Scale-up and sustainability are often studied separately, with few studies examining the interdependencies between these two processes and the implementation contexts of innovations towards malaria prevention and control. Researchers and implementers offer much more attention to the content of innovations, as they focus on the technological dimensions and the conditions for expansion. Researchers have often considered innovation a linear sequence in which scaling up and sustainability represented the last stages. Using systems thinking in this manuscript, we analyze complex scaling and sustainability processes through adopting and implementing seasonal malaria chemoprevention (SMC) in Burkina Faso from 2014 to 2018.
We conducted a qualitative case study involving 141 retrospective secondary data (administrative, press, scientific, tools and registries, and verbatim) spanning from 2012 to 2018. We complemented these data with primary data collected between February and March 2018 in the form of 15 personal semi-structured interviews with SMC stakeholders and non-participant observations. Processual analysis permitted us to conceptualize scale-up and sustainability processes over time according to different vertical and horizontal levels of analysis and their interconnections.
Our results indicated six internal and external determinants of SMC that may negatively or positively influence its scale-up and sustainability. These determinants are effectiveness, monitoring and evaluation systems, resources (financial, material, and human), leadership and governance, adaptation to the local context, and other external elements. Our results revealed that donors and implementing actors prioritized financial resources over other determinants. In contrast, our study clearly showed that the sustainability of the innovation, as well as its scaling up, depends significantly on the consideration of the interconnectedness of the determinants. Each determinant can concurrently constitute an opportunity and a challenge for the success of the innovation.
Our findings highlight the usefulness of the systemic perspective to consider all contexts (international, national, subnational, and local) to achieve large-scale improvements in the quality, equity, and effectiveness of global health interventions. Thus, complex and systems thinking have made it possible to observe emergent and dynamic innovation behaviors and the dynamics particular to sustainability and scaling up processes.

OBJECTIVE: To investigate whether paracetamol use is associated with a reduced risk of epithelial ovarian cancer (EOC).
METHODS: A nationwide nested case-control study.
METHODS: Danish female population.
METHODS: A total of 9589 EOC cases diagnosed from 2000 to 2019 were age-matched with 383 549 randomly selected female controls using risk set sampling.
METHODS: Paracetamol use, reproductive history, history of medication and history of surgery were retrieved from Danish national registers. Paracetamol use was defined as at least two prescriptions for up to 1 year before the index date, and was further classified according to recency, duration, cumulative dose and intensity of dose.
METHODS: Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between paracetamol and EOC risk, overall and by histological subtypes.
RESULTS: \'Ever\' use of paracetamol was associated with a reduced EOC risk after adjusting for potential confounding factors (OR 0.92, 95% CI 0.87-0.97). The association was only significant among recent users (OR 0.89, 95% CI 0.84-0.95). The risk declined further with the increasing level of cumulative dose and intensity; women from the group with a high cumulative dose and a high intensity had a 13% (OR 0.87, 95% CI 0.80-0.94) and 14% (OR 0.86, 95% CI 0.79-0.93) reduced risk, respectively. In the histological subtype analysis, reduced risk with \'ever\' use was most pronounced for serous and clear cell tumours.
CONCLUSIONS: Paracetamol use was associated with a decreased risk of EOC in a dose-response manner. Future studies are needed to validate the findings and investigate the mechanisms behind the association.

Despite scale-up of seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SP-AQ) in children 3-59 months of age in Burkina Faso, malaria incidence remains high, raising concerns regarding SMC effectiveness and selection of drug resistance. Using a case-control design, we determined associations between SMC drug levels, drug resistance markers, and presentation with malaria.
We enrolled 310 children presenting at health facilities in Bobo-Dioulasso. Cases were SMC-eligible children 6-59 months of age diagnosed with malaria. Two controls were enrolled per case: SMC-eligible children without malaria; and older (5-10 years old), SMC-ineligible children with malaria. We measured SP-AQ drug levels among SMC-eligible children and SP-AQ resistance markers among parasitemic children. Conditional logistic regression was used to compute odds ratios (ORs) comparing drug levels between cases and controls.
Compared to SMC-eligible controls, children with malaria were less likely to have any detectable SP or AQ (OR, 0.33 [95% confidence interval, .16-.67]; P = .002) and have lower drug levels (P < .05). Prevalences of mutations mediating high-level SP resistance were rare (0%-1%) and similar between cases and SMC-ineligible controls (P > .05).
Incident malaria among SMC-eligible children was likely due to suboptimal levels of SP-AQ, resulting from missed cycles rather than increased antimalarial resistance to SP-AQ.

The impact of chemoprophylaxis targeting Plasmodium falciparum on Plasmodium vivax and Plasmodium ovale, which may remain quiescent as hypnozoites in the liver, is debated.
We conducted a nested case-control analysis of the outcomes of P. vivax and P. ovale infections in imported malaria cases in France among civilian travelers from 1 January 2006, to 31 December 2017. Using adjusted logistic regression, we assessed the effect of chemoprophylaxis on the incubation period, time from symptoms to diagnosis, management, blood results, symptoms, and hospitalization duration. We analyzed the effect of blood-stage drugs (doxycycline, mefloquine, chloroquine, chloroquine-proguanil) or atovaquone-proguanil on the incubation period. We used a counterfactual approach to ascertain the causal effect of chemoprophylaxis on postinfection characteristics.
Among 247 P. vivax- and 615 P. ovale-infected travelers, 30% and 47%, respectively, used chemoprophylaxis, and 7 (3%) and 8 (1%) were severe cases. Chemoprophylaxis users had a greater risk of presenting symptoms >2 months after returning for both species (P. vivax odds ratio [OR], 2.91 [95% confidence interval {CI}, 1.22-6.95], P = .02; P. ovale OR, 2.28 [95% CI, 1.47-3.53], P < .001). Using drugs only acting on the blood stage was associated with delayed symptom onset after 60 days, while using atovaquone-proguanil was not.
Civilian travelers infected with P. vivax or P. ovale reporting chemoprophylaxis use, especially of blood-stage agents, had a greater risk of delayed onset of illness. The impact of chemoprophylaxis on the outcomes of infection with relapse-causing species calls for new chemoprophylaxis acting against erythrocytic and liver stages.

(1) Background: The pleiotropic effects of statins may explain a chemoprotective action against colorectal cancer (CRC). Many studies have tested this hypothesis, but results have been inconsistent so far. Moreover, few have examined statins individually which is important for determining whether there is a class effect and if lipophilicity and intensity may play a role. (2) Methods: From 2001-2014, we carried out a study comprised of 15,491 incident CRC cases and 60,000 matched controls extracted from the primary healthcare database BIFAP. We fit a logistic regression model to compute the adjusted-odds ratios (AOR) with their 95% confidence intervals (CIs). Additionally, we carried out a systematic review and meta-analysis. (3) Results: Current use of statins showed a reduced risk of CRC (AOR = 0.87; 95% CI: 0.83-0.91) not sustained after discontinuation. The association was time-dependent, starting early (AOR6months-1year = 0.85; 95% CI: 0.76-0.96) but weakened beyond 3-years. A class effect was suggested, although only significant for simvastatin and rosuvastatin. The risk reduction was more marked among individuals aged 70 or younger, and among moderate-high intensity users. Forty-eight studies were included in the meta-analysis (pooled-effect-size = 0.90; 95% CI: 0.86-0.93). (4) Conclusions: Results from the case-control study and the pooled evidence support a moderate chemoprotective effect of statins on CRC risk, modified by duration, intensity, and age.

In drug trials, adverse events (AEs) burden can induce treatment non-adherence or discontinuation. The non-adherence and discontinuation induce selection bias, affecting drug safety interpretation. Nested case-control (NCC) study can efficiently quantify the impact of the AEs, although choice of sampling approach is challenging. We investigated whether NCC study with incidence density sampling is more efficient than NCC with path sampling under conditional logistic or weighted Cox models in assessing the effect of AEs on treatment non-adherence and participation in preventive antimalarial drug during pregnancy trial.
Using data from a trial of medication to prevent malaria in pregnancy that randomized 600 women to receive chloroquine or sulfadoxine-pyrimethamine during pregnancy, we conducted a NCC study assessing the role of prospectively collected AEs, as exposure of interest, on treatment non-adherence and study non-completion. We compared estimates from NCC study with incidence density against those from NCC with path sampling under conditional logistic and weighted Cox models.
Out of 599 women with the outcomes of interest, 474 (79%) experienced at least one AE before delivery. For conditional logistic model, the hazard ratio for the effect of AE occurrence on treatment non-adherence was 0.70 (95% CI: 0.42, 1.17; p = 0.175) under incidence density sampling and 0.68 (95% CI: 0.41, 1.13; p = 0.137) for path sampling. For study non-completion, the hazard ratio was 1.02 (95% CI: 0.56, 1.83; p = 0.955) under incidence density sampling and 0.85 (95% CI: 0.45, 1.60; p = 0.619) under path sampling. We obtained similar hazard ratios and standard errors under incidence density sampling and path sampling whether weighted Cox or conditional logistic models were used.
NCC with incidence density sampling and NCC with path sampling are practically similar in efficiency whether conditional logistic or weighted Cox analytical methods although path sampling uses more unique controls to achieve the similar estimates.
ClinicalTrials.gov: NCT01443130.

BACKGROUND: Preclinical studies have suggested that antidepressant drugs may possess antineoplastic properties. In a nationwide case-control study, we examined the association between use of antidepressants and endometrial-cancer risk with a particular focus on selective serotonin reuptake inhibitors (SSRIs).
METHODS: From the Danish Cancer Registry, we identified all women with a histologically verified diagnosis of endometrial cancer between 2000 and 2016, and, for each woman, 15 age-matched controls. We obtained information on use of SSRIs, tricyclic antidepressants (TCAs) and other antidepressants based on records of filled prescriptions from the National Prescription Register. Using conditional logistic regression, we calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between use of antidepressants and endometrial-cancer risk compared with non-use. In active comparator analyses, SSRI use was compared with TCA use.
RESULTS: The study population comprised 8164 cases and 122 432 controls. Compared with non-use, SSRI use was associated with an OR of 0.88 (95% CI 0.82-0.96) for endometrial cancer, whereas the association with TCA use was close to unity (OR 1.05, 95% CI 0.90-1.22). Use of other antidepressants yielded an OR of 0.86 (95% CI 0.71-1.03). We observed no apparent trends in associations according to cumulative amount. The inverse association with SSRI use persisted when compared with TCA use (OR 0.81, 95% CI 0.66-0.99).
CONCLUSIONS: Use of SSRIs was associated with a decreased risk of endometrial cancer, whereas no inverse association appeared with use of TCAs. The antineoplastic potential of SSRIs should be investigated in future studies.

BACKGROUND: Venous thromboembolism (VTE) is a potentially devastating complication following abdominally based microsurgical breast reconstruction, with a reported incidence of 0.08-4%. The authors aim to describe disease presentation and clinical course following VTE diagnosis in patients within their practice.
METHODS: A retrospective chart review identified patients who underwent microsurgical breast reconstruction from January 2007 through December 2018. Patients with VTE diagnosed within 90 days of surgery were included. Demographics, co-morbidities, signs and symptoms, and characteristics of oncologic, surgical, and post-operative care were analyzed.
RESULTS: Seven hundred one patients underwent microsurgical breast reconstruction. Eleven patients with pulmonary embolism (PE) and four with deep vein thrombosis (DVT) were identified, resulting in VTE incidence of 2.1% (0.57% DVT, 1.6% PE). Patients were on average 51 years old and had an average body mass index (BMI) of 31.7 kg/m2. Two had a history of VTE, and none had a known hypercoagulable disorder. Using the 2005 Caprini model, all were high risk and seven were highest risk. Among those with PE, the most common symptom was shortness of breath, and the most common signs were desaturation or supplemental oxygen requirements. VTE was diagnosed on average 14.2 days post-operatively (range 2-52 days).
CONCLUSIONS: VTE is an infrequent complication following abdominally based microsurgical breast reconstruction. We recommend a high index of suspicion in women reporting shortness of breath or having desaturation, especially in those with high BMI, high Caprini scores, post-operative complications, or early return to the operating room.

Ivermectin is one among several potential drugs explored for its therapeutic and preventive role in SARS-CoV-2 infection. The study was aimed to explore the association between ivermectin prophylaxis and the development of SARS-CoV-2 infection among healthcare workers.
A hospital-based matched case-control study was conducted among healthcare workers of AIIMS Bhubaneswar, India, from September to October 2020. Profession, gender, age and date of diagnosis were matched for 186 case-control pairs. Cases and controls were healthcare workers who tested positive and negative, respectively, for COVID-19 by RT-PCR. Exposure was defined as the intake of ivermectin and/or hydroxychloroquine and/or vitamin-C and/or other prophylaxis for COVID-19. Data collection and entry was done in Epicollect5, and analysis was performed using STATA version 13. Conditional logistic regression models were used to describe the associated factors for SARS-CoV-2 infection.
Ivermectin prophylaxis was taken by 76 controls and 41 cases. Two-dose ivermectin prophylaxis (AOR 0.27, 95% CI, 0.15-0.51) was associated with a 73% reduction of SARS-CoV-2 infection among healthcare workers for the following month. Those involved in physical activity (AOR 3.06 95% CI, 1.18-7.93) for more than an hour/day were more likely to contract SARS-CoV-2 infection. Type of household, COVID duty, single-dose ivermectin prophylaxis, vitamin-C prophylaxis and hydroxychloroquine prophylaxis were not associated with SARS-CoV-2 infection.
Two-dose ivermectin prophylaxis at a dose of 300 μg/kg with a gap of 72 hours was associated with a 73% reduction of SARS-CoV-2 infection among healthcare workers for the following month. Chemoprophylaxis has relevance in the containment of pandemic.

BACKGROUND: Malaria incidence has plateaued in Sub-Saharan Africa despite Seasonal Malaria Chemoprevention\'s (SMC) introduction. Community health workers (CHW) use a door-to-door delivery strategy to treat children with SMC drugs, but for SMC to be as effective as in clinical trials, coverage must be high over successive seasons.
METHODS: We developed and used a microplanning model that utilizes population raster to estimate population size, generates optimal households visit itinerary, and quantifies SMC coverage based on CHWs\' time investment for treatment and walking. CHWs\' performance under current SMC deployment mode was assessed using CHWs\' tracking data and compared to microplanning in villages with varying demographics and geographies.
RESULTS: Estimates showed that microplanning significantly reduces CHWs\' walking distance by 25%, increases the number of visited households by 36% (p < 0.001) and increases SMC coverage by 21% from 37.3% under current SMC deployment mode up to 58.3% under microplanning (p < 0.001). Optimal visit itinerary alone increased SMC coverage up to 100% in small villages whereas in larger or hard-to-reach villages, filling the gap additionally needed an optimization of the CHW ratio.
CONCLUSIONS: We estimate that for a pair of CHWs, the daily optimal number of visited children (assuming 8.5mn spent per child) and walking distance should not exceed 45 (95% CI 27-62) and 5 km (95% CI 3.2-6.2) respectively. Our work contributes to extend SMC coverage by 21-63% and may have broader applicability for other community health programs.