Association between Antiretroviral Therapy and Cancers among Children Living with HIV in Sub-Saharan Africa.

Approximately 91% of the world's children living with HIV (CLWH) are in sub-Saharan Africa (SSA). Living with HIV confers a risk of developing HIV-associated cancers. To determine the incidence and risk factors for cancer among CLWH, we conducted a nested case-control study of children 0-18 years from 2004-2014 at five centers in four SSA countries. Incident cases of cancer and HIV were frequency-matched to controls with HIV and no cancer. We calculated the incidence density by cancer type, logistic regression, and relative risk to evaluate risk factors of cancer. The adjusted incidence density of all cancers, Kaposi sarcoma, and lymphoma were 47.6, 36.6, and 8.94 per 100,000 person-years, respectively. Delayed ART until after 2 years of age was associated with cancer (OR = 2.71, 95% CI 1.51, 4.89) even after adjusting for World Health Organization clinical stage at the time of enrolment for HIV care (OR = 2.85, 95% CI 1.57, 5.13). The relative risk of cancer associated with severe CD4 suppression was 6.19 (p = 0.0002), 2.33 (p = 0.0042), and 1.77 (p = 0.0305) at 1, 5, and 10 years of ART, respectively. The study demonstrates the high risk of cancers in CLWH and the potential benefit of reducing this risk by the early initiation of ART.

Kaposi Sarcoma Herpesvirus Inflammatory Cytokine Syndrome-like Clinical Presentation in Human Immunodeficiency Virus-infected Children in Malawi.

We describe 7 human immunodeficiency virus-infected Malawian children with Kaposi sarcoma who met criteria for Kaposi sarcoma herpesvirus (KSHV) inflammatory cytokine syndrome. Each presented with persistent fevers, bulky lymphadenopathy, massive hepatosplenomegaly, and severe cytopenias. Plasma analyses were performed in 2 patients, both demonstrating extreme elevations of KSHV viral load and interleukin 6.

Global Disparities Between Pediatric Publications and Disease Burden From 2006 to 2015.

There is a disproportionate burden of pediatric disease in low- and middle-income countries (LMICs); however, the proportion and relation of published articles to childhood disease burden in LMICs have not been assessed previously. This study aimed to determine whether published articles and disease topics from research conducted in LMICs in the most widely cited pediatric journals reflected the global burden of childhood disease. We reviewed all articles published from 2006 to 2015 in the 3 pediatric journals with the highest Eigenfactor scores to identify studies conducted in the World Bank-designated LMICs. We abstracted study topic, design, purpose, country, and funding sources. We derived descriptive statistics, Fisher's exact χ2 test, Monte Carlo estimates, and Spearman's rank order coefficients. Of the 19 676 articles reviewed, 10 494 were original research articles. Of those, 965 (9.2%) were conducted in LMICs. Over the study period, the proportion of published articles originating from LMICs increased (r 2 = 0.77). Disease topics did not reflect the underlying burden of disease as measured in disability-adjusted life years (Spearman's rank order coefficient = 0.25). Despite bearing the majority of the world's burden of disease, articles from LMICs made up a small proportion of all published articles in the 3 pediatric journals with the highest Eigenfactor scores. The number of published articles from LMICs increased over the study period; nevertheless, the topics did not coincide with the burden of disease in LMICs. These discrepancies highlight the need for development of a research agenda to address the diseases that are the greatest threat to the majority of children worldwide.

Reciprocity? International Preceptors' Perceptions of Global Health Elective Learners at African Sites.

BACKGROUND: Short-term global health electives (STGHEs) have become increasingly common, with evidence showing educational and clinical benefits for short-term learners (STLs). Despite increased recognition that STGHEs should be mutually beneficial for host sites and STLs, evidence demonstrating the impact on international host preceptors is lacking. OBJECTIVES: To understand international host preceptors' perceptions regarding benefits and burdens of hosting STLs. METHODS: Focus group discussions with a convenience sample of 10 of 18 eligible preceptors were conducted at pediatric STGHE sites in Malawi and Lesotho. Qualitative content analysis was performed to identify themes using a deductive-inductive approach. FINDINGS: Common themes regarding benefits to preceptors included increased knowledge and resources for learning from STLs, broadened differential diagnoses, and the satisfaction of teaching. Regarding burdens, preceptors perceived that supervising STLs decreases efficiency. Preceptors identified the burden of having to intervene in instances that could lead to patient harm. Some preceptors perceived that STLs under-valued preceptors' clinical decision-making in resource-limited contexts. CONCLUSIONS: Our findings emphasize the need for institutions to identify mutuality of benefits between STLs and host sites when developing STGHEs. Host preceptors identified robust pre-departure training for STLs, lengthened duration of STGHEs, and formal preceptor orientation as ways to enhance mutuality of benefits.

KSHV viral load and Interleukin-6 in HIV-associated pediatric Kaposi sarcoma-Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions.

Kaposi sarcoma (KS) is among the most common childhood malignancies in central, eastern, and southern Africa. Although its unique clinical features have been established, biological mechanisms related to the causative agent, KS-associated herpes-virus (KSHV), have yet to be explored in children. We performed a prospective observational pilot study to explore associations between KSHV viral load (VL), human interleukin-6 (IL-6) and IL-10 levels, and clinical characteristics of 25 children with KS in Lilongwe, Malawi from June 2013-August 2015. The median age was 6.4 years. Lymphadenopathy was the most common site of KS involvement (64%), followed by skin and oral mucosa (44% each), woody edema (12%), and pulmonary (8%). Baseline samples for plasma KSHV VL, IL-6 and IL-10 analyses were available for 18/25 patients (72%) at time of KS diagnosis. KSHV VL was detectable at baseline in 12/18 (67%) patients, the median baseline IL-6 level was 8.53 pg/mL (range 4.31-28.33), and the median baseline IL-10 level was 19.53 pg/mL (range 6.91-419.69). Seven (39%) patients presented with an IL-6 level > 10 pg/mL (exceeding twice the upper limit of normal). Detectable KSHV VL was significantly associated with lymphadenopathic KS (p = 0.004), while having undetectable KSHV VL was associated with a higher likelihood of presenting with hyperpigmented skin lesions (p = 0.01). Detectable KSHV VL and elevated IL-6 levels are present in a subset of children with KS. Lytic activation of KSHV and associated elevation in KSHV VL may contribute to the unique clinical manifestations of pediatric KS in KSHV-endemic regions of Africa.

The Standardized Pediatric Expedited Encounters for ART Drugs Initiative (SPEEDI): description and evaluation of an innovative pediatric, adolescent, and young adult antiretroviral service delivery model in Tanzania.

BACKGROUND: As countries scale up antiretroviral therapy (ART) for children, innovative strategies to deliver quality services to children are needed. Differentiated ART delivery models have been successful in adults, but no such program has been described in children. We describe the Standardized Pediatric Expedited Encounters for ART Drugs Initiative (SPEEDI). METHODS: Descriptive analysis of patients eligible for SPEEDI was done via retrospective review of children, adolescents, and young adults on ART at the Baylor Centre of Excellence (COE) in Mbeya, Tanzania between January 2013 and December 2015. Eligibility for SPEEDI visits included the following: stable children, adolescents, and young adults on ART for approximately 3 months or longer, no medical or social complications, good adherence to ART, and presence of reliable caregiver. During a SPEEDI visit, patients were fast tracked in triage to collect medications directly without physically seeing a clinician. SPEEDI patients came to clinic every two months, and alternated SPEEDI visits with standard visits. Baseline characteristics, mortality, and lost-to-follow up rates of SPEEDI patients were analyzed. RESULTS: One thousand one hundred sixty-four patients utilized SPEEDI, totaling 3493 SPEEDI visits. SPEEDI reached 51.3% (1164/2269) of pediatric ART patients, accounting for 7.7% (3493/44489) of total patient encounters. SPEEDI patients were 52% (605/1164) female, median age of 11.7 years (range 1.2-25.5 yr), median time on ART of 21 months (range 4-130 months) and 83.5% (964/1155) categorized as no or mild HIV-associated immunodeficiency. SPEEDI patients had good outcomes (98.8%), low LTFU (0.1%) and low mortality rates (0.61 deaths per 100 patient-years). CONCLUSION: SPEEDI was an effective model for delivering ART to children, adolescents, and young adults in our setting, leading to good clinical outcomes, low mortality, and low LTFU. The SPEEDI program safely and effectively expedited and spaced out ART visits for children, adolescents, and young adults, and can serve as an adaptable ART delivery model for other resource limited settings.

Host clinical preceptors' perceptions of professionalism among learners completing global health electives.

OBJECTIVES: This study aims to gain an understanding of the perceptions of host clinical preceptors in Malawi and Lesotho of the professionalism exhibited by short-term learners from the United States and Canada during short-term global health electives. METHODS: Focus group discussions were conducted with 11 host clinical preceptors at two outpatient pediatric HIV clinics in sub-Saharan Africa (Malawi and Lesotho). These clinics host approximately 50 short-term global health learners from the United States and Canada each year. Focus group moderators used open-ended discussion guides to explore host clinical preceptors' perceptions of the professionalism of short-term global health learners. Thematic analysis with an inductive approach was used to identify salient themes from these focus group discussions. RESULTS: Eleven of the 18 possible respondents participated in two focus group discussions. Adaptability, eagerness to learn, active listening, gratitude, initiative, and punctuality was cited as professional behaviors among short-term global health learners. Cited unprofessional behaviors included disregard of local clinicians' expertise and unresponsiveness to feedback. Host clinical preceptors described difficulty providing feedback to short-term global health learners and discrepancies between what may be considered professional in their home setting versus in the study settings. Respondents requested pre-departure orientation for learners and their own orientation before hosting learners. CONCLUSIONS: Both host clinical preceptors and short-term global health learners should be aware that behaviors that may be considered best practice in one clinical setting may be perceived as unprofessional in another. Future studies to develop a common definition of professionalism during short-term global health electives are merited.

Global Health: Preparation for Working in Resource-Limited Settings.

Trainees and clinicians from high-income countries are increasingly engaging in global health (GH) efforts, particularly in resource-limited settings. Concomitantly, there is a growing demand for these individuals to be better prepared for the common challenges and controversies inherent in GH work. This is a state-of-the-art review article in which we outline what is known about the current scope of trainee and clinician involvement in GH experiences, highlight specific considerations and issues pertinent to GH engagement, and summarize preparation recommendations that have emerged from the literature. The article is focused primarily on short-term GH experiences, although much of the content is also pertinent to long-term work. Suggestions are made for the health care community to develop and implement widely endorsed preparation standards for trainees, clinicians, and organizations engaging in GH experiences and partnerships.

Creating a medical education enterprise: leveling the playing fields of medical education vs. medical science research within core missions.

BACKGROUND: Unlike publications of medical science research that are more readily rewarded, clinician-educators' scholarly achievements are more nebulous and under-recognized. OBJECTIVE: Create an education enterprise that empowers clinician-educators to engage in a broad range of scholarly activities and produce educational scholarship using strategic approaches to level the playing fields within an organization. DESIGN: The authors analyzed the advantages and disadvantages experienced by medical science researchers vs. clinician educators using Bolman and Deal's (B&D) four frames of organization (structural, human resource, political, symbolic). The authors then identified organizational approaches and activities that align with each B&D frame and proposed practical strategies to empower clinician-educators in their scholarly endeavors. RESULTS: Our medical education enterprise enhanced the structural frame by creating a decentralized medical education unit, incorporated the human resource component with an endowed chair to support faculty development, leveraged the political model by providing grant supports and expanding venues for scholarship, and enhanced the symbolic frame by endorsing the value of education and public recognition from leaderships. In five years, we saw an increased number of faculty interested in becoming clinician-educators, had an increased number of faculty winning Educational Awards for Excellence and delivering conference presentations, and received 12 of the 15 college-wide awards for educational scholarship. These satisfactory trends reflect early success of our educational enterprise. CONCLUSIONS: B&D's organizational frames can be used to identify strategies for addressing the pressing need to promote and recognize clinician-educators' scholarship. We realize that our situation is unique in several respects, but this approach is flexible within an institution and transferable to any other institution and its medical education program. ABBREVIATIONS: B&D: Bolman and Deal; CRIS: Center for Research, Innovation, and Scholarship; OOR: Office of Research.

Authorship in paediatric research conducted in low- and middle-income countries: parity or parasitism?

OBJECTIVES: Interest in global health has increased greatly in the past two decades. Concomitantly, the number and complexity of research partnerships between high-income (HIC) and low- and middle-income countries (LMICs) has grown. We aimed to determine whether there is authorship parity (equitable representation and author order) or parasitism (no authors from study countries) in paediatric research conducted in LMICs. METHODS: We reviewed all articles published from 2006 to 2015 in the four paediatric journals with the highest Eigenfactor scores. We limited our review to articles from LMICs and abstracted information on author affiliation and order, funding source and study design. We calculated Student's t-tests and chi-square using Fisher's exact test with Monte Carlo estimates. RESULTS: There were 24 169 articles published during the study period, and 1243 met inclusion criteria. Of those, 95.9% (n = 1,192) included at least one author affiliated with a LMIC. Among multicountry studies (n = 165), 40.4% did not include authors from every LMIC involved. Of the 9876 authors, most were affiliated with institutions from upper-middle-income countries (41.7%) and HICs (32.7%), with far fewer affiliated with lower middle-income (15.5%) and low-income countries (5.4%) (P < 0.001). In articles from low-income countries, first and last authors from HICs were more common than authors with low-income country affiliations (P < 0.001). CONCLUSIONS: Authorship parasitism was rare overall but common in multicountry studies. In studies conducted in low-income countries, HIC authors more commonly occupied first and last author positions than authors from the study countries. Where LMIC authors make substantial contributions, researchers should strive for authorship parity.

Pharmaceutical Dosing Errors at a Pediatric HIV Clinic in Mwanza, Tanzania.

The outpatient medication dosing error rate at a pediatric HIV clinic in Mwanza, Tanzania, was about 1 in every 34 prescriptions. Young children were at highest risk of a dosing error likely because of dose changes with growth and also the inconsistent supply of pediatric formulations. Majority of errors occurred at consecutive visits suggesting clinicians reordered medication without double checking dosing.

The Use of Systemic and Topical Fluoroquinolones.

Appropriate prescribing practices for fluoroquinolones, as well as all antimicrobial agents, are essential as evolving resistance patterns are considered, additional treatment indications are identified, and the toxicity profile of fluoroquinolones in children has become better defined. Earlier recommendations for systemic therapy remain; expanded uses of fluoroquinolones for the treatment of certain infections are outlined in this report. Prescribing clinicians should be aware of specific adverse reactions associated with fluoroquinolones, and their use in children should continue to be limited to the treatment of infections for which no safe and effective alternative exists or in situations in which oral fluoroquinolone treatment represents a reasonable alternative to parenteral antimicrobial therapy.

Antiretroviral Therapy in Children Less Than 24 Months of Age at Pediatric HIV Centers in Tanzania: 12-Month Clinical Outcomes and Survival.

BACKGROUND: Without antiretroviral therapy (ART), approximately one-half of HIV-infected infants will die by two years. In 2010, the World Health Organization (WHO) recommended that all HIV-infected infants < 24 months be initiated on ART regardless of their clinical/immunologic status. However, there remains little published data detailing cohorts of infants on ART in Sub-Saharan Africa. This study describes baseline characteristics and 12 month outcomes of a cohort of HIV-infected children < 24 months of age at pediatric HIV centers in Mwanza and Mbeya, Tanzania. MATERIALS AND METHODS: Retrospective chart review. INCLUSION CRITERIA: children < 24 months of age, initiated on ART at Baylor Children s Foundation Tanzania clinics, between March-December 2011. RESULTS: Baseline: Ninety-three children were initiated on ART at a median age of 13.4 months. Sixty-seven percent had severe immunosuppression and 31.5% had severe malnutrition. OUTCOME: Seventy-three patients were still in care at 12 month follow-up, there were four (4.3%) deaths, five (5.4%) patients transferred, and 11 (11.8%) loss to follow-up. Average CD4% was 32.7 (p < 0.001). Ninety percent of patients were WHO treatment stage I (p < 0.001). Eighty-six percent had normal nutritional status (p < 0.001). CONCLUSION: Our cohort of HIV infected children < 24 months initiated on ART did well clinically at 12 month outcomes despite being severely immunocompromised and malnourished at baseline. Nevirapine based regimens had good 12 month clinical outcomes, regardless of maternal exposure. Loss to follow-up rate was high for our cohort, demonstrating the need to develop strong mechanisms to counteract this.

Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study.

Kaposi sarcoma (KS) is the most common HIV-associated malignancy in children and adolescents in Africa. Pediatric KS is distinct from adult disease. We evaluated the clinical characteristics associated with long-term outcomes. We performed a retrospective observational analysis of 70 HIV-infected children and adolescents with KS less than 18 years of age diagnosed between 8/2010 and 6/2013 in Lilongwe, Malawi. Local first-line treatment included bleomycin and vincristine plus nevirapine-based highly active anti-retroviral therapy (HAART). Median age was 8.6 years (range 1.7-17.9); there were 35 females (50%). Most common sites of presentation were: lymph node (74%), skin (59%), subcutaneous nodules (33%), oral (27%), woody edema (24%), and visceral (16%). Eighteen (26%) presented with lymphadenopathy only. Severe CD4 suppression occurred in 28%. At time of KS diagnosis, 49% were already on HAART. Overall, 28% presented with a platelet count < 100 x 109/L and 37% with hemoglobin < 8 g/dL. The 2-year event-free (EFS) and overall survival (OS) were 46% and 58% respectively (median follow-up 29 months, range 15-50). Multivariable analysis of risk of death and failure to achieve EFS demonstrated that visceral disease (odds ratios [OR] 19.08 and 11.61, 95% CI 2.22-163.90 and 1.60-83.95 respectively) and presenting with more than 20 skin/oral lesions (OR 9.57 and 22.90, 95% CI 1.01-90.99 and 1.00-524.13 respectively) were independent risk factors for both. Woody edema was associated with failure to achieve EFS (OR 7.80, 95% CI 1.84-33.08) but not death. Univariable analysis revealed that lymph node involvement was favorable for EFS (OR 0.28, 95% CI 0.08-0.99), while T1 TIS staging criteria, presence of cytopenias, and severe immune suppression were not associated with increased mortality. Long-term complete remission is achievable in pediatric KS, however outcomes vary according to clinical presentation. Based on clinical heterogeneity, treatment according to risk-stratification is necessary to improve overall outcomes.