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Artemether-lumefantrine (AL) is a first-line agent for uncomplicated malaria caused by Plasmodium falciparum. The WHO recommends periodic therapeutic efficacy studies of antimalarial drugs for the detection of malaria parasite drug resistance and to inform national malaria treatment policies. We conducted a therapeutic efficacy study of AL in a high malaria transmission region of northern Zambia from December 2014 to July 2015. One hundred children of ages 6 to 59 months presenting to a rural health clinic with uncomplicated falciparum malaria were admitted for treatment with AL (standard 6-dose regimen) and followed weekly for 5 weeks. Parasite counts were taken every 6 hours during treatment to assess parasite clearance. Recurrent episodes during follow-up (n = 14) were genotyped to distinguish recrudescence from reinfection and to identify drug resistance single nucleotide polymorphisms (SNPs) and multidrug resistance protein 1 (mdr1) copy number variation. Day 7 lumefantrine concentrations were measured for correspondence with posttreatment reinfection. All children who completed the parasite clearance portion of the study (n = 94) were microscopy-negative by 72 hours. The median parasite elimination half-life was 2.7 hours (interquartile range: 2.1-3.3). Genotype-corrected therapeutic efficacy was 98.8% (95% CI: 97.6-100). Purported artemisinin and lumefantrine drug resistance SNPs in atp6, 3D7_1451200, and mdr1 were detected but did not correlate with parasite recurrence, nor did day 7 lumefantrine concentrations. In summary, AL was highly effective for the treatment of uncomplicated falciparum malaria in northern Zambia during the study period. The high incidence of recurrent parasitemia was consistent with reinfection due to high, perennial malaria transmission.

Antibodies to Plasmodium falciparum are specific biomarkers that can be used to monitor parasite exposure over broader time frames than microscopy, rapid diagnostic tests, or molecular assays. Consequently, seroprevalence surveys can assist with monitoring the impact of malaria control interventions, particularly in the final stages of elimination, when parasite incidence is low. The protein array format to measure antibodies to diverse P. falciparum antigens requires only small sample volumes and is high throughput, permitting the monitoring of malaria transmission on large spatial and temporal scales. We expanded the use of a protein microarray to assess malaria transmission in settings beyond those with a low malaria incidence. Antibody responses in children and adults were profiled, using a P. falciparum protein microarray, through community-based surveys in three areas in Zambia and Zimbabwe at different stages of malaria control and elimination. These three epidemiological settings had distinct serological profiles reflective of their malaria transmission histories. While there was little correlation between transmission intensity and antibody signals (magnitude or breadth) in adults, there was a clear correlation in children younger than 5 years of age. Antibodies in adults appeared to be durable even in the absence of significant recent transmission, whereas antibodies in children provided a more accurate picture of recent levels of transmission intensity. Seroprevalence studies in children could provide a valuable marker of progress toward malaria elimination.IMPORTANCE As malaria approaches elimination in many areas of the world, monitoring the effect of control measures becomes more important but challenging. Low-level infections may go undetected by conventional tests that depend on parasitemia, particularly in immune individuals, who typically show no symptoms of malaria. In contrast, antibodies persist after parasitemia and may provide a more accurate picture of recent exposure. Only a few parasite antigens-mainly vaccine candidates-have been evaluated in seroepidemiological studies. We examined antibody responses to 500 different malaria proteins in blood samples collected through community-based surveillance from areas with low, medium, and high malaria transmission intensities. The breadth of the antibody responses in adults was broad in all three settings and was a poor correlate of recent exposure. In contrast, children represented a better sentinel population for monitoring recent malaria transmission. These data will help inform the use of multiplex serology for malaria surveillance.

BACKGROUND: Southern Province, Zambia has experienced a dramatic decline in Plasmodium falciparum malaria transmission in the past decade and is targeted for elimination. Zambias National Malaria Elimination Program recommends reactive case detection (RCD) within 140 m of index households to enhance surveillance and eliminate remaining transmission foci. METHODS: To evaluate whether RCD captures local transmission, we genotyped 26 microsatellites from 106 samples collected from index (n = 27) and secondary (n = 79) cases detected through RCD in the Macha Hospital catchment area between January 2015 and April 2016. RESULTS: Participants from the same RCD event harbored more genetically related parasites than those from different RCD events, suggesting that RCD captures, at least in part, infections related through local transmission. Related parasites clustered in space and time, up to at least 250 m from index households. Spatial analysis identified a putative focal transmission hotspot. CONCLUSIONS: The current RCD strategy detects focal transmission events, although programmatic guidelines to screen within 140 m of index households may fail to capture all secondary cases. This study highlights the utility of parasite genetic data in assessing programmatic interventions, and similar approaches may be useful to malaria elimination programs seeking to tailor intervention strategies to the underlying transmission epidemiology.

Measles is a highly transmissible systemic viral infection associated with substantial mortality primarily due to secondary infections. Measles induces lifelong immunity to reinfection but loss of immunity to other pathogens. An attenuated live virus vaccine is highly effective, but lapses in delivery have resulted in increasing cases worldwide. Although the primary cause of failure to control measles is failure to vaccinate, waning vaccine-induced immunity and the possible emergence of more virulent virus strains may also contribute. [ABSTRACT FROM AUTHOR]

IMPORTANCE: Opioid misuse and overuse has become an epidemic. Chronic opioid use among oral cavity cancer patients after surgery has not been described. OBJECTIVES: To assess the prevalence of chronic opioid use in patients undergoing surgery for oral cavity cancer, and evaluate possible associated clinical factors; and the association between opioid use and survival. DESIGN, SETTING, AND PARTICIPANTS: For this retrospective cohort study of patients undergoing surgery for oral cavity cancer a consecutive sample of 99 patients between January 1, 2011, and September 30, 2016, were identified through the institutional cancer registry from a single academic center. EXPOSURES: Surgery for oral cavity cancer. MAIN OUTCOMES AND MEASURES: Chronic opioid use, defined as more than 90 days from surgery. Factors associated with chronic opioid use were investigated by univariable and multivariable logistic regression. The Kaplan-Meier method and Cox proportional hazards model were used to assess overall survival and disease-free survival. RESULTS: The mean (SD) patient age was 62.6 (14.3) years; 60 patients (60%) were male. Chronic opioid use was observed in 41 patients (41%). On multivariable logistic regression, preoperative opioid use (odds ratio [OR], 5.6; 95% CI, 2.2-14.3), tobacco use (OR, 2.8; 95% CI, 1.0-8.0), and development of persistence, recurrence, or a second primary tumor (OR, 2.8; 95% CI, 1.0-7.4) were associated with chronic opioid use. Among preoperative opioid users, estimated overall survival (hazard ratio [HR], 3.2; 95% CI, 1.4-7.1) was decreased, and chronic opioid use was associated with decreased disease-free survival (HR, 2.7; 95% CI, 1.1-6.6). CONCLUSIONS AND RELEVANCE: In patients undergoing surgery for oral cavity tumors, the prevalence of chronic opioid use was considerable. Preoperative opioid use, tobacco use, and development of persistence, recurrence, or a second primary tumor were associated with chronic opioid use after surgery, and both preoperative and chronic opioid use were associated with decreased survival.

Measles elimination refers to the interruption of measles virus transmission in a defined geographic area (e.g., country or region) for 12 months or more, and measles eradication refers to the global interruption of measles virus transmission. Measles eradication was first discussed and debated in the late 1960's shortly after the licensure of measles vaccines. Most experts agree that measles meets criteria for disease eradication, but progress toward national and regional measles elimination has slowed. Several paths to measles eradication can be described, including an incremental path through country-wide and regional measles elimination and phased paths through endgame scenarios and strategies. Infectious disease dynamic modeling can help inform measles elimination and eradication strategies, and all paths would be greatly facilitated by innovative technologies such as microarray patches to improve vaccine access and demand, point-of-contact diagnostic tests to facilitate outbreak responses, and point-of-contact IgG tests to identify susceptible populations. A pragmatic approach to measles eradication would identify and realize the necessary preconditions and clearly articulate various endgame scenarios and strategies to achieve measles eradication with an intensified and coordinated global effort in a specified timeframe, i.e., to "go big and go fast". To encourage and promote deliberation among a broad array of stakeholders, we provide a brief historical background and key considerations for setting a measles eradication goal. [ABSTRACT FROM AUTHOR]

ImportanceSurgical repair of congenital aural atresia and hypoplasia (CAAH) is technically challenging. Long-term surgical and audiologic outcomes of atresiaplasty are incompletely understood.ObjectivesTo review the surgical outcomes for CAAH and analyze the hearing results.Design, setting, and participantsA retrospective medical record review of CAAH outcomes was performed during an 11-year period from January 1, 2004, through December 31, 2014. The data analysis was undertaken from December 1, 2014, through January 31, 2015. The mean clinic follow-up time was 3.9 years, and the mean audiologic follow-time was 2.8 years. The study included 98 patients aged 5 to 66 years (mean age, 16.6 years) with CAAH who underwent a total of 104 operations.InterventionsSurgical repair of CAAH.Main outcomes and measuresPreoperative and postoperative pure-tone averages (PTAs), speech reception thresholds (SRTs), air-bone gaps (ABGs), and interaural PTA and SRT differences were compared. Factors that affect hearing outcomes were analyzed. The complication rates were reviewed and compared with results from similar studies.ResultsIn the 98 patients with CAAH, the mean improvement in ABGs and SRTs was 26.7 and 25.9 dB, respectively, resulting in a postoperative ABG of 30 dB or less in 4 of 5 cases. The mean postoperative PTAs and SRTs were 36.9 and 34.3 dB, respectively. Patients with a functional native ossicular chain (36 of 104 [34.6%]) had significantly superior audiometric outcomes when compared with patients in whom a reconstruction prosthesis was required during primary or revision operations. Audiometric results from hypoplasia surgery were not significantly different from those of atresia surgery; results in patients with craniofacial syndromes were similarly not significantly different from those in patients with sporadic CAAH. We report a low incidence of meatal stenosis.Conclusions and relevanceThe mean hearing outcomes for this group compared favorably with other series. The need for ossicular chain reconstruction was associated with poorer audiometric outcomes. The safety profile and the demonstrated hearing improvement of CAAH surgery suggest that it remains a favorable option for patients.

BackgroundExternal auditory canal exostoses are benign, bony overgrowths that arise in patients who experience chronic cold water exposure. While considerable advancement has been made in canalplasty techniques in recent decades, many patients continue to experience prolonged healing periods and recurrent stenosis following surgery.ObjectiveTo perform a retrospective outcomes analysis of our experience with a skin-preserving canalplasty technique with temporoparietal fascia grafting and use of bone wax for skin flap protection.Study designRetrospective review.Subjects and methodsThirty-four patients (41 ears) underwent canalplasty from 2008 to 2014 at a tertiary referral center. Primary outcome measures included rates of prolonged healing and restenosis, need for revision surgery, and audiometric results. Rates of intraoperative and postoperative complications were also tabulated.ResultsNo patient experienced recurrent stenosis or required a revision surgery within the follow-up period. All but one patient (97%) achieved complete healing within 8 weeks. Minimal intraoperative complications were found. Statistically significant improvements in air pure tone averages and air-bone gaps were achieved.ConclusionThe proposed technique is a safe and effective method of canalplasty for exostoses that imparts accelerated wound healing and minimizes the rate of recurrent stenosis.

Understanding the epidemiological features and metrics of malaria in endemic populations is a key component to monitoring and quantifying the impact of current and past control efforts to inform future ones. The International Centers of Excellence for Malaria Research (ICEMR) has the opportunity to evaluate the impact of malaria control interventions across endemic regions that differ in the dominant Plasmodium species, mosquito vector species, resistance to antimalarial drugs and human genetic variants thought to confer protection from infection and clinical manifestations of plasmodia infection. ICEMR programs are conducting field studies at multiple sites with the aim of generating standardized surveillance data to improve the understanding of malaria transmission and to monitor and evaluate the impact of interventions to inform malaria control and elimination programs. In addition, these epidemiological studies provide a vast source of biological samples linked to clinical and environmental "meta-data" to support translational studies of interactions between the parasite, human host, and mosquito vector. Importantly, epidemiological studies at the ICEMR field sites are integrated with entomological studies, including the measurement of the entomological inoculation rate, human biting index, and insecticide resistance, as well as studies of parasite genetic diversity and antimalarial drug resistance.

ObjectivePatients with head and neck squamous cell carcinoma (HNSCC) containing TP53 mutation and 3p deletion ("double-hit") have poorer prognosis compared to patients with either event alone ("single-hit"). The etiology for worse clinical outcomes in patients with "double-hit" cancers is unclear. We compared radiosensitivity of cell lines containing both TP53 mutations and deletion of Fragile Histidine Triad (FHIT, the gene most commonly associated with 3p deletion) to "single-hit" lines with only TP53 mutation. We compared radiosensitivity in a "single-hit" cell line with TP53 mutation converted to "double-hit" using RNA interference targeting FHIT. Finally, we compared matrixmetalloproteinase-2/9 (MMP-2/9) activity, a previously-established biomarker for tumor aggressiveness, in xenograft tumors derived from these cell lines.Materials/methodsTP53 mutation and FHIT deletion profiles of HNSCC lines were established using Cancer Cell Line Encyclopedia (CCLE). We used RNA-interference to convert a "single-hit" cell line (SCC4) to "double-hit". Cultured cells were examined for radiosensitivity and cisplatin sensitivity. MMP-2/9 activity was evaluated in "double-hit" versus "single-hit" tumors using ratiometric activatable cell-penetrating peptide (RACPP) in tongue (n=17) and flank xenografts (n=4).ResultsRadiotherapy caused greater double-stranded DNA breaks in "single-hit" vs naturally occurring and engineered "double-hit" cells. In-vivo, "double-hit" xenografts demonstrated higher MMP-2/9 activity compared to "single-hit" xenografts (p