathways. We discuss successes, challenges, and relevant case studies before highlighting opportunities for future development and evaluation including novel data collection tools, risk-based surveillance, and integrated skin-NTD surveillance. We draw on both experience and available literature to critically evaluate methods of BU surveillance in Africa and highlight new approaches to help achieve 2030 roadmap targets.

Epidemiology of soil-transmitted helminths following sustained implementation of routine preventive chemotherapy: Demographics and baseline results of a cluster randomised trial in southern Malawi.

Malawi has successfully leveraged multiple delivery platforms to scale-up and sustain the implementation of preventive chemotherapy (PCT) for the control of morbidity caused by soil-transmitted helminths (STH). Sentinel monitoring demonstrates this strategy has been successful in reducing STH infection in school-age children, although our understanding of the contemporary epidemiological profile of STH across the broader community remains limited. As part of a multi-site trial evaluating the feasibility of interrupting STH transmission across three countries, this study aimed to describe the baseline demographics and the prevalence, intensity and associated risk factors of STH infection in Mangochi district, southern Malawi. Between October-December 2017, a community census was conducted across the catchment area of seven primary healthcare facilities, enumerating 131,074 individuals across 124 villages. A cross-sectional parasitological survey was then conducted between March-May 2018 in the censused area as a baseline for a cluster randomised trial. An age-stratified random sample of 6,102 individuals were assessed for helminthiasis by Kato-Katz and completed a detailed risk-factor questionnaire. The age-cluster weighted prevalence of any STH infection was 7.8% (95% C.I. 7.0%-8.6%) comprised predominantly of hookworm species and of entirely low-intensity infections. The presence and intensity of infection was significantly higher in men and in adults. Infection was negatively associated with risk factors that included increasing levels of relative household wealth, higher education levels of any adult household member, current school attendance, or recent deworming. In this setting of relatively high coverage of sanitation facilities, there was no association between hookworm and reported access to sanitation, handwashing facilities, or water facilities. These results describe a setting that has reduced the prevalence of STH to a very low level, and confirms many previously recognised risk-factors for infection. Expanding the delivery of anthelmintics to groups where STH infection persist could enable Malawi to move past the objective of elimination of morbidity, and towards the elimination of STH. Trial registration: NCT03014167.

Epidemiologic and Genomic Reidentification of Yaws, Liberia.

We confirmed endemicity and autochthonous transmission of yaws in Liberia after a population-based, community-led burden estimation (56,825 participants). Serologically confirmed yaws was rare and focal at population level (24 cases; 2.6 [95% CI 1.4-3.9] cases/10,000 population) with similar clinical epidemiology to other endemic countries in West Africa. Unsupervised classification of spatially referenced case finding data indicated that yaws was more likely to occur in hard-to-reach communities; healthcare-seeking was low among communities, and clinical awareness of yaws was low among healthcare workers. We recovered whole bacterial genomes from 12 cases and describe a monophyletic clade of Treponema pallidum subspecies pertenue, phylogenetically distinct from known TPE lineages, including those affecting neighboring nonhuman primate populations (Taï Forest, Côte d'Ivoire). Yaws is endemic in Liberia but exhibits low focal population prevalence with evidence of a historical genetic bottleneck and subsequent local expansion. Reporting gaps appear attributable to challenging epidemiology and low disease awareness.

Early transmission and case fatality of Ebola virus at the index site of the 2013-16 west African Ebola outbreak: a cross-sectional seroprevalence survey.

BACKGROUND: To date, epidemiological studies at the index site of the 2013-16 west African Ebola outbreak in Meliandou, Guinea, have been restricted in their scope. We aimed to determine the occurrence of previously undocumented Ebola virus disease (EVD) cases and infections, and to reconstruct transmission events. METHODS: This cross-sectional seroprevalence survey of the adult population of Meliandou used a highly specific oral fluid test and detailed interviews of all households in the village and key informants. Each household was interviewed, with all members prompted to describe the events of the outbreak, any illness within the household, and possible contact with suspected cases. Information for deceased individuals was provided by relatives living in the same household. Symptoms were based on Ebola virus Makona variant EVD case definitions (focusing on fever, vomiting, and diarrhoea). For antibody testing, we used an Ebola virus glycoprotein IgG capture enzyme immunoassay developed from a previously validated assay. A maximum exposure level was assigned to every participant using a predetermined scale. We used a generalised linear model (logit function) to estimate odds ratios for the association of sociodemographic variables and exposure level with Ebola virus infection. We adjusted estimates for age and maximum exposure, as appropriate. FINDINGS: Between June 22, and July 9, 2017, we enrolled 237 participants from 27 households in Meliandou. Two households refused to participate and one was absent. All adults in participating households who were present for the interview provided an oral fluid swab for testing, of which 224 were suitable for analysis. In addition to the 11 EVD deaths described previously, on the basis of clinical description and oral fluid testing, we found two probable EVD deaths and eight previously unrecognised anti-Ebola virus IgG-positive survivors, including one who had mild symptoms and one who was asymptomatic, resulting in a case fatality of 55·6% (95% CI 30·8-78·5) for adults. Health-care work (adjusted odds ratio 6·64, 1·54-28·56; p=0·001) and level of exposure (odds ratio adjusted for linear trend across five levels 2·79, 1·59-4·883; p<0·0001) were independent risk factors for infection. INTERPRETATION: Ebola virus infection was more widespread in this spillover population than previously recognised (21 vs 11 cases). We show the first serological evidence of survivors in this population (eight anti-Ebola virus IgG seropositive) and report a case fatality lower than previously reported (55·6% vs 100% in adults). These data show the high community coverage achievable by using a non-invasive test and, by accurately documenting the beginnings of the west African Ebola virus outbreak, reveal important insight into transmission dynamics and risk factors that underpin Ebola virus spillover events. FUNDING: US Food and Drug Administration, Wellcome Trust, and German Research Council.

Circadian Disruptions in the Myshkin Mouse Model of Mania Are Independent of Deficits in Suprachiasmatic Molecular Clock Function.

BACKGROUND: Alterations in environmental light and intrinsic circadian function have strong associations with mood disorders. The neural origins underpinning these changes remain unclear, although genetic deficits in the molecular clock regularly render mice with altered mood-associated phenotypes. METHODS: A detailed circadian and light-associated behavioral characterization of the Na+/K+-ATPase α3 Myshkin (Myk/+) mouse model of mania was performed. Na+/K+-ATPase α3 does not reside within the core circadian molecular clockwork, but Myk/+ mice exhibit concomitant disruption in circadian rhythms and mood. The neural basis of this phenotype was investigated through molecular and electrophysiological dissection of the master circadian pacemaker, the suprachiasmatic nuclei (SCN). Light input and glutamatergic signaling to the SCN were concomitantly assessed through behavioral assays and calcium imaging. RESULTS: In vivo assays revealed several circadian abnormalities including lengthened period and instability of behavioral rhythms, and elevated metabolic rate. Grossly aberrant responses to light included accentuated resetting, accelerated re-entrainment, and an absence of locomotor suppression. Bioluminescent recording of circadian clock protein (PERIOD2) output from ex vivo SCN revealed no deficits in Myk/+ molecular clock function. Optic nerve crush rescued the circadian period of Myk/+ behavior, highlighting that afferent inputs are critical upstream mediators. Electrophysiological and calcium imaging SCN recordings demonstrated changes in the response to glutamatergic stimulation as well as the electrical output indicative of altered retinal input processing. CONCLUSIONS: The Myshkin model demonstrates profound circadian and light-responsive behavioral alterations independent of molecular clock disruption. Afferent light signaling drives behavioral changes and raises new mechanistic implications for circadian disruption in affective disorders.

A clinical practice guideline for the use of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers

BACKGROUND: The role of hyperbaric oxygen (HBO2) for the treatment of diabetic foot ulcers (DFUs) has been examined in the medical literature for decades. There are more systematic reviews of the HBO2/DFU literature than there have been randomized controlled trials (RCTs), but none of these reviews has resulted in a clinical practice guideline (CPG) that clinicians, patients and policy-makers can use to guide decision-making in everyday practice. METHODS: The Undersea and Hyperbaric Medical Society (UHMS), following the methodology of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group, undertook this systematic review of the HBO2 literature in order to rate the quality of evidence and generate practice recommendations for the treatment of DFUs. We selected four clinical questions for review regarding the role of HBO2 in the treatment of DFUs and analyzed the literature using patient populations based on Wagner wound classification and age of the wound (i.e., acute post-operative wound vs. non-healing wound of 30 or more days). Major amputation and incomplete healing were selected as critical outcomes of interest. RESULTS: This analysis showed that HBO2 is beneficial in preventing amputation and promoting complete healing in patients with Wagner Grade 3 or greater DFUs who have just undergone surgical debridement of the foot as well as in patients with Wagner Grade 3 or greater DFUs that have shown no significant improvement after 30 or more days of treatment. In patients with Wagner Grade 2 or lower DFUs, there was inadequate evidence to justify the use of HBO2 as an adjunctive treatment. CONCLUSIONS: Clinicians, patients, and policy-makers should engage in shared decision-making and consider HBO2 as an adjunctive treatment of DFUs that fit the criteria outlined in this guideline. The current body of evidence provides a moderate level of evidence supporting the use of HBO2 for DFUs. Future research should be directed at improving methods for patient selection, testing various treatment protocols and improving our confidence in the existing estimates.(AU)

Patient satisfaction with oral versus nonoral therapeutic approaches in onychomycosis.

The follow-up results of a 9-month observational study of 150 onychomycosis patients treated with a variety of mechanical, topical, and oral therapies by podiatric physicians and dermatologists are presented. Changes from baseline in toenail condition and patient satisfaction were assessed at 4- and 9-month follow-up. At 9 months, patients who had received oral therapy reported significantly fewer onychomycosis-related problems in social situations, including embarrassment or self-consciousness about the appearance of nails, avoidance of contact by others, being perceived as unclean or untidy, and the desire to keep their nails concealed. Patient-reported satisfaction with the treatment program was significantly higher for those receiving oral therapy than for those receiving nonoral therapy.

Ciclopirox 8% nail lacquer in the treatment of onychomycosis of the toenails in the United States.

Ciclopirox 8% nail lacquer has recently become the first topical antifungal agent to be approved by the US Food and Drug Administration for the treatment of onychomycosis. This article reviews the results of the two pivotal clinical trials of this drug that have been performed in the United States as well as those that have been carried out in other countries. The two US studies were both double-blind, vehicle-controlled, parallel-group, multicenter studies designed to determine the efficacy and safety of ciclopirox nail lacquer in the treatment of mild-to-moderate onychomycosis of the toenails caused by dermatophytes. The combined results show a 34% mycologic cure rate, as compared with 10% for the placebo. Data from the ten studies conducted worldwide show a meta-analytic mean (+/- SE) mycologic cure rate of 52.6% +/- 4.2%. As expected for a topical agent, ciclopirox nail lacquer was found to be extremely safe, with mild, transient irritation at the site of application reported as the most common adverse event. Ciclopirox nail lacquer may also have potential for use in combination or adjunctive therapy. Further studies will help to better position this agent for the treatment of this widespread podiatric condition.

Oral treatment options for onychomycosis.

The author discusses the new oral antifungal agents for the treatment of onychomycosis. The history, mechanisms of action, efficacies, dosing, safety profiles, and costs of itraconazole, terbinafine, and fluconazole are reviewed. The author emphasizes that use of these effective antifungals represents an important paradigm shift for podiatric physicians away from the palliative therapy of nail debridement to a potentially curative treatment.

Prophylaxis in lower-extremity infectious diseases.

This article discusses a number of different situations in which prophylaxis against infection may be considered by the podiatric physician. The authors cover some of these areas, including wound and laceration prophylaxis, surgical prophylaxis, and prophylaxis against the possibility of developing bacterial endocarditis following a podiatric procedure.

The use of oral antibiotics in lower-extremity infections.

It is estimated that American podiatrists write 78,000 prescriptions per week for oral antibiotics. This article discusses the currently available oral antibiotics and their appropriate usage in podiatric medicine.

Bone and soft-tissue infections of the lower extremity in diabetics.

The foot is the most common site of infection in the diabetic individual, and one of every four diabetics eventually seeks medical care for a foot problem. This article examines pathologic conditions of the lower extremity from a variety of views, including pathophysiology, classification, microbiology, infections, osteomyelitis, treatment, and prevention strategies.

Treatment of lower extremity infections in diabetics.

The infected diabetic lower extremity has enjoyed a surge in popularity in the medical literature. There have been numerous papers outlining classification systems for ulcer depth, surgical approaches, and microbiology. Discussions on antibiotic use have usually been directed toward therapy of the "diabetic foot infections" as a group, without regard to differences in severity and location of these infections. These infections can vary from the most superficial of processes to a severe life- and limb-threatening sepsis. The author presents a review of the processes involved in the diabetic lower extremity infection and suggests a classification system for selection of empiric antibiotic therapy based on the severity of the infection.

Treatment of lower extremity infections in diabetics.

Despite recent medical advances in the treatment of diabetes mellitus, foot infection remains a major cause of morbidity and mortality in patients with this disorder. Three main factors are responsible for this: neuropathy, angiopathy and immunopathy. Neuropathy is probably the most important factor: minor irritations and trauma can lead to limb-threatening infections without the patient feeling the changes. Angiopathy plays only a minor role, while immunopathy has implications for antibiotic treatment, in that bactericidal agents are needed. A classification scheme that incorporates clinical and laboratory findings can direct the selection of empirical antibiotic therapy in patients with foot infections. These infections may be defined as mild, moderate and severe. In less severe cases, there are effective oral agents that can stop the progress of the infection and obviate the need for patient hospitalisation. Moderate to severe infections require hospitalisation with the use of parenteral agents. With some of the new broad spectrum drugs, single agent therapy is now possible, eliminating the need for expensive, potentially toxic combinations. Antibiotics, however, are only part of the cure. Aggressive surgical debridement followed by conscientious local wound care plays an equal role. The ultimate goal is foot salvage, and the clinical judgement of the practitioner is paramount in determining the treatment strategies needed to achieve this objective.