Medicine and Health Sciences Commons^™

Building A Predictive Model Of Low Birth Weight In Low- And Middle-Income Countries: A Prospective Cohort Study, Jackie K. Patterson, Vanessa R Thorsten, Barry Eggleston, Tracy Nolen, Adrien Lokangaka, Antoinette Tshefu, Shivaprasad S. Goudar, Richard J. Derman, Elwyn Chomba, Waldemar A. Carlo, Manolo Mazariegos, Nancy F. Krebs, Sarah Saleem, Robert L. Goldenberg, Archana Patel, Patricia L. Hibberd, Fabian Esamai, Edward A. Liechty, Rashidul Haque, Bill Petri, Marion Koso-Thomas, Elizabeth M. Mcclure, Carl L. Bose, Melissa Bauserman

Global Health Articles

BACKGROUND: Low birth weight (LBW, < 2500 g) infants are at significant risk for death and disability. Improving outcomes for LBW infants requires access to advanced neonatal care, which is a limited resource in low- and middle-income countries (LMICs). Predictive modeling might be useful in LMICs to identify mothers at high-risk of delivering a LBW infant to facilitate referral to centers capable of treating these infants.

METHODS: We developed predictive models for LBW using the NICHD Global Network for Women's and Children's Health Research Maternal and Newborn Health Registry. This registry enrolled pregnant women from research sites in the Democratic Republic of the Congo, Zambia, Kenya, Guatemala, India (2 sites: Belagavi, Nagpur), Pakistan, and Bangladesh between January 2017 - December 2020. We tested five predictive models: decision tree, random forest, logistic regression, K-nearest neighbor and support vector machine.

RESULTS: We report a rate of LBW of 13.8% among the eight Global Network sites from 2017-2020, with a range of 3.8% (Kenya) …

Per Oral Endoscopic Myotomy In Pregnancy, Julie Gomez, Laura Felder, Divya Chalikonda, Alexander Schlachterman, Vincenzo Berghella

Department of Obstetrics and Gynecology Faculty Papers

OBJECTIVE: To report the first successful full-term delivery following Per Oral Endoscopic Myotomy (POEM) performed during pregnancy.

METHODS/BACKGROUND: Achalasia is an esophageal motility disorder characterized by dysphagia, regurgitation, reflux, recurrent vomiting, and weight loss. Achalasia in pregnancy can affect nutritional status of the mother, and subsequently, the child, increasing morbidity and creating potential pregnancy complications. POEM is a novel endoscopic procedure which involves cutting the lower esophageal sphincter to allow food to pass, and is considered a safe and effective management option for achalasia in non-pregnant individuals.

RESULTS: We discuss the case of a patient with achalasia and a prior …

Cost-Effectiveness Of Low-Dose Aspirin For The Prevention Of Preterm Birth: A Prospective Study Of The Global Network For Women's And Children's Health Research, Jackie K Patterson, Simon Neuwahl, Norman Goco, Janet Moore, Shivaprasad S Goudar, Richard Derman, Matthew Hoffman, Mrityunjay Metgud, Manjunath Somannavar, Avinash Kavi, Jean Okitawutshu, Adrien Lokangaka, Antoinette Tshefu, Carl L Bose, Abigail Mwapule, Musaku Mwenechanya, Elwyn Chomba, Waldemar A Carlo, Javier Chicuy, Lester Figueroa, Nancy F Krebs, Saleem Jessani, Sarah Saleem, Robert L Goldenberg, Kunal Kurhe, Prabir Das, Archana Patel, Patricia L Hibberd, Emmah Achieng, Paul Nyongesa, Fabian Esamai, Sherri Bucher, Edward A Liechty, Brian W Bresnahan, Marion Koso-Thomas, Elizabeth M Mcclure

Department of Obstetrics and Gynecology Faculty Papers

Background: Premature birth is associated with an increased risk of mortality and morbidity, and strategies to prevent preterm birth are few in number and resource intensive. In 2020, the ASPIRIN trial showed the efficacy of low-dose aspirin (LDA) in nulliparous, singleton pregnancies for the prevention of preterm birth. We sought to investigate the cost-effectiveness of this therapy in low-income and middle-income countries.

Methods: In this post-hoc, prospective, cost-effectiveness study, we constructed a probabilistic decision tree model to compare the benefits and costs of LDA treatment compared with standard care using primary data and published results from the ASPIRIN trial. In …

Cost-Effectiveness Of Low-Dose Aspirin For The Prevention Of Preterm Birth: A Prospective Study Of The Global Network For Women’S And Children’S Health Research, Jackie K Patterson, Simon Neuwahl, Norman Goco, Janet Moore, Shivaprasad S Goudar, Richard Derman, Matthew Hoffman, Mrityunjay Metgud, Manjunath Somannavar, Avinash Kavi, Jean Okitawutshu, Adrien Lokangaka, Antoinette Tshefu, Carl L Bose, Abigail Mwapule, Musaku Mwenechanya, Elwyn Chomba, Waldemar A Carlo, Javier Chicuy, Lester Figueroa, Nancy F Krebs, Saleem Jessani, Sarah Saleem, Robert L Goldenberg, Kunal Kurhe, Prabir Das, Archana Patel, Patricia L Hibberd, Emmah Achieng, Paul Nyongesa, Fabian Esamai, Sherri Bucher, Edward A Liechty, Brian W Bresnahan, Marion Koso-Thomas, Elizabeth M Mcclure

Department of Obstetrics and Gynecology Faculty Papers

Background: Premature birth is associated with an increased risk of mortality and morbidity, and strategies to prevent preterm birth are few in number and resource intensive. In 2020, the ASPIRIN trial showed the efficacy of low-dose aspirin (LDA) in nulliparous, singleton pregnancies for the prevention of preterm birth. We sought to investigate the cost-effectiveness of this therapy in low-income and middle-income countries.

Methods: In this post-hoc, prospective, cost-effectiveness study, we constructed a probabilistic decision tree model to compare the benefits and costs of LDA treatment compared with standard care using primary data and published results from the ASPIRIN trial. In …

The Global Network Socioeconomic Status Index As A Predictor Of Stillbirths, Perinatal Mortality, And Neonatal Mortality In Rural Communities In Low And Lower Middle Income Country Sites Of The Global Network For Women's And Children's Health Research, Archana B Patel, Carla M Bann, Cherryl S Kolhe, Adrien Lokangaka, Antoinette Tshefu, Melissa Bauserman, Lester Figueroa, Nancy F Krebs, Fabian Esamai, Sherri Bucher, Sarah Saleem, Robert L Goldenberg, Elwyn Chomba, Waldemar A Carlo, Shivaprasad Goudar, Richard J Derman, Marion Koso-Thomas, Elizabeth M Mcclure, Patricia L Hibberd

Global Health Articles

BACKGROUND: Globally, socioeconomic status (SES) is an important health determinant across a range of health conditions and diseases. However, measuring SES within low- and middle-income countries (LMICs) can be particularly challenging given the variation and diversity of LMIC populations.

OBJECTIVE: The current study investigates whether maternal SES as assessed by the newly developed Global Network-SES Index is associated with pregnancy outcomes (stillbirths, perinatal mortality, and neonatal mortality) in six LMICs: Democratic Republic of the Congo, Guatemala, India, Kenya, Pakistan, and Zambia.

METHODS: The analysis included data from 87,923 women enrolled in the Maternal and Newborn Health Registry of the NICHD-funded …

Experiences With Menses In Transgender And Gender Nonbinary Adolescents., Beth I. Schwartz, Arielle Effron, Benjamin Bear, Vanessa L Short, Julia Eisenberg, Sarah Felleman, Anne E Kazak

Department of Obstetrics and Gynecology Faculty Papers

STUDY OBJECTIVE: To describe menstrual history, associated dysphoria, and desire for menstrual management in transgender male and gender diverse adolescents who were assigned female at birth

DESIGN: Retrospective chart review

SETTING: Tertiary care children's hospital

PARTICIPANTS: All patients seen in a multidisciplinary pediatric gender program from March 2015 through December 2020 who were assigned female at birth, identified as transgender male or gender nonbinary, and had achieved menarche

INTERVENTION: None

MAIN OUTCOME MEASURES: Patient demographics, menstrual history, interest in and prior experiences with menstrual management, parental support, and concerns about menstrual management

RESULTS: Of the 129 included patients, 116 (90%) …

Preliminary Findings From The Gulf War Women's Cohort: Reproductive And Children's Health Outcomes Among Women Veterans, Alexa Friedman, Patricia A Janulewicz Lloyd, Jeffrey Carlson, Emily Quinn, Dylan Keating, Rosemary Toomey, Timothy Heeren, Steven S Coughlin, Glenn Markenson, Maxine Krengel, Kimberly Sullivan

Journal Articles

Reproductive outcomes, such as preterm birth, miscarriage/stillbirth, and pre-eclampsia, are understudied in veterans, particularly among Gulf War veterans (GWVs). During deployment, women GWVs were exposed to toxicant and nontoxicant exposures that may be associated with adverse reproductive and developmental outcomes. The data come from a survey of 239 participants from northeastern and southern U.S. cohorts of women veterans. The questionnaire collected information about the service history, current and past general health, reproductive and family health, demographic information, and deployment exposures. Odds ratios were computed with 95% confidence intervals between exposures in theater and reproductive/children's health outcomes. GWVs experienced adverse reproductive …

Birth Length Is The Strongest Predictor Of Linear Growth Status And Stunting In The First 2 Years Of Life After A Preconception Maternal Nutrition Intervention: The Children Of The Women First Trial, Nancy F Krebs, K Michael Hambidge, Jamie L Westcott, Ana L Garcés, Lester Figueroa, Antoinette K Tshefu, Adrien L Lokangaka, Shivaprasad S Goudar, Sangappa M Dhaded, Sarah Saleem, Sumera Aziz Ali, Melissa S Bauserman, Richard J Derman, Robert L Goldenberg, Abhik Das, Dhuly Chowdhury

Department of Obstetrics and Gynecology Faculty Papers

BACKGROUND: The multicountry Women First trial demonstrated that nutritional supplementation initiated prior to conception (arm 1) or early pregnancy (arm 2) and continued until delivery resulted in significantly greater length at birth and 6 mo compared with infants in the control arm (arm 3).

OBJECTIVES: We evaluated intervention effects on infants' longitudinal growth trajectory from birth through 24 mo and identified predictors of length status and stunting at 24 mo.

METHODS: Infants' anthropometry was obtained at 6, 12, 18, and 24 mo after the Women First trial (registered at clinicaltrials.gov as NCT01883193), which was conducted in low-resource settings: Democratic Republic …

Rapidiron: Reducing Anaemia In Pregnancy In India-A 3-Arm, Randomized-Controlled Trial Comparing The Effectiveness Of Oral Iron With Single-Dose Intravenous Iron In The Treatment Of Iron Deficiency Anaemia In Pregnant Women And Reducing Low Birth Weight Deliveries., Richard J. Derman, Shivaprasad S. Goudar, Simal Thind, Sudhir Bhandari, Zubair H. Aghai, Michael Auerbach, Rupsa Boelig, Umesh S. Charantimath, Rosemary Frasso, M. S. Ganachari, Kusum Lata Gaur, Michael K. Georgieff, Frances Jaeger, S. Yogeshkumar, Parth Lalakia, Benjamin Leiby, Mita Majumdar, Amarjeet Mehta, Seema Mehta, Sudhir Mehta, Stephen T. Mennemeyer, Amit P. Revankar, Dharmesh Kumar Sharma, Vanessa Short, Manjunath S Somannavar, Dennis Wallace, Hemang Shah, Manjula Singh, Sufia Askari, Mrutyunjaya B. Bellad, Rapidiron Trial Group

Department of Obstetrics and Gynecology Faculty Papers

BACKGROUND: Anaemia is a worldwide problem and iron deficiency is the most common cause. In pregnancy, anaemia increases the risk of adverse maternal, foetal and neonatal outcomes. India's anaemia rate is among the highest in the world with India's National Family Health Survey indicating over 50% of pregnant women were affected by anaemia. India's Anaemia Mukt Bharat-Intensified National Iron Plus Initiative aims to reduce the prevalence of anaemia among reproductive-age women, adolescents and children by 3% per year and facilitate the achievement of a Global World Health Assembly 2025 objective to achieve a 50% reduction of anaemia among women of …

Levonorgestrel Intrauterine Device Use For Medical Indications In Nulliparous Adolescents And Young Adults., Beth I Schwartz, Morgan Alexander, Lesley L Breech

Department of Obstetrics and Gynecology Faculty Papers

PURPOSE: Intrauterine devices (IUDs) are highly effective at preventing pregnancy. Levonorgestrel (LNG) IUDs also have beneficial effects on menstrual bleeding and abdominal and pelvic pain. Although there are increasing data on use of IUDs for contraception in adolescents and for medical indications in adults, there are extremely limited data on LNG IUD use for medical indications in adolescents. Our objective is to describe the characteristics and experiences of LNG IUD use in nulliparous adolescents and young women using IUDs for medical indications.

METHODS: We conducted a retrospective chart review of all nulliparous patients aged 22 years and younger who underwent …

Prenatal Perception Of Wic Breastfeeding Recommendation Affects First Month Postpartum Breastfeeding Outcomes, Qi Zhang, Lamichhane Rajan, Joanne Guthrie

Community & Environmental Health Faculty Publications

No abstract provided.

Child Marriage Legislation In The Asia-Pacific Region, Elisa Scolaro, Aleksandra Blagojevic, Brigitte Fillion, Venkatraman Chandra-Mouli, Lale Say, Joar Svanemyr, Marleen Temmerman

Obstetrics and Gynaecology, East Africa

Child marriage is a human rights violation that robs a girl of her childhood, puts her health, growth, and development at risk, disrupts her education, limits her opportunities for empowerment and social development, and increases her risk of exposure to violence and abuse (for a review of the evidence on the negative effects of child marriage on girls and their children, see Parsons et al. 2015, in this issue). While child marriage is not mentioned specifically in the 1989 Convention on the Rights of the Child (CRC), the Convention does contain a provision requiring governments to abolish “traditional practices prejudicial …

Accelerating The Dual Elimination Of Mother-To-Child Transmission Of Syphilis And Hiv: Why Now?, James Kiarie, Chandra K. Mishra, Marleen Temmerman

Obstetrics and Gynaecology, East Africa

Even though the elimination of congenital syphilis has been on the maternal and child health (MCH) agenda for over a decade, elimination has not yet been achieved; what, then, are the factors currently facilitating the elimination of mother-to-child transmission (MTCT) of syphilis?

Achieving Pregnancy Safely In Hiv-Affected Individuals And Couples: An Important Strategy To Eliminate Hiv Transmission From Mother-To-Child And Between Sexual Partners, Mmeje Okeoma, Betty Njoroge, Craig Cohen, Marleen Temmerman, Sten H. Vermund, Sheryl Van Der Poel

Obstetrics and Gynaecology, East Africa

HIV-infected individuals are living longer, more productive lives. HIV-affected individuals and couples experience personal and social desires to reproduce for all the same reasons as uninfected individuals and couples,1 and thus require safe reproductive options. HIV prevention interventions often do not consider the childbearing desires of HIV-affected individuals or couples, especially in low- and middle-income countries (LMICs). Failure to assist women with desired fertility can contribute to continued HIV transmission and must be addressed within national elimination of mother-to-child transmission (eMTCT) strategies.

A human rights perspective suggests that HIV-affected couples* should have the same ability to choose if and when …

Achievement Test Performance In Children Conceived By Ivf, L. Mains, M. Zimmerman, J. Blaine, B. Stegmann, Amy Sparks, T. Ansley, Bradley Van Voorhis

Amy E.T. Sparks

BACKGROUND: Long-term follow-up studies of children conceived by IVF are limited. We examine academic performance on standardized tests [Iowa Tests of Basic Skills/Educational Development (ITBS/ITED)] of children conceived by IVF. METHODS: Parents of children 8-17 years of age at the onset of the study (March 2008) who were conceived by IVF at the University of Iowa Hospitals and Clinics and living in the state of Iowa were contacted by mail. Parents completed questionnaires on their child's health and education and parental education. ITBS/ITED scores from school grades 3-12 were obtained on IVF children and a group of anonymous children matched …

The Cost Of Infertility Evaluation And Therapy: Findings Of A Self-Insured University Healthcare Plan., D. Stovall, B. Allen, Amy Sparks, Craig Syrop, R. Saunders, Bradley Van Voorhis

Amy E.T. Sparks

OBJECTIVE: To assess the total costs of infertility coverage, determine the proportion of healthcare costs related to infertility, compare infertility costs to those of other diseases, and calculate a per member per month cost of an infertility benefit. DESIGN: Historical prospective analysis. SETTING: A university-based, self-insured, fee-for-service healthcare plan. PATIENT(S): Healthcare policy members from January 1993 through December 1995. INTERVENTION(S): General and infertility-specific healthcare that included diagnostic tests for infertility, induction of ovulation, artificial insemination, donor gametes, in vitro fertilization, gamete intrafallopian transfer, zygote intrafallopian transfer, microsurgical epididymal sperm aspiration, embryo cryopreservation, and frozen embryo transfer. MAIN OUTCOME MEASURE(S): Healthcare …

The Cost Of Infertility Evaluation And Therapy: Findings Of A Self-Insured University Healthcare Plan., D. Stovall, B. Allen, Amy Sparks, Craig Syrop, R. Saunders, Bradley Van Voorhis

Bradley J Van Voorhis

OBJECTIVE: To assess the total costs of infertility coverage, determine the proportion of healthcare costs related to infertility, compare infertility costs to those of other diseases, and calculate a per member per month cost of an infertility benefit. DESIGN: Historical prospective analysis. SETTING: A university-based, self-insured, fee-for-service healthcare plan. PATIENT(S): Healthcare policy members from January 1993 through December 1995. INTERVENTION(S): General and infertility-specific healthcare that included diagnostic tests for infertility, induction of ovulation, artificial insemination, donor gametes, in vitro fertilization, gamete intrafallopian transfer, zygote intrafallopian transfer, microsurgical epididymal sperm aspiration, embryo cryopreservation, and frozen embryo transfer. MAIN OUTCOME MEASURE(S): Healthcare …

Achievement Test Performance In Children Conceived By Ivf, L. Mains, M. Zimmerman, J. Blaine, B. Stegmann, Amy Sparks, T. Ansley, Bradley Van Voorhis

Bradley J Van Voorhis

BACKGROUND: Long-term follow-up studies of children conceived by IVF are limited. We examine academic performance on standardized tests [Iowa Tests of Basic Skills/Educational Development (ITBS/ITED)] of children conceived by IVF. METHODS: Parents of children 8-17 years of age at the onset of the study (March 2008) who were conceived by IVF at the University of Iowa Hospitals and Clinics and living in the state of Iowa were contacted by mail. Parents completed questionnaires on their child's health and education and parental education. ITBS/ITED scores from school grades 3-12 were obtained on IVF children and a group of anonymous children matched …

Ultrasound-Assisted Repair Of A Unique Case Of Distal Vaginal Agenesis, J. Kresowik, Ginny Ryan, J. Austin, Bradley Van Voorhis

Bradley J Van Voorhis

OBJECTIVE: To describe a unique vaginal outlet obstruction and its ultrasound-assisted surgical correction. DESIGN: Case report. SETTING: An academic medical center. PATIENT(S): A 12-year-old girl was seen with cyclic abdominal pain, nausea, and an abdominal mass. External genital examination revealed no vaginal opening or dimple. Transabdominal ultrasound revealed a large hematometrocolpos 5 cm proximal to the perineum, with an otherwise normal-appearing uterus and ovaries. INTERVENTION(S): Surgical treatment included perineal incision, creation of a 5-cm passage through connective tissue, drainage of the hematometrocolpos, and mobilization of the proximal vagina, allowing for pull-through vaginoplasty. Ultrasound guidance was used throughout the surgery and …

Ultrasound-Assisted Repair Of A Unique Case Of Distal Vaginal Agenesis, J. Kresowik, Ginny Ryan, J. Austin, Bradley Van Voorhis

Ginny L. Ryan

OBJECTIVE: To describe a unique vaginal outlet obstruction and its ultrasound-assisted surgical correction. DESIGN: Case report. SETTING: An academic medical center. PATIENT(S): A 12-year-old girl was seen with cyclic abdominal pain, nausea, and an abdominal mass. External genital examination revealed no vaginal opening or dimple. Transabdominal ultrasound revealed a large hematometrocolpos 5 cm proximal to the perineum, with an otherwise normal-appearing uterus and ovaries. INTERVENTION(S): Surgical treatment included perineal incision, creation of a 5-cm passage through connective tissue, drainage of the hematometrocolpos, and mobilization of the proximal vagina, allowing for pull-through vaginoplasty. Ultrasound guidance was used throughout the surgery and …

Intrinsic Differences In The Response Of The Human Lutropin Receptor Versus The Human Follitropin Receptor To Activating Mutations, Meilin Zhang, Ya-Xiong Tao, Ginny Ryan, Xiuyan Feng, Francesca Fanelli, Deborah Segaloff

Ginny L. Ryan

In contrast to the human lutropin receptor (hLHR), very few naturally occurring activating mutations of the structurally related human follitropin receptor (hFSHR) have been identified. The present study was undertaken to determine if one aspect underlying this discrepancy might be a general resistance of the hFSHR to mutation-induced constitutive activity. Five different mutations were introduced into both the hLHR and hFSHR (four based on activating mutations of the hLHR gene, one based on an activating mutation of the hFSHR gene). Our results demonstrate that hFSHR constitutively activating mutants (CAMs) were not as active as hLHR CAMs containing the comparable mutation. …

Evaluating The Roles Of Follicle-Stimulating Hormone Receptor Polymorphisms In Gonadal Hyperstimulation Associated With Severe Juvenile Primary Hypothyroidism, Ginny Ryan, X. Feng, C. D'Alva, M. Zhang, Bradley Van Voorhis, E. Pinto, A. Kubias, S. Antonini, A. Latronico, D. Segaloff

Ginny L. Ryan

CONTEXT: Rare activating mutations of the human (h)FSHR have been reported in some women with spontaneous ovarian hyperstimulation in pregnancy, where follicular growth is inappropriately stimulated by elevated concentrations of human chorionic gonadotropin acting through the hFSHR. It is not known whether ovarian hyperstimulation in peripubertal girls with untreated primary hypothyroidism is caused by hFSHR mutations and/or influenced by hFSHR allelic variants, rendering the hFSHR more sensitive to circulating TSH. OBJECTIVE: The aim of the study was to determine whether mutations of the hFSHR and/or hFSHR allelic variants are associated with greater sensitivity of the hFSHR to TSH. DESIGN: The …

Cornual Contraction Ring With Retained Placenta In Midtrimester Abortion, Jennifer Niebyl, A. Montague, A. Tapper, T. Horrigan

Jennifer R Niebyl

No abstract provided.

25(Oh)D3 And Cardiovascular Risk Factors In Female Nonhuman Primates., Matthew J Jorgensen, Lawrence L Rudel, Matthew Nudy, Jay R Kaplan, Thomas B Clarkson, Nicholas M Pajewski, Peter F Schnatz

Division of Internal Medicine Faculty Papers & Presentations

OBJECTIVE: To determine if interindividual differences in plasma concentrations of 25-hydroxyvitamin D(3) (25(OH)D(3)) have pathophysiologic significance, we evaluated a cohort of female monkeys, seeking to identify associations with clinically relevant cardiovascular risk factors, including age, abdominal obesity (waist circumference), and high-density lipoprotein cholesterol (HDL-C).

METHODS: One hundred fifty-five female vervet monkeys (Chlorocebus aethiops sabaeus) aged 3-25 years consumed a typical western diet for 7-8 weeks that provided a woman's equivalent of approximately 1000 IU/day of vitamin D(3). Measurements of vitamin D(3) and HDL-C concentrations, as well as waist circumference, were obtained.

RESULTS: Among young monkeys (aged 3-5 years), compared to …

Breast Milk From Tanzanian Women Has Divergent Effects On Cell-Free And Cell-Associated Hiv-1 Infection In Vitro, Magdalena A. Lyimo, Matilda Ngarina Mosi, Molly L. Housman, Muhammad Zain-Ul-Abideen, Frederick V. Lee, Alexandra L. Howell, Ruth I. Connor

Dartmouth Scholarship

Transmission of HIV-1 during breastfeeding is a significant source of new pediatric infections in sub-Saharan Africa. Breast milk from HIV-positive mothers contains both cell-free and cell-associated virus; however, the impact of breast milk on HIV-1 infectivity remains poorly understood. In the present study, breast milk was collected from HIV-positive and HIV-negative Tanzanian women attending antenatal clinics in Dar es Salaam. Milk was analyzed for activity in vitro against both cell-free and cell-associated HIV-1. Potent inhibition of cell-free R5 and X4 HIV-1 occurred in the presence of milk from all donors regardless of HIV-1 serostatus. Inhibition of cell-free HIV-1 infection positively …