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Introduction: Women in fishing communities have both high HIV prevalence and incidence, hence they are a priority population for HIV prevention and treatment interventions. However, their mobility is likely to compromise the effectiveness of interventions. We assessed the acceptability, feasibility and of using phones and global positioning system (GPS) devices for tracking mobility, to inform future health research innovations. Methods: A mult-site formative qualitative study was conducted in six purposively selected Fishing Communities on the shores of Lake Victoria in Kenya, Tanzania, and Uganda. Participants were selected based on duration of stay in the community and frequency of movement. Sixty-four (64) women participated in the study (16 per fishing community). Twenty-four (24) participants were given a study phone; 24 were asked to use their own phones and 16 were provided with a portable GPS device to understand what is most preferred. Women were interviewed about their experiences and recommendations on carrying GPS devices or phones. Twenty four (24) Focus Group Discussions with 8–12 participants were conducted with community members to generate data on community perceptions regarding GPS devices and phones acceptability among women. Data were analyzed thematically and compared across sites/countries. Results: Women reported being willing to use tracking devices (both phones and GPS) because they are easy to carry. Their own phone was preferred compared to a study phone and GPS device because they were not required to carry an additional device, worry about losing it or be questioned about the extra device by their sexual partner. Women who carried GPS devices suggested more sensitization in communities to avoid domestic conflicts and public concern. Women suggested changing the GPS colour from white to a darker colour and, design to look like a commonly used object such as a telephone Subscriber Identity Module (SIM) card, a rosary/necklace or a ring for easy and safe storage. Conclusion: Women in the study communities were willing to have their movements tracked, embraced the use of phones and GPS devices for mobility tracking. Devices need to be redesigned to be more discrete, but they could be valuable tools to understanding movement patterns and inform design of interventions for these mobile populations. [ABSTRACT FROM AUTHOR]

HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from a pool of genetically diverse quasispecies establishes infection. The IAVI protocol C cohort of discordant couples, female sex workers, other heterosexuals and men who have sex with men (MSM) present varying risks of HIV infection, diverse HIV-1 subtypes and represent a unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome is known. To identify the TF, the HIV-1 repertoire of 38 MSM participants' samples was sequenced close to transmission (median 21 days post infection, IQR 18–41) and assessment of multivariant infection done. Patient derived gag genes were cloned into an NL4.3 provirus to generate chimeric viruses which were characterized for replicative capacity (RC). Finally, an evaluation of how the TF virus predicted disease progression and modified the immune response at both acute and chronic HIV-1 infection was done. There was higher prevalence of multivariant infection compared with previously described heterosexual cohorts. A link was identified between multivariant infection and replicative capacity conferred by gag, whereby TF gag tended to be of lower replicative capacity in multivariant infection (p = 0.02) suggesting an overall lowering of fitness requirements during infection with multiple variants. Notwithstanding, multivariant infection was associated with rapid CD4+ T cell decline and perturbances in the CD4+ T cell and B cell compartments compared to single variant infection, which were reversible upon control of viremia. Strategies aimed at identifying and mitigating multivariant infection could contribute toward improving HIV-1 prognosis and this may involve strategies that tighten the stringency of the transmission bottleneck such as treatment of STI. Furthermore, the sequences and chimeric viruses help with TF based experimental vaccine immunogen design and can be used in functional assays to probe effective immune responses against TF. Author summary: The development of a safe and effective HIV-1 vaccine alongside cure strategies is a major public health concern and requires in-depth knowledge of the HIV-1 populations that establish infection. Here we sequenced the HIV genetic populations present during the acute stage of HIV-1 infection in 38 Men who have sex with men (MSM) and identified the transmitted/founder variant's sequence. We then cloned the gag gene from each patient's transmitted/founder gag sequences in both single and multiple variant infection into a common, lab-adapted virus and measured the replicative capacity it conferred on this virus. Finally, cellular immune responses were compared between single variant and multiple variant infection at 0–3, 6–9 and 24–30 months after infection. We observed a higher frequency of multivariant infection in MSM than has been previously described in heterosexually infected participants, and this was associated with faster decline of CD4+ T cells and perturbances in the CD4+ T cell and the B cell compartment. Moreover, the replicative capacity conferred by gag was lower in multivariant infection, suggesting a less stringent transmission bottleneck that allowed for less fit variants to establish infection. These results suggest that strategies to tighten the stringency of the transmission bottleneck may be of benefit to patients by reducing the likelihood of multivariant transmission and potentially slowing down disease progression. [ABSTRACT FROM AUTHOR]

Introduction: fishing communities in Uganda are key populations for HIV, with persistently higher prevalence and incidence than the general population. Methods: between March and August 2014, a cross sectional survey was conducted in 10 fishing communities of Lake Victoria in Uganda. Data was collected on socio-behavioural characteristics using interviewer administered questionnaires and venous blood collected for HIV testing. Prevalent HIV infections among adolescents and young people aged 13 to 24 years was estimated and the factors associated with those infections determined using multi variable logistic regression modelling. Results: HIV prevalence was 10.8% among the 630 (96.5%) who provided a blood sample. Females were 3.5 times as likely to have HIV infection as males (aOR=3.52, 95% CI: 1.34-9.22). Young people aged 20-24 years were twice as likely to be HIV infected as those aged 13-19 years (aOR=1.77, 95% CI: 0.05-2.10), participants without formal education or those who had studied up to primary level were more likely to be HIV infected than those who had post primary education ((aOR=2.45, 95% CI: 1.19-5.07) or (5.29 (1.35-20.71) respectively). Reporting more than one sexual partner in the past 6 months was associated with HIV prevalent infection than those reporting no sexual partners (aOR=6.44, 95% CI: 1.27-32.83). Conclusion: adolescents and young people aged 13-24 years in fishing communities around Lake Victoria, Uganda, have a high HIV prevalence, with females having a three-fold higher level than males. These findings highlight-the need to improve HIV prevention among young females living in these fishing communities. [ABSTRACT FROM AUTHOR]

Background: HIV-prevalence and incidence is high in many fishing communities around Lake Victoria in East Africa. In these settings, mobility among women is high and may contribute to increased risk of HIV infection and poor access to effective prevention and treatment services. Understanding the nature and patterns of this mobility is important for the design of interventions. We conducted an exploratory study to understand the nature and patterns of women's mobility to inform the design of HIV intervention trials in fishing communities of Lake Victoria.Methods: This was a cross-sectional formative qualitative study conducted in six purposively selected fishing communities in Kenya, Tanzania and Uganda. Potential participants were screened for eligibility on age (18+ years) and having stayed in the fishing community for more than 6 months. We collected data using introductory and focus group discussions, and in-depth interviews with key informants. Data focused on: history and patterns of mobility, migration in and out of fishing communities and the relationship between mobility and HIV infection. Since the interviews and discussions were not audio-recorded, detailed notes were taken and written up into full scripts for analysis. We conducted a thematic analysis using constant comparison analysis.Results: Participants reported that women in fishing communities were highly mobile for work-related activities. Overall, we categorized mobility as travels over long and short distances or periods depending on the kind of livelihood activity women were involved in. Participants reported that women often travelled to new places, away from familiar contacts and far from healthcare access. Some women were reported to engage in high risk sexual behaviour and disengaging from HIV care. However, participants reported that women often returned to the fishing communities they considered home, or followed a seasonal pattern of work, which would facilitate contact with service providers.Conclusion: Women exhibited circular and seasonal mobility patterns over varying distances and duration away from their home communities. These mobility patterns may limit women's access to trial/health services and put them at risk of HIV-infection. Interventions should be tailored to take into account mobility patterns of seasonal work observed in this study. [ABSTRACT FROM AUTHOR]

Introduction: People living in fishing communities around Lake Victoria may be suitable for enrolment in HIV prevention trials because of high HIV incidence. We assessed the ability to recruit and retain individuals from fishing communities into an HIV vaccine preparedness cohort study in Masaka, Uganda. Methods: HIV high risk, sero-negative adults (18–49 years) were identified from four fishing villages bordering Lake Victoria through door-to-door HIV counselling and testing (HCT). Interested persons were referred for screening, enrolment, and quarterly follow-up visits at a study clinic located approximately 30–40 kilometres away. Repeat HCT, HIV risk assessment, and evaluation and treatment for sexually transmitted infections were provided. Rates of and factors associated with study dropout were assessed using Poisson regression models. Results: A total of 940 participants were screened between January 2012 and February 2015, of whom 654 were considered for the analysis. Over a two-year follow-up period, 197 (30.1%) participants dropped out of the study over 778.9 person-years, a dropout rate of 25.3 / 100 person-years of observation. Dropout was associated with being female (aRR = 1.56, 95% confidence interval [CI] 1.12–2.18), being 18–24 years (aRR = 1.64; 95% CI 1.03–2.60) or being 25–34 years (aRR = 1.63; 95% CI 1.04–2.55) compared to being 35+ years; having no education (aRR = 2.02; 95% CI: 1.23–3.31); living in the community for less than one year (aRR = 2.22; 95% CI: 1.46–3.38), or 1–5 years (aRR = 1.68; 95% CI: 1.16–2.45), compared to more than five years. Conclusions: Our results suggest that individuals from fishing communities can be recruited and retained in longitudinal studies; however, intensified participant tracing may be necessary for women, younger volunteers, those who are less educated and new residents. [ABSTRACT FROM AUTHOR]

In this study, we assessed the feasibility of collecting standardized nasal and salivary samples at centers in Nairobi (Kenya), Kigali (Rwanda), and London (United Kingdom) using different collection devices and media (synthetic absorptive matrices versus flocked swabs, and Salimetrics oral swabs versus whole oral fluid collection). We detected anti-Gag (p24) and envelope (gp140) antibodies in both nasal fluid and salivary collections from all HIVinfected individuals, and cross-reactive anti-p24 antibodies were detected in 10% of HIV-uninfected individuals enrolled at one site. Collections from the nasal turbinates were comparable with samples collected deeper in the nasopharyngeal tract, and the yield of antip24 IgA in the whole oral fluid samples was higher than in samples collected from the parotid gland. We noted a trend toward reduced levels of anti-HIV antibody in the volunteers receiving anti-retroviral therapy. Levels of antibodies were stable over multiple collection visits. Overall, this study shows that nasal and salivary samples can be collected in a standardized manner over repeated visits in both low- and high-resource settings. These methods may be used in support for future HIV vaccine clinical trials. [ABSTRACT FROM AUTHOR]

Background: 2013 WHO guidelines recommend starting ART at CD4+ T-cell counts ≤500 cells/μL. We present the T-cell counts from adult Africans with HIV shortly following transmission to their sexual partners. Methods: HIV-discordant couples in Zambia, Uganda and Rwanda were followed prospectively and received couples counseling and condoms. HIV uninfected partners were tested for HIV at least quarterly and HIV-infected partners received HIV care and referral for ART per national guidelines. Upon diagnosis of incident HIV infection in the previously HIV-uninfected partner, a blood sample was collected from both partners to measure CD4+ T-cells and perform viral linkage. The estimated date of infection (EDI) of the incident case was calculated based on testing history. EDI was unknown for suspected transmitting partners. Results: From 2006–2011, 4,705 HIV-discordant couples were enrolled in this cohort, and 443 cases of incident HIV infection were documented. Virus linkage analysis was performed in 374 transmission pairs, and 273 (73%) transmissions were linked genetically. CD4 counts in the transmitting partner were measured a median of 56 days after EDI (mean:90.5, min:10, max:396). The median CD4 count was 339 cells/μl (mean:386.4, min:15, max:1,434), and the proportion of partners with a CD4+ T-cell count above 500/μl was 25% (95% CI:21, 31). Conclusions: In our cohort of discordant couples, 73% of HIV transmissions occurred within the relationship, and the transmitter CD4+ T cell count shortly after the transmission event was frequently higher than the WHO 2013 ART-initiation guidelines. [ABSTRACT FROM AUTHOR]

Serum was analyzed from 146 healthy adult volunteers in eastern Africa to evaluate measles virus (MV) and canine distemper virus (CDV) neutralizing antibody (nAb) prevalence and potency. MV plaque reduction neutralization test (PRNT) results indicated that all sera were positive for MV nAbs. Furthermore, the 50% neutralizing dose (ND50) for the majority of sera corresponded to antibody titers induced by MV vaccination. CDV nAbs titers were low and generally were detected in sera with high MV nAb titers. A mutant CDV was generated that was less sensitive to neutralization by human serum. The mutant virus genome had 10 nucleotide substitutions, which coded for single amino acid substitutions in the fusion (F) and hemagglutinin (H) glycoproteins and two substitutions in the large polymerase (L) protein. The H substitution occurred in a conserved region involved in receptor interactions among morbilliviruses, implying that this region is a target for cross-reactive neutralizing antibodies. [ABSTRACT FROM AUTHOR]

Background: Mucosal specimens are essential to evaluate compartmentalized immune responses to HIV vaccine candidates and other mucosally targeted investigational products. We studied the acceptability and feasibility of repeated mucosal sampling in East African clinical trial participants at low risk of HIV and other sexually transmitted infections. Methods and Findings: The Kenya AIDS Vaccine Initiative (KAVI) enrolled participants into three Phase 1 trials of preventive HIV candidate vaccines in 2011–2012 at two clinical research centers in Nairobi. After informed consent to a mucosal sub-study, participants were asked to undergo collection of mucosal secretions (saliva, oral fluids, semen, cervico-vaginal and rectal), but could opt out of any collection at any visit. Specimens were collected at baseline and two additional time points. A tolerability questionnaire was administered at the final sub-study visit. Of 105 trial participants, 27 of 34 women (79%) and 62 of 71 men (87%) enrolled in the mucosal sub-study. Nearly all sub-study participants gave saliva and oral fluids at all visits. Semen was collected from about half the participating men (47–48%) at all visits. Cervico-vaginal secretions were collected by Softcup from about two thirds of women (63%) at baseline, increasing to 78% at the following visits, with similar numbers for cervical secretion collection by Merocel sponge; about half of women (52%) gave cervico-vaginal samples at all visits. Rectal secretions were collected with Merocel sponge from about a quarter of both men and women (24%) at all 3 visits, with 16% of men and 19% of women giving rectal samples at all visits. Conclusions: Repeated mucosal sampling in clinical trial participants in Kenya is feasible, with a good proportion of participants consenting to most sampling methods with the exception of rectal samples. Experienced staff members of both sexes and trained counselors with standardized messaging may improve acceptance of rectal sampling. [ABSTRACT FROM AUTHOR]

Standards of care provided to volunteers in HIV prevention research in developing countries are evolving. Inconsistency in standards, particularly within a research network highlights the need to balance volunteers' health and wellness with the efficient conduct of research. Ten research centers (RC's) in East and Southern Africa affiliated with the International AIDS Vaccine Initiative (IAVI) were studied using a mixed methods approach to understand variations, similarities and gaps in services provided, recipients of services, referral systems, and barriers to referral uptake. These data were then used to develop expected standards across the 10 RCs. Findings indicated that RCs consistently provided HIV risk reduction and family planning (FP) counseling, male condoms, management of sexually transmitted infections, CD-4 counts, and general medical care to volunteers and non-research volunteers. Services that were less consistently provided on-site included: female condoms, adult male circumcision (AMC), antiretroviral therapy (ART) and post-exposure prophylaxis (PEP) in case of rape. The FP options provided on-site varied, with few providing implants, intrauterine devices, tubal ligation, and vasectomy. Most RCs had established referral systems for ART, AMC, PEP, and FP, but few had referral points for psychosocial services. Few RCs had comprehensive guidelines on referrals other than those related to adverse events. Findings indicate that the greatest challenges for referral uptake were transportation and health care costs, poor quality and inconsistency of services at some referral points. Few RCs covered the cost of referrals for non-study related adverse events. A collaborative process between IAVI and the RCs was undertaken to reach consensus on expected standards of care. A set of required and recommended services to be provided on-site or by referral was developed. In developing such standards, we tried to balance scientific priorities, equity, contextual realities, community expectations, and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Standards of care provided to volunteers in HIV prevention research in developing countries are evolving. Inconsistency in standards, particularly within a research network highlights the need to balance volunteers' health and wellness with the efficient conduct of research. Ten research centers (RC's) in East and Southern Africa affiliated with the International AIDS Vaccine Initiative (IAVI) were studied using a mixed methods approach to understand variations, similarities and gaps in services provided, recipients of services, referral systems, and barriers to referral uptake. These data were then used to develop expected standards across the 10 RCs. Findings indicated that RCs consistently provided HIV risk reduction and family planning (FP) counseling, male condoms, management of sexually transmitted infections, CD-4 counts, and general medical care to volunteers and non-research volunteers. Services that were less consistently provided on-site included: female condoms, adult male circumcision (AMC), antiretroviral therapy (ART) and post-exposure prophylaxis (PEP) in case of rape. The FP options provided on-site varied, with few providing implants, intrauterine devices, tubal ligation, and vasectomy. Most RCs had established referral systems for ART, AMC, PEP, and FP, but few had referral points for psychosocial services. Few RCs had comprehensive guidelines on referrals other than those related to adverse events. Findings indicate that the greatest challenges for referral uptake were transportation and health care costs, poor quality and inconsistency of services at some referral points. Few RCs covered the cost of referrals for non-study related adverse events. A collaborative process between IAVI and the RCs was undertaken to reach consensus on expected standards of care. A set of required and recommended services to be provided on-site or by referral was developed. In developing such standards, we tried to balance scientific priorities, equity, contextual realities, community expectations, and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Background & objective: A phase 1 trial of adeno-associated virus based HIV-1 subtype C vaccine (tgAAC09) was conducted at two sites in Germany and Belgium and one site in India. This paper reports the safety and immunogenicity of tgAAC09 in healthy adult Indian volunteers. Methods: Between January 2005 and December 2006, 30 consenting volunteers were enrolled in the placebo controlled double-blind dose-escalation trial [3x109, 3x1010 and 3x1011 DNase resistant particles (DRPs)/ml]. Single injection of the candidate vaccine was administered to ten volunteers randomized in 8:2 ratio in vaccine and placebo arms at each dosage level. Results: The mean age of study volunteers (16 men and 14 women) was 34 yr. Six local reactogenicity events and 14 systemic reactogenicity events like malaise, fever, headache and myalgia were reported, both were dose-dependent. The difference between the adverse events reported by vaccine and placebo recipients (79 and 67%) was not significant. A modest IFN-γ ELISPOT response [248 spot forming units (SFU)/million cells] was detected in one volunteer from high dose group and low response (56 and 75 SFU/million cells) in two volunteers in low and mid-dose groups. A post-vaccination dose-dependent increase was observed in anti AAV2 neutralizing titres. None of the volunteers showed a positive antibody response to HIV-1. Interpretation & conclusions: The trial was a benchmark in phase 1 clinical evaluation of HIV candidate vaccines in India. The vaccine was generally well tolerated and raised no safety concerns. The vaccine was found to be weakly immunogenic. It is essential to understand the role of pre-existing immunity against vectors and significance of evaluation in a prime-boost strategy. [ABSTRACT FROM AUTHOR]

Background: A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4 subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an emulsion in incomplete Freund's adjuvant (IFA). Methods: Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, and selected using criteria specifying that 50% in each study group would be HLA-B7+. Immunizations were scheduled at 0, 1, and 6 months using a total peptide dose of 1 or 4 mg. Adaptive immune responses in16 vaccine recipients and two placebo recipients after the 2nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays of cryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, 51Cr release assays were performed on fresh PBMCs following 14-day stimulation with individual vaccine peptide antigens. Results: 24 subjects were enrolled; 18 completed 2 injections. The study was prematurely terminated because 4 vaccinees developed prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two other subjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurred after the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectable MN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, using both ELISpot and ICS, 8/16 vaccinees (5/7 HLA-B7+) and 0/2 controls had detectable vaccine-specific CD8 T-cell responses. Subjects with moderate or severe systemic or local reactions tended to have more frequent T cell responses and higher antibody responses than those with mild or no reactions. Conclusions: The severity of local responses related to the formulation of these four peptides in IFA is clinically unacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitude of response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunit vaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimize the risk of adverse events. [ABSTRACT FROM AUTHOR]

Quality improvement (QI) has been widely implemented in health services but has not been widely applied in HIV prevention research. Most prevention research centers have commonly employed traditional approaches (e.g., checklists) to quality control that document what has been done but not the quality of what has been done. Unlike other health settings, prevention research settings have unique characteristics and ethical requirements that require the development or adaptation of specific quality indicators. A QI model for health services was adapted for use in prevention research settings and was piloted between August 2006 and July 2007 at three research centers in East Africa. Four hundred and twenty-six volunteers exit interviews were administered in two cycles. Quantitative and qualitative data were analyzed using Excel worksheets. QI meeting reports and QI plans were used to complement data from exit interviews. On average, 52% of total enrolled volunteers participated in the exit interview. The designed QI plans successfully helped reduce volunteers' reported waiting time to see counselors (p<0.001) and pharmacists (p<0.001). It also increased the percentage of interviewed volunteers who reported being counseled on family planning at clinical trials (from 66 to 93%; p=0.02) at follow-up visits, and who were refreshed on informed consent at follow-up visits (from 90 to 96%; p=0.009). The percentage of interviewed volunteers that expressed satisfaction with services received from counselors increased (from 87 to 94%; p=0.009) while the percentage of volunteer satisfied with services from trial physicians remained constant (93%). The majority of volunteers interviewed reported satisfaction with other major components of research such as confidentiality, understanding of trial objectives, benefits and risks of participation, and risk reduction counseling. However, satisfaction with services from community outreach workers and other staff at research centers dropped over the course of the study (from 88% in Cycle 1 to 74% in Cycle 3; p= < 0.001). Increased commitment to QI is crucial in ensuring quality of services and ethical conduct of HIV prevention research centers. [ABSTRACT FROM AUTHOR]

Background: An understanding of the health of potential volunteers in Africa is essential for the safe and efficient conduct of clinical trials, particularly for trials of preventive technologies such as vaccines that enroll healthy individuals. Clinical safety laboratory values used for screening, enrolment and follow-up of African clinical trial volunteers have largely been based on values derived from industrialized countries in Europe and North America. This report describes baseline morbidity during recruitment for a multi-center, African laboratory reference intervals study. Methods: Asymptomatic persons, aged 18-60 years, were invited to participate in a cross-sectional study at seven sites (Kigali, Rwanda; Masaka and Entebbe, Uganda; Kangemi, Kenyatta National Hospital and Kilifi, Kenya; and Lusaka, Zambia). Gender equivalency was by design. Individuals who were acutely ill, pregnant, menstruating, or had significant clinical findings were not enrolled. Each volunteer provided blood for hematology, immunology, and biochemistry parameters and urine for urinalysis. Enrolled volunteers were excluded if found to be positive for HIV, syphilis or Hepatitis B and C. Laboratory assays were conducted under Good Clinical Laboratory Practices (GCLP). Results and Conclusions: Of the 2990 volunteers who were screened, 2387 (80%) were enrolled, and 2107 (71%) were included in the analysis (52% men, 48% women). Major reasons for screening out volunteers included abnormal findings on physical examination (228/603, 38%), significant medical history (76, 13%) and inability to complete the informed consent process (73, 13%). Once enrolled, principle reasons for exclusion from analysis included detection of Hepatitis B surface antigen (106/280, 38%) and antibodies against Hepatitis C (95, 34%). This is the first large scale, multi-site study conducted to the standards of GCLP to describe African laboratory reference intervals applicable to potential volunteers in clinical trials. Approximately one-third of all potential volunteers screened were not eligible for analysis; the majority were excluded for medical reasons. [ABSTRACT FROM AUTHOR]