Efficacy and safety of apremilast in pediatric patients with moderate-to-severe plaque psoriasis: 16-week results from SPROUT, a randomized controlled trial.

BACKGROUND: Approved systemic treatment options are limited for pediatric patients with moderate to severe plaque psoriasis. OBJECTIVE: To assess the efficacy and safety of apremilast over 16 weeks in pediatric patients with plaque psoriasis. METHODS: SPROUT (NCT03701763) was a phase 3, multicenter, randomized, double-blind, placebo-controlled study of apremilast in patients aged 6-17 years with moderate-to-severe psoriasis (Psoriasis Area and Severity Index [PASI] ≥12, body surface area ≥10%, static Physician Global Assessment [sPGA] ≥3) inadequately controlled by/inappropriate for topical therapy. Patients were stratified by age group and randomized (2:1) to apremilast (20 or 30 mg BID based on weight) or placebo for 16 weeks, followed by apremilast extension to 52 weeks. RESULTS: Of 245 patients randomized (apremilast: 163; placebo: 82), 221 (90%) completed the double-blind phase (apremilast: 149; placebo: 72). Significantly more patients achieved sPGA response and ≥75% reduction in PASI with apremilast than placebo, regardless of baseline age, weight, or disease severity. No new safety signals were observed. LIMITATIONS: Sample size of subgroup analyses. CONCLUSIONS: Improvements in global disease activity and skin involvement were significantly greater in pediatric patients treated with apremilast versus placebo. Adverse events were consistent with the known apremilast safety profile.

Pharmacokinetics and safety of apremilast in pediatric patients with moderate to severe plaque psoriasis: Results from a phase 2 open-label study.

BACKGROUND: No oral systemic treatments are approved for pediatric patients with psoriasis. OBJECTIVE: To evaluate the pharmacokinetics and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in pediatric patients with psoriasis. METHODS: This phase 2, multicenter, open-label study enrolled pediatric patients with moderate to severe plaque psoriasis. Patients received apremilast twice daily without titration for 2 weeks (group 1 [age, 12-17 years; weight, ≥35 kg]: apremilast 20 or 30 mg; group 2 [age, 6-11 years; weight, ≥15 kg]: apremilast 20 mg), followed by a 48-week extension. Primary endpoints were pharmacokinetics and safety. Other endpoints were taste/acceptability and change from baseline in score on the Psoriasis Area and Severity Index. RESULTS: A total of 42 enrolled patients (21 adolescents [age, 12-17 years] and 21 children [age, 6-11 years]) received apremilast. Pharmacokinetics modeling and noncompartmental analyses showed that weight-based dosing with apremilast 20 mg twice daily in children or apremilast 20 or 30 mg twice daily in adolescents provides exposure (area under the concentration-time curve from time 0 to 12 hours after the dose) that is comparable to that achieved with apremilast 30 mg twice daily in adults. The safety profile was generally similar to that in adults. Most study participants liked the taste of the tablet. Improvements from baseline in mean Psoriasis Area and Severity Index score were 68% for adolescents (overall) and 79% for children. LIMITATIONS: No children weighing less than 20 kg were enrolled. CONCLUSIONS: This first-time-in-children phase 2 study supports weight-based apremilast dosing for future phase 3 studies of pediatric plaque psoriasis.

Environmental Contamination and Persistence of Ebola Virus RNA in an Ebola Treatment Center.

BACKGROUND: Ebola viruses (EBOVs) are primarily transmitted by contact with infected body fluids. Ebola treatment centers (ETCs) contain areas that are exposed to body fluids through the care of patients suspected or confirmed to have EBOV disease. There are limited data documenting which areas/fomites within ETCs pose a risk for potential transmission. This study conducted environmental surveillance in 2 ETCs in Freetown, Sierra Leone, during the 2014-2016 West African Ebola outbreak. METHODS: ETCs were surveyed over a 3-week period. Sites to be swabbed were identified with input from field personnel. Swab samples were collected and tested for the presence of EBOV RNA. Ebola-positive body fluid-impregnated cotton pads were serially sampled. RESULTS: General areas of both ETCs were negative for EBOV RNA. The immediate vicinity of patients was the area most likely to be positive for EBOV RNA. Personal protective equipment became positive during patient care, but chlorine solution washes rendered them negative. CONCLUSIONS: Personal protective equipment and patient environs do become positive for EBOV RNA, but careful attention to decontamination seems to remove it. EBOV RNA was not detected in general ward spaces. Careful attention to decontamination protocols seems to be important in minimizing the presence of EBOV RNA within ETC wards.

Recommendations for dealing with waste contaminated with Ebola virus: a Hazard Analysis of Critical Control Points approach.

OBJECTIVE: To assess, within communities experiencing Ebola virus outbreaks, the risks associated with the disposal of human waste and to generate recommendations for mitigating such risks. METHODS: A team with expertise in the Hazard Analysis of Critical Control Points framework identified waste products from the care of individuals with Ebola virus disease and constructed, tested and confirmed flow diagrams showing the creation of such products. After listing potential hazards associated with each step in each flow diagram, the team conducted a hazard analysis, determined critical control points and made recommendations to mitigate the transmission risks at each control point. FINDINGS: The collection, transportation, cleaning and shared use of blood-soiled fomites and the shared use of latrines contaminated with blood or bloodied faeces appeared to be associated with particularly high levels of risk of Ebola virus transmission. More moderate levels of risk were associated with the collection and transportation of material contaminated with bodily fluids other than blood, shared use of latrines soiled with such fluids, the cleaning and shared use of fomites soiled with such fluids, and the contamination of the environment during the collection and transportation of blood-contaminated waste. CONCLUSION: The risk of the waste-related transmission of Ebola virus could be reduced by the use of full personal protective equipment, appropriate hand hygiene and an appropriate disinfectant after careful cleaning. Use of the Hazard Analysis of Critical Control Points framework could facilitate rapid responses to outbreaks of emerging infectious disease.

Apremilast Long-Term Safety Up to 5 Years from 15 Pooled Randomized, Placebo-Controlled Studies of Psoriasis, Psoriatic Arthritis, and Behçet's Syndrome.

BACKGROUND: Since US FDA approval in 2014, apremilast has consistently demonstrated a favorable benefit-risk profile in 706,585 patients (557,379 patient-years of exposure) worldwide across approved indications of plaque psoriasis, psoriatic arthritis, and Behçet's syndrome; however, long-term exposure across these indications has not been reported. OBJECTIVE: The aim of this study was to conduct a pooled analysis of apremilast data from 15 clinical studies with open-label extension phases, focusing on long-term safety. METHODS: We analyzed longer-term safety and tolerability of apremilast 30 mg twice daily across three indications for up to 5 years, focusing on adverse events of special interest, including thrombotic events, malignancies, major adverse cardiac events (MACE), serious infections, and depression. Data were pooled across 15 randomized, placebo-controlled studies and divided into placebo-controlled or all-apremilast-exposure groups. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Overall, 4183 patients were exposed to apremilast (6788 patient-years). Most TEAEs were mild to moderate in the placebo-controlled period (96.6%) and throughout all apremilast exposure (91.6%). TEAE rates of special interest were similar between treatment groups in the placebo-controlled period and remained low throughout all apremilast exposure. Exposure-adjusted incidence rates per 100 patient-years during all apremilast exposure were MACE, 0.30; thrombotic events, 0.10; malignancies, 1.0; serious infections, 1.10; serious opportunistic infections, 0.21; and depression, 1.78. Safety findings were consistent across indications and regions. No new safety signals were identified. CONCLUSIONS: The incidence of serious TEAEs and TEAEs of special interest was low despite long-term exposure, further establishing apremilast as a safe oral option for long-term use across indications with a favorable benefit-risk profile. CLINICAL TRIAL REGISTRATION: NCT00773734, NCT01194219, NCT01232283, NCT01690299, NCT01988103, NCT02425826, NCT03123471, NCT03721172, NCT01172938, NCT01212757, NCT01212770, NCT01307423, NCT01925768, NCT00866359, NCT02307513.

Elevation and cholera: an epidemiological spatial analysis of the cholera epidemic in Harare, Zimbabwe, 2008-2009.

BACKGROUND: In highly populated African urban areas where access to clean water is a challenge, water source contamination is one of the most cited risk factors in a cholera epidemic. During the rainy season, where there is either no sewage disposal or working sewer system, runoff of rains follows the slopes and gets into the lower parts of towns where shallow wells could easily become contaminated by excretes. In cholera endemic areas, spatial information about topographical elevation could help to guide preventive interventions. This study aims to analyze the association between topographic elevation and the distribution of cholera cases in Harare during the cholera epidemic in 2008 and 2009. METHODS: We developed an ecological study using secondary data. First, we described attack rates by suburb and then calculated rate ratios using whole Harare as reference. We illustrated the average elevation and cholera cases by suburbs using geographical information. Finally, we estimated a generalized linear mixed model (under the assumption of a Poisson distribution) with an Empirical Bayesian approach to model the relation between the risk of cholera and the elevation in meters in Harare. We used a random intercept to allow for spatial correlation of neighboring suburbs. RESULTS: This study identifies a spatial pattern of the distribution of cholera cases in the Harare epidemic, characterized by a lower cholera risk in the highest elevation suburbs of Harare. The generalized linear mixed model showed that for each 100 meters of increase in the topographical elevation, the cholera risk was 30% lower with a rate ratio of 0.70 (95% confidence interval=0.66-0.76). Sensitivity analysis confirmed the risk reduction with an overall estimate of the rate ratio between 20% and 40%. CONCLUSION: This study highlights the importance of considering topographical elevation as a geographical and environmental risk factor in order to plan cholera preventive activities linked with water and sanitation in endemic areas. Furthermore, elevation information, among other risk factors, could help to spatially orientate cholera control interventions during an epidemic.

Identifying transferable lessons from cholera epidemic responses by Médecins Sans Frontières in Mozambique, Malawi and the Democratic Republic of Congo, 2015-2018: a scoping review.

BACKGROUND: Cholera epidemics occur frequently in low-income countries affected by concurrent humanitarian crises. Evaluations of these epidemic response remains largely unpublished and there is a need to generate evidence on response efforts to inform future programmes. This review of MSF cholera epidemic responses aimed to describe the main characteristics of the cholera epidemics and related responses in these three countries, to identify challenges to different intervention strategies based on available data; and to make recommendations for epidemic prevention and control practice and policy. METHODS: Case studies from the Democratic Republic of Congo, Malawi and Mozambique were purposively selected by MSF for this review due to the documented burden of cholera in each country, frequency of cholera outbreaks, and risk of humanitarian crises. Data were extracted on the characteristics of the epidemics; time between alert and response; and, the delivery of health and water, sanitation and hygiene interventions. A Theory of Change for cholera response programmes was built to assess factors that affected implementation of the responses. RESULTS AND CONCLUSIONS: 20 epidemic response reports were identified, 15 in DRC, one in Malawi and four in Mozambique. All contexts experienced concurrent humanitarian crises, either armed conflict or natural disasters. Across the settings, median time between the date of alert and date of the start of the response by MSF was 23 days (IQR 14-41). Almost all responses targeted interventions community-wide, and all responses implemented in-patient treatment of suspected cholera cases in either established health care facilities (HCFs) or temporary cholera treatment units (CTUs). In three responses, interventions were delivered as case-area targeted interventions (CATI) and four responses targeted households of admitted suspected cholera cases. CATI or delivery of interventions to households of admitted suspected cases occurred from 2017 onwards only. Overall, 74 factors affecting implementation were identified including delayed supplies of materials, insufficient quantities of materials and limited or lack of coordination with local government or other agencies. Based on this review, the following recommendations are made to improve cholera prevention and control efforts: explore improved models for epidemic preparedness, including rapid mobilisation of supplies and deployment of trained staff; invest in and strengthen partnerships with national and local government and other agencies; and to standardise reporting templates that allow for rigorous and structured evaluations within and across countries to provide consistent and accessible data.

Long-lasting insecticidal nets provide protection against malaria for only a single year in Burundi, an African highland setting with marked malaria seasonality.

BACKGROUND: Long-lasting insecticidal nets (LLINs) are one of the key interventions in the global fight against malaria. Since 2014, mass distribution campaigns of LLINs aim for universal access by all citizens of Burundi. In this context, we assess the impact of LLINs mass distribution campaigns on malaria incidence, focusing on the endemic highland health districts. We also explored the possible correlation between observed trends in malaria incidence with any variations in climate conditions. METHODS: Malaria cases for 2011-2019 were obtained from the National Health Information System. We developed a generalised additive model based on a time series of routinely collected data with malaria incidence as the response variable and timing of LLIN distribution as an explanatory variable to investigate the duration and magnitude of the LLIN effect on malaria incidence. We added a seasonal and continuous-time component as further explanatory variables, and health district as a random effect to account for random natural variation in malaria cases between districts. RESULTS: Malaria transmission in Burundian highlands was clearly seasonal and increased non-linearly over the study period. Further, a fast and steep decline of malaria incidence was noted during the first year after mass LLIN distribution (p<0.0001). In years 2 and 3 after distribution, malaria cases started to rise again to levels higher than before the control intervention. CONCLUSION: This study highlights that LLINs did reduce the incidence in the first year after a mass distribution campaign, but in the context of Burundi, LLINs lost their impact after only 1 year.

Improving water, sanitation, and hygiene (WASH), with a focus on hand hygiene, globally for community mitigation of COVID-19.

Continuity of key water, sanitation, and hygiene (WASH) infrastructure and WASH practices-for example, hand hygiene-are among several critical community preventive and mitigation measures to reduce transmission of infectious diseases, including COVID-19 and other respiratory diseases. WASH guidance for COVID-19 prevention may combine existing WASH standards and new COVID-19 guidance. Many existing WASH tools can also be modified for targeted WASH assessments during the COVID-19 pandemic. We partnered with local organizations to develop and deploy tools to assess WASH conditions and practices and subsequently implement, monitor, and evaluate WASH interventions to mitigate COVID-19 in low- and middle-income countries in Latin America and the Caribbean and Africa, focusing on healthcare, community institution, and household settings and hand hygiene specifically. Employing mixed-methods assessments, we observed gaps in access to hand hygiene materials specifically despite most of those settings having access to improved, often onsite, water supplies. Across countries, adherence to hand hygiene among healthcare providers was about twice as high after patient contact compared to before patient contact. Poor or non-existent management of handwashing stations and alcohol-based hand rub (ABHR) was common, especially in community institutions. Markets and points of entry (internal or external border crossings) represent congregation spaces, critical for COVID-19 mitigation, where globally-recognized WASH standards are needed. Development, evaluation, deployment, and refinement of new and existing standards can help ensure WASH aspects of community mitigation efforts that remain accessible and functional to enable inclusive preventive behaviors.

Menstrual Hygiene Management-Knowledge, Attitudes, and Practices Among Female College Students in Bhutan.

Background: Girls and women face substantial menstrual hygiene management (MHM) challenges in low- and middle-income countries. These challenges are related to inadequate knowledge and insufficient water, sanitation, and hygiene (WASH) facilities. Currently, the literature on MHM among college-attending women in Bhutan is scarce. We aimed to explore the knowledge, attitudes, and practices (KAP) of female college students from all the 10 government colleges of Bhutan, documenting the conditions of available MHM facilities, from August to September 2018. Methods: A cross-sectional KAP survey was conducted with a random sample of female students from all years and a random sample of MHM facilities at each college and hostel. A questionnaire was adapted from a similar study conducted with school students in Bhutan. Socio-demographics, overall KAP findings, and differences in KAP between first and final year students were analyzed; college and hostel toilets were self-reported and directly observed. Results: In the survey, 1,010 participants completed the self-administered questionnaire. The comprehensive knowledge of menstruation was found to be low (35.5%) among participants. Half of the participants (50.3%) reported their mother as the source of information, and 35.1% of the participants agreed that women should not enter a shrine during menstruation. It was also reported that approximately 4% of median monthly pocket money was spent on the absorbents, and 96.9% of absorbents were wrapped before disposal. Half of the participants (55.1%) reported that their daily activities were affected due to menstruation, and 24.2% of the female students missed college due to dysmenorrhea. One-fifth of the participants (21.3%) reported unavailability of water in college, 80.1% of the participants reported absence of soap for hand washing, and 24.1% described no bins for disposal. The participants also reported that in 33.7% of hostel toilets, the door locks were missing. The direct observations also had similar findings. Conclusions: Female students living in hostels during college years lose considerable resources during their formative years of learning, such as time, energy, and money, due to issues of menstruation management. Although the overall understanding of menstruation was low, the MHM practices of our participants scored highly, and the vast majority of them asked for a platform to discuss menstruation. Despite some agreement with menstrual taboos (e.g., visiting shrine), only 5.1% of the participants were uncomfortable conversing about MHM. Improved public health knowledge, psychosocial/medical support, and WASH infrastructure with freely available menstrual products could lead to more effective MHM practices among female college students.

Effectiveness of hygiene kit distribution to reduce cholera transmission in Kasaï-Oriental, Democratic Republic of Congo, 2018: a prospective cohort study.

INTRODUCTION: Household contacts of cholera cases are at a greater risk of Vibrio cholerae infection than the general population. There is currently no agreed standard of care for household contacts, despite their high risk of infection, in cholera response strategies. In 2018, hygiene kit distribution and health promotion was recommended by Médecins Sans Frontières for admitted patients and accompanying household members on admission to a cholera treatment unit in the Democratic Republic of Congo. METHODS: To investigate the effectiveness of the intervention and risk factors for cholera infection, we conducted a prospective cohort study and followed household contacts for 7 days after patient admission. Clinical surveillance among household contacts was based on self-reported symptoms of cholera and diarrhoea, and environmental surveillance through the collection and analysis of food and water samples. RESULTS: From 94 eligible households, 469 household contacts were enrolled and 444 completed follow-up. Multivariate analysis suggested evidence of a dose-response relationship with increased kit use associated with decreased relative risk of suspected cholera: household contacts in the high kit-use group had a 66% lower incidence of suspected cholera (adjusted risk ratio (aRR) 0.34, 95% CI 0.11 to 1.03, p=0.055), the mid-use group had a 53% lower incidence (aRR 0.47, 95% CI 0.17 to 1.29, p=1.44) and low-use group had 22% lower incidence (aRR 0.78, 95% CI 0.24 to 2.53, p=0.684), compared with household contacts without a kit. Drinking water contamination was significantly reduced among households in receipt of a kit. There was no significant effect on self-reported diarrhoea or food contamination. CONCLUSION: The integration of a hygiene kit intervention to case-households may be effective in reducing cholera transmission among household contacts and environmental contamination within the household. Further work is required to evaluate whether other proactive localised distribution among patients and case-households or to households surrounding cholera cases can be used in future cholera response programmes in emergency contexts.

Long-lasting insecticide-treated net usage in eastern Sierra Leone - the success of free distribution.

OBJECTIVE: Médecins Sans Frontières (MSF) runs a malaria control project in Bo and Pujehun districts (population 158 000) that includes the mass distribution, routine delivery and demonstration of correct use of free, long-lasting insecticide-treated nets (LLINs). In 2006/2007, around 65 000 LLINs were distributed. The aim of this follow-up study was to measure LLIN usage and ownership in the project area. METHODS: Heads of 900 randomly selected households in 30 clusters were interviewed, using a standardized questionnaire, about household use of LLINs. The condition of any LLIN was physically assessed. RESULTS: Of the 900 households reported, 83.4% owning at least one LLIN. Of the 16.6% without an LLIN, 91.9% had not participated in the MSF mass distribution. In 94.1% of the households reporting LLINs, the nets were observed hanging correctly over the beds. Of the 1135 hanging LLINs, 75.2% had no holes or 10 or fewer finger-size holes. The most common source of LLINs was MSF (75.2%). Of the 4997 household members, 67.2% reported sleeping under an LLIN the night before the study, including 76.8% of children under 5 years and 73.0% of pregnant women. CONCLUSION: Our results show that MSF achieved good usage with freely distributed LLINs. It is one of the few areas where results almost achieve the new targets set in 2005 by Roll Back Malaria to have at least 80% of pregnant women and children under 5 years using LLINs by 2010.

Distribution of household disinfection kits during the 2014-2015 Ebola virus outbreak in Monrovia, Liberia: The MSF experience.

During the initial phase of the 2014-2016 Ebola virus disease (EVD) outbreak in Monrovia, Liberia, all hospitals' isolation capacities were overwhelmed by the sheer caseload. As a stop-gap measure to halt transmission, Medecins sans Frontieres (MSF) distributed household disinfection kits to those who were at high risk of EVD contamination. The kit contained chlorine and personal protective materials to be used for the care of a sick person or the handling of a dead body. This intervention was novel and controversial for MSF. This paper shed the light on this experience of distribution in Monrovia and assess if kits were properly used by recipients. Targeted distribution was conducted to those at high risk of EVD (relatives of confirmed EVD cases) and health staff. Mass distributions were also conducted to households in the most EVD affected urban districts. A health promotion strategy focused on the purpose and use of the kit was integrated into the distribution. Follow-up phone calls to recipients were conducted to enquire about the use of the kit. Overall, 65,609 kits were distributed between September and November 2014. A total of 1,386 recipients were reached by phone. A total of 60 cases of sickness and/or death occurred in households who received a kit. The majority of these (46, 10%) were in households of relatives of confirmed EVD cases. Overall, usage of the kits was documented in 56 out of 60 affected households. Out of the 1322 households that did not experience sickness and/or death after the distribution, 583 (44%) made use of elements of the kit, mainly (94%) chlorine for hand-washing. At the peak of an EVD outbreak, the distribution of household disinfection kits was feasible and kits were appropriately used by the majority of recipients. In similar circumstances in the future, the intervention should be considered.

Distribution of hygiene kits during a cholera outbreak in Kasaï-Oriental, Democratic Republic of Congo: a process evaluation.

BACKGROUND: Cholera remains a leading cause of infectious disease outbreaks globally, and a major public health threat in complex emergencies. Hygiene kits distributed to cholera case-households have previously shown an effect in reducing cholera incidence and are recommended by Médecins Sans Frontières (MSF) for distribution to admitted patients and accompanying household members upon admission to health care facilities (HCFs). METHODS: This process evaluation documented the implementation, participant response and context of hygiene kit distribution by MSF during a 2018 cholera outbreak in Kasaï-Oriental, Democratic Republic of Congo (DRC). The study population comprised key informant interviews with seven MSF staff, 17 staff from other organisations and a random sample of 27 hygiene kit recipients. Structured observations were conducted of hygiene kit demonstrations and health promotion, and programme reports were analysed to triangulate data. RESULTS AND CONCLUSIONS: Between Week (W) 28-48 of the 2018 cholera outbreak in Kasaï-Oriental, there were 667 suspected cholera cases with a 5% case fatality rate (CFR). Across seven HCFs supported by MSF, 196 patients were admitted with suspected cholera between W43-W47 and hygiene kit were provided to patients upon admission and health promotion at the HCF was conducted to accompanying household contacts 5-6 times per day. Distribution of hygiene kits was limited and only 52% of admitted suspected cholera cases received a hygiene kit. The delay of the overall response, delayed supply and insufficient quantities of hygiene kits available limited the coverage and utility of the hygiene kits, and may have diminished the effectiveness of the intervention. The integration of a WASH intervention for cholera control at the point of patient admission is a growing trend and promising intervention for case-targeted cholera responses. However, the barriers identified in this study warrant consideration in subsequent cholera responses and further research is required to identify ways to improve implementation and delivery of this intervention.

Prevention and control of cholera with household and community water, sanitation and hygiene (WASH) interventions: A scoping review of current international guidelines.

INTRODUCTION: Cholera remains a frequent cause of outbreaks globally, particularly in areas with inadequate water, sanitation and hygiene (WASH) services. Cholera is spread through faecal-oral routes, and studies demonstrate that ingestion of Vibrio cholerae occurs from consuming contaminated food and water, contact with cholera cases and transmission from contaminated environmental point sources. WASH guidelines recommending interventions for the prevention and control of cholera are numerous and vary considerably in their recommendations. To date, there has been no review of practice guidelines used in cholera prevention and control programmes. METHODS: We systematically searched international agency websites to identify WASH intervention guidelines used in cholera programmes in endemic and epidemic settings. Recommendations listed in the guidelines were extracted, categorised and analysed. Analysis was based on consistency, concordance and recommendations were classified on the basis of whether the interventions targeted within-household or community-level transmission. RESULTS: Eight international guidelines were included in this review: three by non-governmental organisations (NGOs), one from a non-profit organisation (NPO), three from multilateral organisations and one from a research institution. There were 95 distinct recommendations identified, and concordance among guidelines was poor to fair. All categories of WASH interventions were featured in the guidelines. The majority of recommendations targeted community-level transmission (45%), 35% targeted within-household transmission and 20% both. CONCLUSIONS: Recent evidence suggests that interventions for effective cholera control and response to epidemics should focus on case-centred approaches and within-household transmission. Guidelines did consistently propose interventions targeting transmission within households. However, the majority of recommendations listed in guidelines targeted community-level transmission and tended to be more focused on preventing contamination of the environment by cases or recurrent outbreaks, and the level of service required to interrupt community-level transmission was often not specified. The guidelines in current use were varied and interpretation may be difficult when conflicting recommendations are provided. Future editions of guidelines should reflect on the inclusion of evidence-based approaches, cholera transmission models and resource-efficient strategies.

Typhoid fever outbreak in the Democratic Republic of Congo: Case control and ecological study.

During 2011 a large outbreak of typhoid fever affected an estimated 1430 people in Kikwit, Democratic Republic of Congo. The outbreak started in military camps in the city but then spread to the general population. This paper reports the results of an ecological analysis and a case-control study undertaken to examine water and other possible transmission pathways. Attack rates were determined for health areas and risk ratios were estimated with respect to spatial exposures. Approximately 15 months after the outbreak, demographic, environmental and exposure data were collected for 320 cases and 640 controls residing in the worst affected areas, using a structured interview questionnaire. Unadjusted and adjusted odds ratios were estimated. Complete data were available for 956 respondents. Residents of areas with water supplied via gravity on the mains network were at much greater risk of disease acquisition (risk ratio = 6.20, 95%CI 3.39-11.35) than residents of areas not supplied by this mains network. In the case control study, typhoid was found to be associated with ever using tap water from the municipal supply (OR = 4.29, 95% CI 2.20-8.38). Visible urine or faeces in the latrine was also associated with increased risk of typhoid and having chosen a water source because it is protected was negatively associated. Knowledge that washing hands can prevent typhoid fever, and stated habit of handwashing habits before cooking or after toileting was associated with increased risk of disease. However, observed associations between handwashing or plate-sharing with disease risk could very likely be due to recall bias. This outbreak of typhoid fever was strongly associated with drinking water from the municipal drinking water supply, based on the descriptive and analytic epidemiology and the finding of high levels of faecal contamination of drinking water. Future outbreaks of potentially waterborne disease need an integrated response that includes epidemiology and environmental microbiology during early stages of the outbreak.

Spatial targeted vector control in the highlands of Burundi and its impact on malaria transmission.

BACKGROUND: Prevention of malaria epidemics is a priority for African countries. The 2000 malaria epidemic in Burundi prompted the government to implement measures for preventing future outbreaks. Case management with artemisinin-based combination therapy and malaria surveillance were nationally improved. A vector control programme was initiated in one of the most affected highland provinces. The focal distribution of malaria vectors in the highlands was the starting point for designing a targeted vector control strategy. The objective of this study was to present the results of this strategy on malaria transmission in an African highland region. METHODS: In Karuzi, in 2002-2005, vector control activities combining indoor residual spraying and long-lasting insecticidal nets were implemented. The interventions were done before the expected malaria transmission period and targeted the valleys between hills, with the expectation that this would also protect the populations living at higher altitudes. The impact on the Anopheles population and on malaria transmission was determined by nine cross-sectional surveys carried out at regular intervals throughout the study period. RESULTS: Anopheles gambiae s.l. and Anopheles funestus represented 95% of the collected anopheline species. In the valleys, where the vector control activities were implemented, Anopheles density was reduced by 82% (95% CI: 69-90). Similarly, transmission was decreased by 90% (95% CI: 63%-97%, p = 0.001). In the sprayed valleys, Anopheles density was further reduced by 79.5% (95% CI: 51.7-91.3, p < 0.001) in the houses with nets as compared to houses without them. No significant impact on vector density and malaria transmission was observed in the hill tops. However, the intervention focused on the high risk areas near the valley floor, where 93% of the vectors are found and 90% of the transmission occurs. CONCLUSION: Spatial targeted vector control effectively reduced Anopheles density and transmission in this highland district. Bed nets have an additional effect on Anopheles density though this did not translate in an additional impact on transmission. Though no impact was observed in the hilltops, the programme successfully covered the areas most at risk. Such a targeted strategy could prevent the emergence and spread of an epidemic from these high risk foci.

Vector control in a malaria epidemic occurring within a complex emergency situation in Burundi: a case study.

BACKGROUND: African highlands often suffer of devastating malaria epidemics, sometimes in conjunction with complex emergencies, making their control even more difficult. In 2000, Burundian highlands experienced a large malaria outbreak at a time of civil unrest, constant insecurity and nutritional emergency. Because of suspected high resistance to the first and second line treatments, the provincial health authority and Médecins Sans Frontières (Belgium) decided to implement vector control activities in an attempt to curtail the epidemic. There are few reported interventions of this type to control malaria epidemics in complex emergency contexts. Here, decisions and actions taken to control this epidemic, their impact and the lessons learned from this experience are reported. CASE DESCRIPTION: Twenty nine hills (administrative areas) were selected in collaboration with the provincial health authorities for the vector control interventions combining indoor residual spraying with deltamethrin and insecticide-treated nets. Impact was evaluated by entomological and parasitological surveys. Almost all houses (99%) were sprayed and nets use varied between 48% and 63%. Anopheles indoor resting density was significantly lower in treated as compared to untreated hills, the latter taken as controls. Despite this impact on the vector, malaria prevalence was not significantly lower in treated hills except for people sleeping under a net. DISCUSSION: Indoor spraying was feasible and resulted in high coverage despite being a logistically complex intervention in the Burundian context (scattered houses and emergency situation). However, it had little impact on the prevalence of malaria infection, possibly because it was implemented after the epidemic's peak. Nevertheless, after this outbreak the Ministry of Health improved the surveillance system, changed its policy with introduction of effective drugs and implementation of vector control to prevent new malaria epidemics. CONCLUSION: In the absence of effective drugs and sufficient preparedness, present study failed to demonstrate any impact of vector control activities upon the course of a short-duration malaria epidemic. However, the experience gained lead to increased preparedness and demonstrated the feasibility of vector control measures in this specific context.

Localised transmission hotspots of a typhoid fever outbreak in the Democratic Republic of Congo.

INTRODUCTION: In a semi-urban setting in the Democratic Republic of Congo, this study aims to understand the dynamic of a typhoid fever (TF) outbreak and to assess: a) the existence of hot spots for TF transmission and b) the difference between typhoid cases identified within those hot spots and the general population in relation to socio-demographic characteristics, sanitation practice, and sources of drinking water. METHODS: This was a retrospective analysis of TF outbreaks in 2011 in Kikwit, DRC using microbiological analysis of water sources and a structured interview questionnaire. RESULTS: There were a total of 1430 reported TF cases. The outbreak's epidemic curve shows earliest and highest peak attack rates (AR) in three military camps located in Kikwit (Ebeya 3.2%; Ngubu 3.0%; and Nsinga 2.2%) compared to an average peak AR of 0.6% in other affected areas. A total 320 cases from the military camps and the high burden health areas were interviewed. Typhoid cases in the military camps shared a latrine with more than one family (P<0.02). All tap water sources in both the military camps and general population were found to be highly contaminated with faecal coliforms. CONCLUSION: The role of military camps in Kikwit as early hotspots of TF transmission was likely associated with lower sanitary and hygiene conditions. The proximity of camps to the general population might have been responsible for disseminating TF to the general population. Mapping of cases during an outbreak could be crucial to identify hot spots for transmission and institute corrective measures.

Apremilast in Patients With Active Rheumatoid Arthritis: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study.

OBJECTIVE: To study the efficacy/safety of apremilast, an oral phosphodiesterase 4 inhibitor, compared with placebo in patients with active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX). METHODS: Patients were randomized 1:1:1 to receive placebo, apremilast 20 mg twice a day, or apremilast 30 mg twice a day. Patients whose swollen and tender joint counts had not improved by ≥20% were considered nonresponders at week 16 and were required to enter the protocol-defined early escape. At week 24, patients were transitioned in a blinded manner to receive apremilast 20 mg twice a day if they were initially randomized to receive placebo. Patients who were not initially randomized to receive placebo continued to receive their target apremilast dose. Patients were required to take a stable dose of MTX (7.5-25 mg/week) throughout the study. Magnetic resonance imaging (MRI) was performed in a subset of patients. RESULTS: A total of 237 patients who were receiving MTX therapy were randomized and received ≥1 dose of study medication. At week 16, similar proportions of patients receiving placebo (35%), apremilast 20 mg twice a day (28%), and apremilast 30 mg twice a day (34%) met the American College of Rheumatology criteria for 20% improvement in disease activity (the primary efficacy end point). In the MRI substudy, mean change from baseline in total joint damage scores according to the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system was generally similar with either apremilast dose at week 16. At week 52, no trends were noted for clinical end points by treatment group. Both apremilast doses were generally well tolerated. CONCLUSION: Apremilast efficacy was not demonstrated in patients who had active RA despite stable MTX therapy.