Doxycycline for the treatment of nodding syndrome: a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Nodding syndrome is a poorly understood neurological disorder that predominantly occurs in Africa. We hypothesised that nodding syndrome is a neuroinflammatory disorder, induced by antibodies to Onchocerca volvulus or its Wolbachia symbiont, cross-reacting with host neuronal proteins (HNPs), and that doxycycline can be used as treatment. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, we recruited participants from districts affected by nodding syndrome in northern Uganda. We included children and adolescents aged 8-18 years with nodding syndrome, as defined by WHO consensus criteria. Participants were randomly assigned (1:1) to receive either 100 mg doxycycline daily or placebo for 6 weeks via a computer-generated schedule stratified by skin microscopy results, and all parties were masked to group assignment. Diagnoses of O volvulus and antibodies to HNPs were made using luciferase immunoprecipitation system assays and immunohistochemistry. The primary outcome was change in the proportion with antibodies to HNPs, assessed at 24 months. All participants were included in safety analyses, and surviving participants (those with samples at 24 months) were included in primary analyses. Secondary outcomes were: change in concentrations of antibodies to HNPs at 24 months compared with baseline; proportion of participants testing positive for antibodies to O volvulus-specific proteins and concentrations of Ov16 or OVOC3261 antibodies at 24 months compared with baseline; change in seizure burden, proportion achieving seizure freedom, and the proportions with interictal epileptiform discharges on the diagnostic EEG; overall quality of life; disease severity at 24 months; and incidence of all-cause adverse events, serious adverse events, and seizure-related mortality by 24 months. This trial is registered with ClinicalTrials.gov, NCT02850913. FINDINGS: Between Sept 1, 2016, and Aug 31, 2018, 329 children and adolescents were screened, of whom 240 were included in the study. 140 (58%) participants were boys and 100 (42%) were girls. 120 (50%) participants were allocated to receive doxycycline and 120 (50%) to receive placebo. At recruitment, the median duration of symptoms was 9 years (IQR 6-10); 232 (97%) participants had O volvulus-specific antibodies and 157 (65%) had autoantibodies to HNPs. The most common plasma autoantibodies were to human protein deglycase DJ-1 (85 [35%] participants) and leiomodin-1 (77 [32%] participants) and, in cerebrospinal fluid (CSF), to human DJ-1 (27 [11%] participants) and leiomodin-1 (14 [6%] participants). On immunohistochemistry, 46 (19%) participants had CSF autoantibodies to HNPs, including leiomodin-1 (26 [11%]), γ-aminobutyric acid B receptors (two [<1%]), CASPR2 (one [<1%]), or unknown targets (28 [12%]). At 24 months, 161 (72%) of 225 participants had antibodies to HNPs compared with 157 (65%) of 240 at baseline. 6 weeks of doxycycline did not affect the concentration of autoantibodies to HNPs, seizure control, disease severity, or quality of life at the 24-month follow-up but substantially decreased Ov16 antibody concentrations; the median plasma signal-to-noise Ov16 ratio was 16·4 (95% CI 6·4-38·4), compared with 27·9 (8·2-65·8; p=0·033) for placebo. 14 (6%) participants died and, other than one traffic death, all deaths were seizure-related. Acute seizure-related hospitalisations (rate ratio [RR] 0·43 [95% CI 0·20-0·94], p=0·028) and deaths (RR 0·46 [0·24-0·89], p=0·028) were significantly lower in the doxycycline group. At 24 months, 96 (84%) of 114 participants who received doxycycline tested positive for antibodies to Ov16, compared with 97 (87%) of 111 on placebo (p=0·50), and 74 (65%) participants on doxycycline tested positive for antibodies to OVOC3261, compared with 57 (51%) on placebo (p=0·039). Doxycycline was safe; there was no difference in the incidence of grade 3-5 adverse events across the two groups. INTERPRETATION: Nodding syndrome is strongly associated with O volvulus and the pathogenesis is probably mediated through an O volvulus induced autoantibody response to multiple proteins. Although it did not reverse disease symptoms, doxycycline or another prophylactic antibiotic could be considered as adjunct therapy to antiseizure medication, as it might reduce fatal complications from acute seizures and status epilepticus induced by febrile infections. FUNDING: Medical Research Council (UK). TRANSLATION: For the Luo translation of the abstract see Supplementary Materials section.

Conceptual Framework to Guide Early Diagnosis Programs for Symptomatic Cancer as Part of Global Cancer Control.

Diagnosing cancer earlier can enable timely treatment and optimize outcomes. Worldwide, national cancer control plans increasingly encompass early diagnosis programs for symptomatic patients, commonly comprising awareness campaigns to encourage prompt help-seeking for possible cancer symptoms and health system policies to support prompt diagnostic assessment and access to treatment. By their nature, early diagnosis programs involve complex public health interventions aiming to address unmet health needs by acting on patient, clinical, and system factors. However, there is uncertainty regarding how to optimize the design and evaluation of such interventions. We propose that decisions about early diagnosis programs should consider four interrelated components: first, the conduct of a needs assessment (based on cancer-site-specific statistics) to identify the cancers that may benefit most from early diagnosis in the target population; second, the consideration of symptom epidemiology to inform prioritization within an intervention; third, the identification of factors influencing prompt help-seeking at individual and system level to support the design and evaluation of interventions; and finally, the evaluation of factors influencing the health systems' capacity to promptly assess patients. This conceptual framework can be used by public health researchers and policy makers to identify the greatest evidence gaps and guide the design and evaluation of local early diagnosis programs as part of broader cancer control strategies.

Women's appraisal, interpretation and help-seeking for possible symptoms of breast and cervical cancer in South Africa: a qualitative study.

BACKGROUND: In South Africa, breast cancer is the most commonly diagnosed cancer and cervical cancer the leading cause of cancer mortality. Most cancers are diagnosed at a late-stage and following symptomatic presentation. The overall purpose of the study was to inform interventions aimed at improving timely diagnosis of breast and cervical cancer. METHODS: In-depth interviews were conducted with women with potential breast or cervical cancer symptoms from urban and rural South Africa. Participants were recruited from a community-based cross-sectional study on breast and cervical cancer awareness. Data were analysed using a thematic analysis approach. RESULTS: Eighteen women were interviewed (10 urban, 8 rural): the median age was 34.5 years (range 22-58). Most were unemployed, and five were HIV positive. Themes included impact and attribution of bodily changes; influence of social networks and health messaging in help-seeking; management of symptoms and help-seeking barriers. Breast changes were often attributed to manual activities or possible cancer. Women were often unsure how to interpret vaginal symptoms, attributing them to HIV, hormonal contraceptives, or partner infidelity. Concerns about cancer were based on health information from the radio, social networks, or from primary care providers. Prompt care seeking was triggered by impact of symptoms on personal lives. Rural women, especially with possible symptoms of cervical cancer, experienced challenges during help-seeking including judgmental attitudes of clinic staff. Most participants were skeptical of traditional medicine. CONCLUSIONS: This is the first study exploring interpretation of possible breast and cervical cancer symptoms at a community level in South Africa. The process of interpreting bodily changes, symptom attribution and help-seeking is complex and influenced by women's everyday life experiences. Timely diagnosis interventions should not only include cancer symptom awareness but also address individual, structural and health systems related barriers to care.

A health care professionals training needs assessment for oncology in Uganda.

BACKGROUND: Cancer incidence and mortality in sub-Saharan Africa are increasing and do account for significant premature death. The expertise of health care providers is critical to downstaging cancer at diagnosis and improving survival in low- and middle-income countries. We set out to determine the training needs of health care providers for a comprehensive oncology services package in selected hospitals in Uganda, in order to inform capacity development intervention to improve cancer outcomes in the East African region. METHODS: This was a cross-sectional survey using the WHO Hennessey-Hicks questionnaire to identify the training needs of health workers involved in cancer care, across 22 hospitals in Uganda. Data were captured in real time using the Open Data Kit platform from which the data was exported to Stata version 15 for analysis using the Wilcoxon signed-rank test and Somers-Delta. RESULTS: There were 199 respondent health professionals who were predominately female (146/199, 73.37%), with an average age of 38.97 years. There were 158/199 (79.40%) nurses, 24/199 (12.06%) medical doctors and 17/199 (8.54%) allied health professionals. Overall, the research and audit domain had the highest ranking for all the health workers (Somers-D = 0.60). The respondent's level of education had a significant effect on the observed ranking (P value = 0.03). Most of the continuing medical education (CME) topics suggested by the participants were in the clinical task-related category. CONCLUSION: The "research and audit" domain was identified as the priority area for training interventions to improve oncology services in Uganda. There are opportunities for addressing the identified training needs with an expanded cancer CME programme content, peer support networks and tailored training for the individual health care provider.

Setting up a clinical trial for a novel disease: a case study of the Doxycycline for the Treatment of Nodding Syndrome Trial - challenges, enablers and lessons learned.

A large amount of preparation goes into setting up trials. Different challenges and lessons are experienced. Our trial, testing a treatment for nodding syndrome, an acquired neurological disorder of unknown cause affecting thousands of children in Eastern Africa, provides a unique case study. As part of a study to determine the aetiology, understand pathogenesis and develop specific treatment, we set up a clinical trial in a remote district hospital in Uganda. This paper describes our experiences and documents supportive structures (enablers), challenges faced and lessons learned during set-up of the trial. Protocol development started in September 2015 with phased recruitment of a critical study team. The team spent 12 months preparing trial documents, procurement and training on procedures. Potential recruitment sites were pre-visited, and district and local leaders met as key stakeholders. Key enablers were supportive local leadership and investment by the district and Ministry of Health. The main challenges were community fears about nodding syndrome, adverse experiences of the community during previous research and political involvement. Other challenges included the number and delays in protocol approvals and lengthy procurement processes. This hard-to-reach area has frequent power and Internet fluctuations, which may affect cold chains for study samples, communication and data management. These concerns decreased with a pilot community engagement programme. Experiences and lessons learnt can reduce the duration of processes involved in trial-site set-up. A programme of community engagement and local leader involvement may be key to the success of a trial and in reducing community opposition towards participation in research.

Awareness of cervical cancer risk factors and symptoms: cross-sectional community survey in post-conflict northern Uganda.

BACKGROUND: Lack of awareness of risk factors and symptoms for cancer may lead to late diagnosis and poor prognosis. OBJECTIVE: We assessed community awareness about cervical cancer risk factors and symptoms and perceptions about prevention and cure of cervical cancer in order to contribute data to inform interventions to improve cervical cancer survival. DESIGN: Cross-sectional population-based survey. SETTING AND PARTICIPANTS: We conducted this study in Gulu, a post-conflict district in Uganda in 2012. The sample included 448 persons aged 18 years and above, selected through a multi-stage stratified cluster sampling process. DATA COLLECTION METHODS AND ANALYSIS: We collected data using a pretested structured questionnaire. Logistic regressions were used to determine magnitudes of associations between socio-demographic and outcome variables. RESULTS: Most participants (444/448) had heard about cervical cancer. Known risk factors including multiple sexual partners, human papillomavirus infection, and early onset of sexual activity, were recognized by 88%, 82%, and 78% of respondents respectively. 63% of participants believed that prolonged use of family planning pills and injections caused cervical cancer. The majority of participants recognized symptoms of cervical cancer including inter-menstrual bleeding (85%), post-menopausal bleeding (84%), and offensive vaginal discharge (83%). 70% of participants believed that cervical cancer is preventable and 92% believed that it could be cured if diagnosed at an early stage. DISCUSSION AND CONCLUSIONS: Recognition of cervical cancer risk factors and symptoms was high among study participants. Targeted interventions including increasing availability of HPV vaccination, population-based cervical screening and diagnostic services can translate high awareness into actual benefits.

Patients with nodding syndrome in Uganda improve with symptomatic treatment: a cross-sectional study.

OBJECTIVES: Nodding syndrome (NS) is a poorly understood neurological disorder affecting thousands of children in Africa. In March 2012, we introduced a treatment intervention that aimed to provide symptomatic relief. This intervention included sodium valproate for seizures, management of behaviour and emotional difficulties, nutritional therapy and physical rehabilitation. We assessed the clinical and functional outcomes of this intervention after 12 months of implementation. DESIGN: This was a cross-sectional study of a cohort of patients with NS receiving the specified intervention. We abstracted preintervention features from records and compared these with the current clinical status. We performed similar assessments on a cohort of patients with other convulsive epilepsies (OCE) and compared the outcomes of the two groups. PARTICIPANTS: Participants were patients with WHO-defined NS and patients with OCE attending the same centres. OUTCOME MEASURES: The primary outcome was the proportion of patients with seizure freedom (≥1 month without seizures). Secondary outcome measures included a reduction in seizure frequency, resolution of behaviour and emotional difficulties, and independence in basic self-care. RESULTS: Patients with NS had had a longer duration of symptoms (median 5 (IQR 3, 6) years) compared with those with OCE (4 (IQR 2, 6) years), p<0.001. The intervention resulted in marked improvements in both groups; compared to the preintervention state, 121/484 (25%) patients with NS achieved seizure freedom and there was a >70% reduction in seizure frequency; behaviour and emotional difficulties resolved in 194/327 (59%) patients; 193/484 (40%) patients had enrolled in school including 17.7% who had earlier withdrawn due to severe seizures, and over 80% had achieved independence in basic self-care. These improvements were, however, less than that in patients with OCE of whom 243/476 (51.1%) patients were seizure free and in whom the seizure frequency had reduced by 86%. CONCLUSIONS: Ugandan children with NS show substantial clinical and functional improvements with symptomatic treatments suggesting that NS is probably a reversible encephalopathy.

Mind the gaps: a qualitative study of perceptions of healthcare professionals on challenges and proposed remedies for cervical cancer help-seeking in post conflict northern Uganda.

BACKGROUND: There are limited data on perceptions of health professionals on challenges faced by cervical cancer patients seeking healthcare in the developing countries. We explored the views of operational level health professionals on perceived barriers to cervical screening and early help-seeking for symptomatic cervical cancer and the proposed remedies to the challenges. METHODS: Fifteen key informant interviews were held with health professionals including medical directors, gynecologists, medical officers, nurses and midwives in the gynecology and obstetrics departments of two hospitals in northern Uganda during August 2012 to April 2013. We used content analysis techniques to analyze the data. RESULTS: Health professionals' perceived barriers to cervical cancer care included: (i) patients and community related barriers e.g. lack of awareness on cervical cancer and available services, discomfort with exposure of women's genitals and perceived pain during pelvic examinations, and men's lack of emotional support to women (ii) individual healthcare professional's challenges e.g. inadequate knowledge and skills about cervical cancer management; (iii) health facility related barriers e.g. long distances and lack of transport to cervical cancer screening and care centers, few gynecologists and lack of pathologists, delayed histology results, lack of established palliative care services and inadequate pain control; and (iv) health policy challenges e.g. lack of specialized cancer treatment services, and lack of vaccination for human papilloma virus. Other challenges included increased number of cervical cancer patients and late stage of cervical cancer at presentations. CONCLUSIONS: Operational level healthcare professionals in northern Uganda reported several practical challenges facing cervical cancer care that influence their decisions, management goals and practices. The challenges and proposed remedies can inform targeted interventions for early detection, management, and control of cervical cancer in Uganda.

Perceptions of diabetes in rural areas of Eastern Uganda.

BACKGROUND: People diagnosed with diabetes mellitus are increasing in sub-Saharan Africa and prompt care seeking depends on perceptions of the illness. OBJECTIVE: The objective was to explore perceptions of diabetes in rural areas. METHOD: We conducted a qualitative, explorative and descriptive study in rural eastern Uganda. Eight focus group discussions with community members were conducted. Community members were presented with a story about a person with diabetes symptoms and their perceptions of the diagnosis and treatment elicited. Four focus group discussions with people with diabetes and seven key informant interviews with health workers were conducted. Respondents were asked how the community interpreted symptoms of diabetes, its causes and whether it was curable. Manifest content analysis was used. RESULTS: Some respondents thought people with diabetes symptoms had HIV or were bewitched. Causes of diabetes mentioned included consuming too much fatty food. Some respondents thought diabetes is transmitted through air, sharing utensils with or sitting close to people with diabetes. Some respondents thought that diabetes could heal fast whilst others thought it was incurable. CONCLUSION: Misdiagnosis may cause delay in seeking proper care. Preventive programmes could build on people's thinking that too much fatty food causes diabetes to promote diets with less fat. The perception of diabetes as a contagious disease leads to stigmatisation and affects treatment seeking. Seeing diabetes as curable could create patient expectations that may not be fulfilled in the management of diabetes. Rural communities would benefit from campaigns creating awareness of prevention, symptoms, diagnosis and management of diabetes.