Peripheral and Placental Prevalence of Sulfadoxine-Pyrimethamine Resistance Markers in Plasmodium falciparum among Pregnant Women in Southern Province, Rwanda.

Intermittent preventive therapy during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended in areas of moderate to high malaria transmission intensity. As a result of the increasing prevalence of SP resistance markers, IPTp-SP was withdrawn from Rwanda in 2008. Nonetheless, more recent findings suggest that SP may improve birthweight even in the face of parasite resistance, through alternative mechanisms that are independent of antimalarial effects. The prevalence of single nucleotide polymorphisms in Plasmodium falciparum dihydropteroate synthase (pfdhps) and dihydrofolate reductase (pfdhfr) genes associated with SP resistance among 148 pregnant women from 2016 to 2018 within Rwanda's Southern Province (Huye and Kamonyi districts) was measured using a ligase detection reaction-fluorescent microsphere assay. The frequency of pfdhps K540E, A581G, and the quintuple (pfdhfr N51I + C59R + S108N/pfdhps A437G + K540E) and sextuple (pfdhfr N51I + C59R + S108N/pfdhps A437G + K540E + A581G) mutant genotypes was 90%, 38%, 75%, and 28%, respectively. No significant genotype difference was seen between the two districts, which are approximately 50 km apart. Observed agreements for matched peripheral to placental blood were reported and found to be 207 of 208 (99%) for pfdhfr and 239 of 260 (92%) for pfdhps. The peripheral blood sample did not miss any pfdhfr drug-resistant mutants or pfdhps except at the S436 loci. At this level of the sextuple mutant, the antimalarial efficacy of SP for preventing low birthweight is reduced, although overall SP still exerts a nonmalarial benefit during pregnancy. This study further reveals the need to intensify preventive measures to sustain malaria control in Rwanda to keep the overall incidence of malaria during pregnancy low.

Effectiveness of Intermittent Screening and Treatment of Malaria in Pregnancy on Maternal and Birth Outcomes in Selected Districts in Rwanda: A Cluster Randomized Controlled Trial.

BACKGROUND: Malaria during pregnancy can cause serious consequences including maternal anemia and low birthweight (LBW). Routine antenatal care (ANC) in Rwanda includes malaria symptom screening at each ANC visit. This cluster randomized controlled trial investigated whether adding intermittent screening with a malaria rapid diagnostic test at each routine ANC visit and treatment of positives during pregnancy (ISTp) is more effective than routine ANC for reducing malaria prevalence at delivery. METHODS: Between September 2016 and June 2018, pregnant women initiating ANC at 14 health centers in Rwanda were enrolled into ISTp or control arms. All women received an insecticide-treated bed net at enrollment. Hemoglobin concentration, placental and peripheral parasitemia, newborn outcome, birthweight, and prematurity were assessed at delivery. RESULTS: Nine hundred seventy-five women were enrolled in ISTp and 811 in the control group. Routine ANC plus ISTp did not significantly reduce polymerase chain reaction-confirmed placental malaria compared to control (adjusted relative risk [aRR], 0.94 [95% confidence interval {CI}, .59-1.50]; P = .799). ISTp had no impact on anemia (aRR, 1.08 [95% CI, .57-2.04]; P = .821). The mean birthweight of singleton newborns was not significantly different between arms (3054 g vs 3096 g, P = .395); however, women in the ISTp arm had a higher proportion of LBW (aRR, 1.59 [95% CI, 1.02-2.49]; P = .042). CONCLUSIONS: This is the only study to compare ISTp to symptomatic screening at ANC in a setting where intermittent preventive treatment is not routinely provided. ISTp did not reduce the prevalence of malaria or anemia at delivery and was associated with an increased risk of LBW. CLINICAL TRIALS REGISTRATION: NCT03508349.

Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study.

BACKGROUND: Partial artemisinin resistance is suspected if delayed parasite clearance (ie, persistence of parasitaemia on day 3 after treatment initiation) is observed. Validated markers of artemisinin partial resistance in southeast Asia, Plasmodium falciparum kelch13 (Pfkelch13) R561H and P574L, have been reported in Rwanda but no association with parasite clearance has been observed. We aimed to establish the efficacy of artemether-lumefantrine and genetic characterisation of Pfkelch13 alleles and their association with treatment outcomes. METHODS: This open-label, single-arm, multicentre, therapeutic efficacy study was done in 2018 in three Rwandan sites: Masaka, Rukara, and Bugarama. Children aged 6-59 months with P falciparum monoinfection and fever were eligible and treated with a 3-day course of artemether-lumefantrine. Treatment response was monitored for 28 days using weekly microscopy screenings of blood samples for P falciparum. Mutations in Pfkelch13 and P falciparum multidrug resistance-1 (Pfmdr1) genes were characterised in parasites collected from enrolled participants. Analysis of flanking microsatellites surrounding Pfkelch13 was done to define the origins of the R561H mutations. The primary endpoint was PCR-corrected parasitological cure on day 28, as per WHO protocol. FINDINGS: 228 participants were enrolled and 224 (98·2%) reached the study endpoint. PCR-corrected efficacies were 97·0% (95% CI 88-100) in Masaka, 93·8% (85-98) in Rukara, and 97·2% (91-100) in Bugarama. Pfkelch13 R561H mutations were present in 28 (13%) of 218 pre-treatment samples and P574L mutations were present in two (1%) pre-treatment samples. 217 (90%) of the 240 Pfmdr1 haplotypes observed in the pretreatment samples, had either the NFD (N86Y, Y184F, D1246Y) or NYD haplotype. Eight (16%) of 51 participants in Masaka and 12 (15%) of 82 participants in Rukara were microscopically positive 3 days after treatment initiation, which was associated with pre-treatment presence of Pfkelch13 R561H in Masaka (p=0·0005). Genetic analysis of Pfkelch13 R561H mutations suggest their common ancestry and local origin in Rwanda. INTERPRETATION: We confirm evidence of emerging artemisinin partial resistance in Rwanda. Although artemether-lumefantrine remains efficacious, vigilance for decreasing efficacy, further characterisation of artemisinin partial resistance, and evaluation of additional antimalarials in Rwanda should be considered. FUNDING: The US President's Malaria Initiative. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Establishing a Timeline to Discontinue Routine Testing of Asymptomatic Pregnant Women for Zika Virus Infection - American Samoa, 2016-2017.

The first patients with laboratory-confirmed cases of Zika virus disease in American Samoa had symptom onset in January 2016 (1). In response, the American Samoa Department of Health (ASDoH) implemented mosquito control measures (1), strategies to protect pregnant women (1), syndromic surveillance based on electronic health record (EHR) reports (1), Zika virus testing of persons with one or more signs or symptoms of Zika virus disease (fever, rash, arthralgia, or conjunctivitis) (1-3), and routine testing of all asymptomatic pregnant women in accordance with CDC guidance (2,3). All collected blood and urine specimens were shipped to the Hawaii Department of Health Laboratory for Zika virus testing and to CDC for confirmatory testing. Early in the response, collection and testing of specimens from pregnant women was prioritized over the collection from symptomatic nonpregnant patients because of limited testing and shipping capacity. The weekly numbers of suspected Zika virus disease cases declined from an average of six per week in January-February 2016 to one per week in May 2016. By August, the EHR-based syndromic surveillance (1) indicated a return to pre-outbreak levels. The last Zika virus disease case detected by real-time, reverse transcription-polymerase chain reaction (rRT-PCR) occurred in a patient who had symptom onset on June 19, 2016. In August 2016, ASDoH requested CDC support in assessing whether local transmission had been reduced or interrupted and in proposing a timeline for discontinuation of routine testing of asymptomatic pregnant women. An end date (October 15, 2016) was determined for active mosquito-borne transmission of Zika virus and a timeline was developed for discontinuation of routine screening of asymptomatic pregnant women in American Samoa (conception after December 10, 2016, with permissive testing for asymptomatic women who conceive through April 15, 2017).

Antihypertensive medication adherence and blood pressure control among central Alabama veterans.

Medication nonadherence is associated with adverse outcomes. To evaluate antihypertensive medication adherence and its association with blood pressure (BP) control, the authors described population adherence to prescribed antihypertensive medication (proportion of days covered ≥80%) and BP control (mean BP <140/90 mm Hg) among central Alabama veterans during the fiscal year 2015. Overall, 75.1% of patients receiving antihypertensive medication were considered adherent, and 66.1% had adequate BP control. Patients adherent to antihypertensive medication were more likely to have adequate BP control compared with patients classified as nonadherent (67.4% vs 62.0%; adjusted odds ratio 1.33; 95% confidence interval, 1.22-1.44 [P<.0001]). Among patients who had uncontrolled BP, 73.6% were considered adherent to medication. Adherence to antihypertensive medication was associated with adequate BP control; however, a substantial proportion of patients with inadequate BP control were also considered adherent. Interventions to increase BP control could address more aggressive medication management to achieve BP goals.

Predictors of health worker performance after Integrated Management of Childhood Illness training in Benin: a cohort study.

BACKGROUND: Correct treatment of potentially life-threatening illnesses (PLTIs) in children under 5 years, such as malaria, pneumonia, and diarrhea, can substantially reduce mortality. The Integrated Management of Childhood Illness (IMCI) strategy has been shown to improve treatment of child illnesses, but multiple studies have shown that gaps in health worker performance remain after training. To better understand factors related to health worker performance, we analyzed 9,330 patient consultations in Benin from 2001-2002, after training one of the first cohorts of 32 health workers in IMCI. METHODS: With data abstracted from patient registers specially designed for IMCI-trained health workers, we examined associations between health facility-, health worker-, and patient-level factors and 10 case-management outcomes for PLTIs. RESULTS: Altogether, 63.6% of children received treatment for all their PLTIs in accordance with IMCI guidelines, and 77.8% received life-saving treatment (i.e., clinically effective treatment, even if not exactly in accordance with IMCI guidelines). Performance of individual health workers varied greatly, from 15-88% of patients treated correctly, on average. Multivariate regression analyses identified several factors that might have influenced case-management quality, many outside a manager's direct control. Younger health workers significantly outperformed older ones, and infants received better care than older children. Children with danger signs, those with more complex illnesses, and those with anemia received worse care. Health worker supervision was associated with improved performance for some outcomes. CONCLUSIONS: A variety of factors, some outside the direct control of program managers, can influence health worker practices. An understanding of these influences can help inform the development of strategies to improve performance.

Antimicrobial and analgesic prescribing patterns for acute otitis externa, 2004-2010.

OBJECTIVE: Acute otitis externa (AOE) is a common but preventable ear condition. Clinical guidelines issued in 2006 recommended topical treatments for uncomplicated AOE, but systemic antimicrobials appear to be commonly prescribed. The objective of this analysis was to describe pre- and postguideline prescribing patterns by clinician specialty and antimicrobial type and assess trends over time. STUDY DESIGN: Retrospective longitudinal analysis of a large insurance database. SETTING: Outpatient departments in the United States. METHODS: Initial outpatient visits in 2004 to 2010 for AOE (excluding visits with complicating conditions) were extracted from an insurance database. Prescription drug claims were linked and categorized by clinician specialty and antimicrobial type. RESULTS: The analysis included 907,261 initial outpatient visits. Use of systemic antimicrobials declined by 4.9% (95% confidence interval [CI], 4.1%, 5.7%) from 36.5% of initial visits in 2004 to 32.1% in 2010. Use of systemic antimicrobials varied by specialty. Systemic antimicrobials were prescribed in 47.1% of 2010 emergency department (ED) visits (-6.9% from 2004, 95% CI -12.3, -1.5), 25.9% of otolaryngologist visits (-1.6%, 95% CI -5.6, 2.4), and 20.4% of pediatrician visits (-6.6%, 95% CI -8.8, -4.4). Penicillins were prescribed most frequently (42.3% of systemic prescriptions in 2010), followed by cephalosporins (19.8%), erythromycin/macrolides (17.4%), and quinolones (11.1%). Opioids were prescribed in 26.4% of ED visits and 9% of outpatient visits. CONCLUSIONS: Use of systemic antimicrobials declined over time, but one-third of 2010 visits resulted in systemic antimicrobials, despite exclusion of visits with complicating factors. Use of systemic antimicrobials varied by specialty. Further educational efforts and outreach to other specialties might be warranted.

Trends in health worker performance after implementing the Integrated Management of Childhood Illness strategy in Benin.

OBJECTIVE: Training health workers to use Integrated Management of Childhood Illness (IMCI) guidelines can improve care for ill children in outpatient settings in developing countries. However, even after IMCI training, important performance gaps exist. One potential reason is that the effect of training can rapidly wane. Our aim was to determine if the performance of IMCI-trained health workers deteriorated over 3 years. METHODS: We studied two departments in Benin. First, we performed a record review of 32 IMCI-trained health workers during the first year of IMCI implementation (2001-2002). Second, we analysed data from cross-sectional health facility surveys from 2001 to 2004 that represented the entire study area. Primary outcomes were the proportion of children under 5 years old with potentially life-threatening illnesses who received either recommended or adequate treatment, and among all children, an index of overall guideline adherence. Secondary outcomes reflected the treatment of individual diseases. Outcomes were calculated monthly, and time trends were evaluated with regression modelling. RESULTS: The record review included 9393 consultations, and the surveys included 411 consultations performed by 105 health workers. For both data sources, performance trends were essentially flat for nearly all outcomes. Absolute levels of performance revealed substantial performance gaps. CONCLUSIONS: We found no evidence that performance declined over 3 years after IMCI training. However, important performance gaps found immediately after IMCI training persisted and should be addressed.

Winter storm-related injuries in Oklahoma, January 2007.

INTRODUCTION: A January 2007 ice storm occurred in Oklahoma, causing power outages and hazardous travel conditions. The objective of this investigation was to describe the nature of winter storm-related injuries among Oklahoma residents, to determine populations at risk, and to inform prevention-planning personnel. METHODS: Winter storm-related injuries were a temporarily reportable condition; all acute-care hospitals and the state medical examiner logged storm-related injuries and deaths during January 12-30, 2007. Medical records were retrospectively abstracted. Risk of injury was described by demographic group, injury type, and mechanism. RESULTS: Among 6,047 persons experiencing winter storm-related injuries, 74% were injured in falls, 13% in motor-vehicle collisions (MVCs), 8% while sledding, 1% by unintentional carbon monoxide poisoning, 1% in cleanup activities, and 3% by other mechanisms. Median age of injured persons was 39years. Persons aged ≥ 40 years were 1.4 times more likely to experience falls as the cause of injury than those aged < 40 years, and falls were twice as likely as other mechanisms to cause fractures among persons aged ≥ 40 years. Injured persons aged < 40 years were 2.2 times more likely to experience MVC-related injuries, and 19 times more likely to experience sledding-related injuries than persons aged ≥ 40 years. CONCLUSIONS: Younger persons were more likely injured in MVCs and sledding incidents, whereas older persons were more likely to experience falls and fractures. IMPACT ON INDUSTRY: Prevention messages for winter storm-related injuries should target winter-driving safety tips to younger adults and precautions regarding falls to older adults.

Hemolytic Uremic Syndrome After an Escherichia coli O111 Outbreak.

BACKGROUND: In August 2008, the largest known US serotype 1 Escherichia coli O111 outbreak occurred in Oklahoma, causing 341 illnesses, including hemolytic uremic syndrome (HUS). HUS is not well described in non-O157 E coli outbreaks but occurs in 2% to 15% of O157 infections, predominantly among children. We examined outbreak-related hospitalizations to characterize E coli O111 illness, the HUS attack rate, and factors associated with subsequent HUS diagnosis among hospitalized patients. METHODS: Medical records were reviewed for clinical presentation and evidence of HUS among hospitalized patients identified during the outbreak investigation. Characteristics of hospitalized patients with vs without HUS were compared. RESULTS: HUS was identified in 26 of 156 (16.7%) confirmed or probable E coli O111 infections; 65.4% of patients with HUS required dialysis, and 1 patient died. The median age of patients with HUS was 43.5 years (age range, 1-88 years); adults composed 57.7% of HUS cases. Characteristics at hospital admission associated with subsequent HUS diagnosis included white blood cell count of at least 20 000/µL (adjusted odds ratio [aOR], 11.3; 95% confidence interval [CI], 1.7-75.3), elevated serum creatinine level for age (9.7; 1.4-69.2), and vomiting before hospital admission (6.8; 1.5-31.3). Administration of antimicrobial agents (risk ratio [RR], 1.0; 95% CI, 0.5-1.8) or medication with antimotility effects (1.4; 0.6-2.9) was not associated with subsequent HUS. CONCLUSIONS: The HUS attack rate in this E coli O111 outbreak was comparable to that for E coli O157-related illnesses, but most cases occurred among adults. On admission, factors associated with subsequent HUS can identify patients who require close monitoring and early aggressive supportive care to improve outcomes.

Increase in unintentional medication overdose deaths: Oklahoma, 1994-2006.

BACKGROUND: During 1999-2006, rates of unintentional drug-related deaths increased 120% in the U.S. PURPOSE: This report describes demographics and trends of unintentional medication overdose deaths among Oklahoma residents to target prevention strategies. METHODS: Oklahoma medical examiner data regarding fatal unintentional poisonings involving at least one prescription or over-the-counter medication during 1994-2006 and opioid retail sales data during 1997-2006 were analyzed during 2008-2009 to determine demographic-specific rates of overdose deaths and changes in 3-year mean death rates. RESULTS: A total of 2112 fatal unintentional medication overdoses were identified (4.7 deaths/100,000 population) involving a median of two substances/decedent. The highest fatality rates occurred among men (5.9/100,000) and people aged 35-54 years (11/100,000). Crude overdose death rates increased sevenfold during the investigation period, peaking at 11/100,000 in 2006. Death rates increased more for women (ninefold) than men (sixfold); rates among residents of rural counties increased more (eightfold) than urban county rates (sixfold). Leading drug types involved in fatalities were opioids and anxiolytics. The individual drugs contributing most frequently included methadone (31%); hydrocodone (19%); alprazolam (15%); and oxycodone (15%). During 1997-2006, Oklahoma prescription opioid sales increased fourfold. Methadone was associated with the highest number of deaths per equianalgesic dose sold (23.3), whereas hydrocodone and oxycodone had the highest increases in deaths per equianalgesic dose sold (threefold increase each). CONCLUSIONS: Unintentional medication-related deaths are increasing in Oklahoma and often involve multiple substances. Substances most frequently contributing to deaths were prescription opioid analgesics. Prevention strategies should target people aged 35-54 years and emphasize the dangers of coingesting substances and misusing prescription pain medications.

Tight Long-term dynamic doxycycline responsive nigrostriatal GDNF using a single rAAV vector.

Glial cell line-derived neurotrophic factor (GDNF) gene transfer is being developed as a treatment for Parkinson's disease (PD). Due to the potential for side effects, external transgene regulation should enhance this strategy's safety profile. Here, we demonstrate dynamic control during long-term expression of GDNF using a recombinant adeno-associated virus (rAAV)-based bicistronic tetracycline (tet)-off construct. Nigrostriatal GDNF overexpression induces body weight alterations in rodents, enabling longitudinal in vivo tracking of GDNF expression after nigral vector delivery. Regulated GDNF expression was highly sensitive to dietary doxycycline (DOX), displaying undetectable striatal GDNF levels at serum DOX levels below those required for antimicrobial activity. However, in the absence of DOX, striatal GDNF levels exceeded levels required for efficacy in PD models. We also demonstrate the absence of a series of known GDNF-associated side effects when using direct intrastriatal vector delivery. Therefore, this single rAAV vector system meets most of the requirements for an experimental reagent for treatment of PD.