Design, implementation, and evaluation of PINDAR, a novel short program on GCP for academic medical center principal investigators conducting human subject research.

The Principal INvestigator Development and Resources (PINDAR) program was developed at the NYU-H+H Clinical and Translational Science Award (CTSA) hub in response to a perceived need for focused good clinical practice (GCP) training designed specifically for principal investigators (PIs) performing human subject research. PINDAR is a novel 6-hour, instructor lead, participatory, in-person course for PIs developed de novo, piloted, and implemented. One hundred and seventeen faculty PIs participated in PINDAR from November 2016 through September 2018. All obtained mutual recognition for ICH E6 GCP training from TransCelerate Biopharma. PINDAR was well received by participant PIs, and feedback surveys have revealed a high degree of satisfaction with the program. Other CTSA hubs and research-intensive health systems should consider adopting a similar course focused on GCP for PIs.

Challenges in initiating antiretroviral therapy for all HIV-infected people regardless of CD4 cell count.

INTRODUCTION: Recently published large randomized controlled trials, START, TEMPRANO and HPTN 052 show the clinical benefit of early initiation of antiretroviral treatment (ART) in HIV-infected persons and in reducing HIV transmission. The trials influenced the World Health Organization (WHO) decision to issue updated recommendations to prescribe ART to all individuals living with HIV, irrespective of age and CD4 cell count. DISCUSSION: It is clear that the new 2015 WHO recommendations if followed, will change the face of the HIV epidemic and probably curb its burden over time. Implementation however, requires that health systems, especially those in low and middle-income settings, be ready to face this challenge on a large scale. HIV prevention and treatment are easy in theory yet hard in practice. The new WHO guidelines for initiation of ART regardless of CD4 cell count will lead to upfront increases in the costs of healthcare delivery as the goal is to treat all those now newly eligible for ART. Around 22 million people living with HIV qualify and will therefore require ART. Related challenges immediately follow: firstly, that everyone must be tested for HIV; secondly, that anyone who has had an HIV test should know their result and understand its significance; and, thirdly, that every person identified as HIV-positive should receive and remain on ART. The emergence of HIV drug resistant strains when treatment is started at higher CD4 cell count thresholds is a further concern as persons on HIV treatment for longer periods of time are at increased risk of intermittent medication adherence. CONCLUSIONS: The new WHO recommendations for ART are welcome, but lacking as they fail to consider meaningful solutions to the challenges inherent to implementation. They fail to incorporate actual strategies on how to disseminate and adopt these far-reaching guidelines, especially in sub-Saharan Africa, an area with weak healthcare infrastructures. Well-designed, high-quality research is needed to assess the feasibility, safety, acceptability, impact, and cost of innovations such as the universal voluntary testing and immediate treatment approaches, and broad consultation must address community, human rights, ethical, and political concerns.

The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer.

The huge communities of residential microbes, including bacteria, viruses, Archaea, and Eukaryotes, that colonize humans are increasingly recognized as playing important roles in health and disease. A complex populous ecosystem, the human gastrointestinal (GI) tract harbors up to 10(11) bacterial cells per gram of luminal content, whose collective genome, the gut metagenome, contains a vastly greater number of individual genes than the human genome. In health, the function of the microbiome might be considered to be in dynamic equilibrium with the host, exerting both local and distant effects. However, 'disequilibrium' may contribute to the emergence of disease, including malignancy. In this review, we discuss how the intestinal bacterial microbiome and in particular how an 'estrobolome,' the aggregate of enteric bacterial genes capable of metabolizing estrogens, might affect women's risk of developing postmenopausal estrogen receptor-positive breast cancer. Estrobolome composition is impacted by factors that modulate its functional activity. Exploring variations in the composition and activities of the estrobolome in healthy individuals and in women with estrogen-driven breast cancer may lead to development of microbiome-based biomarkers and future targeted interventions to attenuate cancer risk.

Teaching Translational Research to Medical Students: The New York University School of Medicine's Master's of Science in Clinical Investigation Dual-Degree Program.

To develop the next generation of translational investigators, New York University School of Medicine (NYUSOM) and the NYU-NYC Health and Hospitals Corporation Clinical and Translational Science Institute (NYU-HHC CTSI) developed the Master's of Science in Clinical Investigation dual-degree (MD/MSCI) program. This 5-year program dedicates 1 year to coursework and biomedical research, followed by a medical school/research overlap year, to prepare students for academic research careers. This paper details the MD/MSCI program's curriculum and approach to mentorship, describes the research/professional interests of students, and reports student productivity. In the first 4 years of the program (2010-2014) 20 students were matriculated; 7 (35%) were women, and 12 (60%) research projects were in surgical specialties. To date, 14 students have applied to residency, and half pursued surgical residency programs. Our students have produced 68 accepted abstracts, 15 abstracts in submission, 38 accepted papers, and 24 papers in submission. Despite the time-limited nature of this program, additional training in research design and implementation has promoted a high level of productivity. We conclude that dual-degree training in medicine and translational research is feasible for medical students and allows for meaningful participation in valuable projects. Follow-up is warranted to evaluate the academic trajectory of these students.

Early Mortality during Initial Treatment of Tuberculosis in Patients Co-Infected with HIV at the Yaoundé Central Hospital, Cameroon: An 8-Year Retrospective Cohort Study (2006-2013).

BACKGROUND: Understanding contributors to mortality during the initial phase of tuberculosis (TB) treatment in patients co-infected with HIV would guide targeted interventions to improve survival. The aim of this study was to ascertain the incidence of death during the initial 2 months (new cases) and 3 months (retreatment cases) of TB treatment and to assess correlates of mortality in HIV co-infected patients. METHODS: We conducted a hospital-based retrospective cohort study from January 2006 to December 2013 at Yaoundé Central Hospital, Cameroon. We reviewed medical records to identify co-infected TB/HIV inpatients aged 15 years and older who died during TB treatment. Death was defined as any death occurring during TB treatment, as per World Health Organization recommendations. We collected socio-demographic, clinical and laboratory data. We conducted multivariable logistic binary regression analysis to identify factors associated with death during the intensive phase of TB treatment. Magnitudes of associations were expressed by adjusted odds ratio (aOR) with 95% confidence interval. A p value < 0.05 was considered statistically significant. RESULTS: The 99 patients enrolled had a mean age of 39.5 (standard deviation 10.9) years and 53% were male. Patients were followed for 276.3 person-months of observation (PMO). Forty nine patients were died during intensive phase of TB treatment. Death incidence during the intensive phase of TB treatment was 32.2 per 100 PMO. Having a non-AIDS comorbidity (aOR 2.47, 95%CI 1.22-5.02, p = 0.012), having extra-pulmonary TB (aOR 1.89, 95%CI 1.05-3.43, p = 0.035), and one year increase in duration of known HIV infection (aOR 1.23, 95%CI 1.004-1.49) were independently associated with death during the intensive phase of TB treatment. CONCLUSIONS: Mortality incidence during intensive phase of TB treatment was high among TB/HIV co-infected patients during TB treatment; and strongly associated with extra pulmonary TB suggesting advanced stage of immunosuppression and non-AIDS comorbidities. Early HIV diagnosis and care and good management of non-comorbidities can reduce this incidence.

Characteristics of patients co-infected with HIV at the time of inpatient tuberculosis treatment initiation in Yaoundé, Cameroon: a tertiary care hospital-based cross-sectional study.

BACKGROUND: Knowledge of the characteristics of patients co-infected with tuberculosis (TB) and human immunodeficiency virus (HIV) when TB treatment is initiated would allow clinicians to improve care and help policy-makers develop relevant and realistic guidelines. The aim of this study was to describe socio-demographic, clinical, and laboratory characteristics of TB/HIV co-infected patients starting inpatient TB treatment in Yaoundé, Cameroon. METHODS: We conducted a retrospective cross-sectional study, collecting data from medical records of HIV-infected patients with TB, aged 15 years old or more, hospitalized in the Infectious Diseases Unit of the Yaoundé Central Hospital, Cameroon from January 1, 2006 to June 30, 2013. RESULTS: The mean age of 337 patients meeting study inclusion criteria was 39.3 years. More than half were female (53.4%). Most (89.3%) resided in urban areas, 44.2% had a secondary education, and 46.0% were married. The majority was receiving co-trimoxazole prophylaxis (79.5%), and two thirds were taking antiretroviral therapy (67.4%). The mean duration of known HIV infection before TB treatment was 8.4 months. Most (88.1%) had newly diagnosed TB, rather than relapsed disease. Smear-positive pulmonary TB was documented in a third, (35.3%). Laboratory data revealed a median white blood cell count of 5,100 cells/mm(3) (IQR 3,300-7,990 cells/mm(3)), a median hemoglobin level of 8 g/dl (IQR 7-10 g/dl), and a median CD4 cell count of 102 cells/mm(3) (IQR 33-178 cells/mm(3)). Sex differences in our study included older age in the men (p < 0.001), more of whom were married (p < 0.001) and had achieved a higher level of education (p = 0.042). Men had fewer diagnoses of smear-positive pulmonary TB (p = 0.020). They weighed more than the women (p = 0.001) and had higher hemoglobin levels (p = 0.003). CONCLUSIONS: Suboptimal adherence to WHO treatment recommendations in our Cameroonian study reinforces the importance of prescribing co-trimoxazole in HIV infection and ART for all TB/HIV co-infected persons. We urge that Ministries of Health continue implementing and disseminating guidelines for management of TB/HIV co-infected patients, and we call for measures ensuring that healthcare facilities' stocks of ART and co-trimoxazole are sufficient to meet the need for both.

Factors associated with death during tuberculosis treatment of patients co-infected with HIV at the Yaoundé Central Hospital, Cameroon: an 8-year hospital-based retrospective cohort study (2006-2013).

BACKGROUND: Contributors to fatal outcomes in TB/HIV co-infected patients actively undergoing TB treatment are poorly characterized. The aim was to assess factors associated with death in TB/HIV co-infected patients during the initial 6 months of TB treatment. METHODS: We conducted a hospital-based retrospective cohort study from January 2006 to December 2013 at the Yaoundé Central Hospital, Cameroon. We reviewed medical records to identify hospitalized co-infected TB/HIV patients aged 15 years and older. Death was defined as any death occurring during TB treatment, as per the World Health Organization's recommendations. We conducted logistic regression analysis to identify factors associated with a fatal outcome. Magnitudes of associations were expressed by adjusted odds ratio (aOR) with 95% confidence interval. RESULTS: The 337 patients enrolled had a mean age of 39.3 (standard deviation 10.3) years and 54.3% were female. TB treatment outcomes were distributed as follows: 205 (60.8%) treatment success, 99 (29.4%) deaths, 18 (5.3%) not evaluated, 14 (4.2%) lost to follow-up, and 1 (0.3%) failed. After exclusion of patients lost to follow-up and not evaluated, death in TB/HIV co-infected patients during TB treatment was associated with a TB diagnosis made before 2010 (aOR = 2.50 [1.31-4.78]; p = 0.006), the presence of other AIDS-defining diseases (aOR = 2.73 [1.27-5.86]; p = 0.010), non-AIDS comorbidities (aOR = 3.35 [1.37-8.21]; p = 0.008), not receiving cotrimoxazole prophylaxis (aOR = 3.61 [1.71-7.63]; p = 0.001), not receiving antiretroviral therapy (aOR = 2.45 [1.18-5.08]; p = 0.016), and CD4 cells count <50 cells/mm3 (aOR = 16.43 [1.05-258.04]; p = 0.047). CONCLUSIONS: The TB treatment success rate among TB/HIV co-infected patients in our setting is low. Mortality was high among TB/HIV co-infected patients during TB treatment and is strongly associated with clinical and biological factors, highlighting the urgent need for specific interventions focused on enhancing patient outcomes.

Barriers to the implementation of mobile phone reminders in pediatric HIV care: a pre-trial analysis of the Cameroonian MORE CARE study.

BACKGROUND: Mobile health (mhealth) has emerged as a powerful resource in the medical armamentarium against human immunodeficiency virus (HIV) infection. We sought to determine among adult caregivers of HIV-exposed/infected children; the extent of mobile phone ownership, the ability to communicate in Cameroon's national official languages (NOL), and the refusal to receive such reminders. METHODS: We conducted a pre-trial analysis of potentials participants of the MORE CARE trial. MORE CARE took place from January through March 2013 in three geographic locations in Cameroon. We included caregivers aged 18 years or older. Written communication was assessed by the ability to read and understand information presented in the consent form. Verbal communication was assessed during a two-way conversation and in a discussion about HIV infection. A question about mobile phone ownership and another about refusal to receive reminders via mobile phone were phrased to allow "Yes" or "No" as the only possible reply. A p <0.05 was considered statistically significant. RESULTS: We enrolled 301 caregivers of HIV-exposed/infected children from rural (n = 119), semi-urban (n = 142) and urban (n = 40) areas of Cameroon. The mean caregiver age was 42.9 years (SD 13.4) and 85% were women. A fifth of our study population overall had at least one of the three obstacles to mobile phone reminders. By region, 39.5% in rural, 6.3% in semi-urban, and 7.5% in urban setting had at least one obstacle, with significant differences between the rural and urban settings (p<0.001) and the rural and semi-urban settings (p<0.001). The acceptability of SMS was 96.3% and of mobile phone calls 96% (p = 0.054). The ability to communicate in NOL orally was 89.7% and 84.4% in writing (p = 0.052). Mobile phone ownership (p<0.001; p = 0.03) and the ability to communicate in an NOL orally (p<0.001; p = 0.002) or in writing (both p<0.001), were significantly lower in rural compared to semi-urban and urban settings respectively. CONCLUSIONS: The use of mHealth was limited in about one fifth of our population. The greatest obstacle was the inability to use oral or written NOL, followed by non-ownership of a mobile phone. These impediments were higher in a rural setting as compared to urban or semi-urban areas.

Designing and implementing INTREPID, an intensive program in translational research methodologies for new investigators.

Senior housestaff and junior faculty are often expected to perform clinical research, yet may not always have the requisite knowledge and skills to do so successfully. Formal degree programs provide such knowledge, but require a significant commitment of time and money. Short-term training programs (days to weeks) provide alternative ways to accrue essential information and acquire fundamental methodological skills. Unfortunately, published information about short-term programs is sparse. To encourage discussion and exchange of ideas regarding such programs, we here share our experience developing and implementing INtensive Training in Research Statistics, Ethics, and Protocol Informatics and Design (INTREPID), a 24-day immersion training program in clinical research methodologies. Designing, planning, and offering INTREPID was feasible, and required significant faculty commitment, support personnel and infrastructure, as well as committed trainees.

Effect of mobile phone reminders on follow-up medical care of children exposed to or infected with HIV in Cameroon (MORE CARE): a multicentre, single-blind, factorial, randomised controlled trial.

BACKGROUND: Missed scheduled HIV appointments lead to increased mortality, resistance to antiretroviral therapy, and suboptimum virological response. We aimed to assess whether reminders sent to carers by text message, mobile phone call, or concomitant text message and mobile phone call increase attendance at medical appointments for HIV care in a population of children infected with or exposed to HIV in Cameroon. We also aimed to ascertain the most cost-effective method of mobile-phone-based reminder. METHODS: MORE CARE was a multicentre, single-blind, factorial, randomised controlled trial in urban, semi-urban, and rural settings in Cameroon. Carers of children who were infected with or had been exposed to HIV were randomly assigned electronically in blocks of four and allocated (1:1:1:1) sequentially to receive a text message and a call, a text message only, a call only, or no reminder (control). Investigators were masked to group assignment. Text messages were sent and calls made 2 or 3 days before a scheduled follow-up appointment. The primary outcomes were efficacy (the proportion of patients attending a previously scheduled appointment) and efficiency (attendance/[measures of staff working time × cost of the reminders]), as a measure of cost-effectiveness. The primary analysis was by intention to treat. This study is registered with the Pan African Clinical Trials Register, number PACTR201304000528276. FINDINGS: The study took place between Jan 28 and May 24, 2013. We randomly assigned 242 adult-child (carer-patient) pairs into four groups: text message plus call (n=61), call (n=60), text message (n=60), and control (n=61). 54 participants (89%) in the text message plus call group, 51 (85%) in the call group, 45 (75%) in the text message group, and 31 (51%) in the control group attended their scheduled appointment. Compared with control, the odds ratios for improvement in the primary efficacy outcome were 7·5 (95% CI 2·9-19·0; p<0·0001) for text message plus call, 5·5 (2·3-13·1; p=0·0002) for call, and 2·9 (1·3-6·3; p=0·012) for text message. No significant differences were seen in comparisons of the three intervention groups with each other, and there was no synergism between text messages and calls. For the primary efficiency outcome, the mean difference for text message versus text message plus call was 1·5 (95% CI 0·7 to 2·4; p=0·002), for call versus text message plus call was 1·2 (0·7 to 1·6; p<0·0001), and for call versus text message was 0·4 (-1·3 to 0·6; p=0·47). INTERPRETATION: Mobile-phone-based reminders of scheduled HIV appointments for carers of paediatric patients in low-resource settings can increase attendance. The most effective method of reminder was text message plus phone call, but text messaging alone was the most efficient (ie, cost-effective) method. FUNDING: No external funding.

Factors associated with non-adherence to scheduled medical follow-up appointments among Cameroonian children requiring HIV care: a case-control analysis of the usual-care group in the MORE CARE trial.

BACKGROUND: A better understanding of why HIV-exposed/infected children fail to attend their scheduled follow-up medical appointments for HIV-related care would allow for interventions to enhance the delivery of care. The aim of this study was to determine characteristics of the caregiver-child dyad (CCD) associated with children's non-adherence to scheduled follow-up medical appointments in HIV programs in Cameroon. METHODS: We conducted a case-control analysis of the usual-care group of CCDs from the MORE CARE trial, in which the effect of mobile phone reminders for HIV-exposed/infected children in attending follow-up appointments was assessed from January to March 2013. For this study, the absence of a child at their appointment was considered a case and the presence of a child at their appointment was defined as a control. We used three multivariate binary logistic regression analyses. The best-fit model was the one which had the smallest chi-square value with the Hosmer-Lemeshow test (HLχ²). Magnitudes of associations were expressed by odds ratio (OR), with a p-value <0.05 considered as statistically significant. RESULTS: We included 30 cases and 31 controls. Our best-fit model which considered the sex of the adults and children separately (HL χ²=3.5) showed that missing scheduled medical appointments was associated with: lack of formal education of the caregiver (OR 29.1, 95% CI 1.1-777.0; p=0.044), prolonged time to the next appointment/follow-up (OR [1 week increase] 1.4, 95% CI 1.03-2.0; p=0.032), and being a female child (OR 5.2, 95% CI 1.2-23.1; p=0.032). One model (HLχ²=10.5) revealed that woman-boy pairs adhered less to medical appointments compared to woman-girl pairs (OR 4.9, 95% CI 1.05-22.9; p=0.044). Another model (HLχ²=11.1) revealed that man-boy pairs were more likely to attend appointments compared to woman-girl pairs (OR 0.23, 95% CI 0.06-0.93; p=0.039). There were no statistical associations for the ages of the children or the caregivers, the study sites, or the HIV status (confirmed vs. suspected) of the children. CONCLUSION: The profile of children who would not attend follow-up medical appointments in an HIV program was: a female, with a caregiver who has had no formal education, and with a longer follow-up appointment interval. There is a possibility that female children are favored by female caregivers and that male children are favored by male caregivers when they come to medical care.

A randomized blinded controlled trial of mobile phone reminders on the follow-up medical care of HIV-exposed and HIV-infected children in Cameroon: study protocol (MORE CARE).

BACKGROUND: In Cameroon, only two-thirds of children with HIV exposure or infection receive appropriate HIV-directed medical care. Mortality, antiretroviral therapy resistance and suboptimal virological response are strongly related to missed opportunities for treatment, and, more specifically, to skipped scheduled medical appointments. The present trial, MORE CARE (Mobile Reminders for Cameroonian Children Requiring HIV Care) seeks to determine if reminders sent by text message (SMS), phone call, or concomitant SMS and phone calls most increase the presence at medical appointments of HIV-infected or -exposed children (efficacy), and which is the most efficient related to working time and financial cost (efficiency). METHODS/DESIGN: We will carry out a multicenter single-blind, randomized, factorial controlled trial. A randomization list will be electronically generated using random block sizes. Central allocation will be determined by sequentially numbered. A total of 224 subjects will be randomized into four groups (SMS, Call, SMS + Call, and Control) with an allocation ratio of 1:1:1:1. SMS and calls will be sent between 48 and 72 hours before the scheduled appointment. A medical assistant will send out text messages and will call participants. Our primary outcome is appointment measured by efficacy and efficiency of interventions. We hypothesize that two reminders (concomitant use of SMS and phone calls) as an appointment reminder is more effective to improve appointment compared to one reminder (only SMS or only call), and that the most efficient is use of only SMS. The analysis will be intention to treat. DISCUSSION: This trial investigates the potential of SMS and phone calls as motivational reminders to improve children's adherence to medical appointments for HIV-related care in Cameroon. The intervention will act to end missed appointment due to forgetfulness. TRIAL REGISTRATION: Pan African Clinical Trials Registry: PACTR201304000528276.

Microbiome and malignancy.

Current knowledge is insufficient to explain why only a proportion of individuals exposed to environmental carcinogens or carrying a genetic predisposition to cancer develop disease. Clearly, other factors must be important, and one such element that has recently received attention is the human microbiome, the residential microbes including Bacteria, Archaea, Eukaryotes, and viruses that colonize humans. Here, we review principles and paradigms of microbiome-related malignancy, as illustrated by three specific microbial-host interactions. We review the effects of the microbiota on local and adjacent neoplasia, present the estrobolome model of distant effects, and discuss the complex interactions with a latent virus leading to malignancy. These are separate facets of a complex biology interfacing all the microbial species we harbor from birth onward toward early reproductive success and eventual senescence.