Life-Saving Treatments for Spinal Muscular Atrophy: Global Access and Availability.

Background and Objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disorder manifesting with progressive muscle weakness and atrophy. SMA type 1 used to be fatal within the first 2 years of life, but is now treatable with therapies targeting splicing modification and gene replacement. Nusinersen, risdiplam, and onasemnogene abeparvovec-xioi improve survival, motor strength, endurance, and ability to thrive, allowing many patients to potentially attain a normal life; all have been recently approved by major regulatory agencies. Although these therapies have revolutionized the world of SMA, they are associated with a high economic burden, and access to these therapies is limited in some countries. The primary objective of this study was to compare the availability and implementation of treatment of SMA from different regions of the world. Methods: In this qualitative study, we surveyed health care providers from 21 countries regarding their experiences caring for patients with SMA. The main outcome measures were provider survey responses on newborn screening, drug availability/access, barriers to treatment, and related questions. Results: Twenty-four providers from 21 countries with decades of experience (mean 26 years) in treating patients with SMA responded to the survey. Nusinersen was the most available therapy for SMA. Our survey showed that while genetic testing is usually available, newborn screening is still unavailable in many countries. The provider-reported treatment cost also varied between countries, and economic burden was a major barrier in treating patients with SMA. Discussion: Overall, this survey highlights the global inequality in managing patients with SMA. The spread of newborn screening is essential in ensuring improved access to care for patients with SMA. With the advancement of neurotherapeutics, more genetic diseases will soon be treatable, and addressing the global inequality in clinical care will require novel approaches to mitigate such inequality in the future.

Establishing performance standards for child development: learnings from the ECDI2030.

BACKGROUND: Standards of early childhood development (ECD) are needed to determine whether children living in different contexts are developmentally on track. The Early Childhood Development Index 2030 (ECDI2030) is a population-level measure intended to be used in household surveys to collect globally comparable data on one of the indicators chosen to monitor progress toward target 4.2 of the Sustainable Development Goals: The proportion of children aged 24-59 months who are developmentally on track in health, learning and psychosocial well-being. METHODS: To define performance cut-scores for the ECDI2030 we followed a criterion-referenced standard setting exercise using the modified Angoff method. The exercise gauged the expectations from 15 global experts in ECD and was informed by representative population data collected in Mexico and the State of Palestine. The final calibrated age-specific performance cut-scores were applied to these data to estimate the proportion of children developmentally on track, disaggregated by background characteristics, including the child's sex and attendance to early childhood education. RESULTS: Through a process of standard setting, we generated robust performance standards for the ECDI2030 by establishing five age-specific cut-scores to identify children as developmentally on track. CONCLUSIONS: This paper demonstrated how the standard setting methodology, typically applied to measures in the health and education fields, could be applied to a measure of child development. By creating robust criterion-referenced standards, we have been able to ensure that the cut-scores related to age for the ECDI2030 are based on performance standards set by global experts in the ECD field for defining on and off track development.

Assessment of Preparedness for Remote Teaching and Learning to Transform Health Professions Education in Sub-Saharan Africa in Response to the COVID-19 Pandemic: Protocol for a Mixed Methods Study With a Case Study Approach.

BACKGROUND: The current COVID-19 pandemic is affecting all aspects of society worldwide. To combat the pandemic, measures such as face mask-wearing, hand-washing and -sanitizing, movement restrictions, and social distancing have been introduced. These measures have significantly disrupted education, particularly health professions education, which depends on student-patient contact for the development of clinical competence. The wide-ranging consequences of the pandemic are immense, and health professions education institutions in sub-Saharan Africa have not been spared. OBJECTIVE: This paper describes a protocol for assessing the preparedness of selected health professions education institutions in sub-Saharan Africa for remote teaching and learning during the COVID-19 pandemic. METHODS: A mixed-methods design with a case study approach will be used. The awareness, desire, knowledge, ability, and reinforcement model of change was selected as the conceptual framework to guide the study. Eight higher education institutions in 6 sub-Saharan countries have participated in this study. Data will be collected through electronic surveys from among whole populations of academic staff, students, and administrators in undergraduate medicine and nursing programs. Qualitative and quantitative data from each institution will be analyzed as a case study, which will yield an inventory of similar cases grouped for comparison. Quantitative data will be analyzed for each institution and then compared to determine associations among variables and differences among programs, institutions, or countries. RESULTS: Our findings will provide information to higher education institutions, particularly those offering health professions education programs, in Africa regarding the preparedness for remote teaching and learning to influence efforts related to web-based teaching and learning, which is envisaged to become the new normal in the future. CONCLUSIONS: This study has not received any funding, and any costs involved were borne by individual consortium members at the various institutions. Ethics approval from the institutional review board was obtained at various times across the participating sites, which were free to commence data collection as soon as approval was obtained. Data collection was scheduled to begin on October 1, 2020, and end on February 28, 2021. As of this submission, data collection has been completed, and a total of 1099 participants have been enrolled. Data analysis has not yet commenced. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/28905.

Early child development in children who are HIV-exposed uninfected compared to children who are HIV-unexposed: observational sub-study of a cluster-randomized trial in rural Zimbabwe.

INTRODUCTION: Exposure to maternal HIV may affect early child development (ECD), although previous studies have reported heterogeneous findings. We evaluated ECD among children who were HIV-exposed uninfected (CHEU) and children who were HIV-unexposed (CHU) recruited to the SHINE trial in rural Zimbabwe. METHODS: SHINE was a community-based cluster-randomized trial of improved infant feeding and/or improved water, sanitation and hygiene. Pregnant women were enrolled between 2012 and 2015. We assessed ECD in a sub-study at 24 months of age, between 2016 and 2017, using the Malawi Developmental Assessment Tool (MDAT; assessing motor, cognitive, language and social development); MacArthur-Bates Communicative Development Inventory (CDI) (assessing vocabulary and grammar); A-not-B test (assessing object permanence); and a self-control task. Mothers and infants were tested longitudinally for HIV. We used generalized estimating equations to compare ECD scores between CHEU and CHU, accounting for the cluster-randomized design. Primary results were adjusted for trial-related factors that could affect measurement reliability of ECD: study nurse, age of child, calendar month of birth, sex and randomized arm. RESULTS: A total of 205 CHEU and 1175 CHU were evaluated. Mean total MDAT score was 90.6 (SD 8.7) in CHEU compared to 92.4 (9.1) in CHU (adjusted mean difference -1.3, 95% CI: -2.3, -0.3), driven mostly by differences in gross motor (-0.5, 95% CI: -0.9, -0.2) and language scores (-0.6, 95% CI: -1.1, -0.1). There was evidence that fine motor scores were lower in CHEU (adjusted mean difference -0.4, 95% CI: -0.8, 0.0) but no evidence of a difference in social scores (0.1, 95% CI: -0.2, 0.4). Mean MacArthur-Bates CDI vocabulary score was 57.9 (SD 19.2) in CHEU compared to 61.3 (18.8) in CHU (adjusted mean difference -2.9 words, 95% CI: -5.7, -0.1). Object permanence and self-control scores were similar between groups. CONCLUSIONS: CHEU in rural Zimbabwe had total child development and vocabulary scores that were approximately 0.15 standard deviations lower than CHU at two years of age. More detailed and specific studies are now needed to unravel the reasons for developmental delay in CHEU and the likelihood that these delays persist in the longer term.

Effects of improved complementary feeding and improved water, sanitation and hygiene on early child development among HIV-exposed children: substudy of a cluster randomised trial in rural Zimbabwe.

Introduction: HIV-exposed uninfected children may be at risk of poor neurodevelopment. We aimed to test the impact of improved infant and young child feeding (IYCF) and improved water, sanitation and hygiene (WASH) on early child development (ECD) outcomes. Methods: Sanitation Hygiene Infant Nutrition Efficacy was a cluster randomised 2×2 factorial trial in rural Zimbabwe ClinicalTrials.gov NCT01824940). Pregnant women were eligible if they lived in study clusters allocated to standard-of-care (SOC; 52 clusters); IYCF (20 g small-quantity lipid-based nutrient supplement/day from 6 to 18 months, complementary feeding counselling; 53 clusters); WASH (pit latrine, 2 hand-washing stations, liquid soap, chlorine, play space, hygiene counselling; 53 clusters) or IYCF +WASH (53 clusters). Participants and fieldworkers were not blinded. ECD was assessed at 24 months using the Malawi Developmental Assessment Tool (MDAT; assessing motor, cognitive, language and social skills); MacArthur Bates Communication Development Inventory (assessing vocabulary and grammar); A-not-B test (assessing object permanence) and a self-control task. Intention-to-treat analyses were stratified by maternal HIV status. Results: Compared with SOC, children randomised to combined IYCF +WASH had higher total MDAT scores (mean difference +4.6; 95% CI 1.9 to 7.2) and MacArthur Bates vocabulary scores (+8.5 words; 95% CI 3.7 to 13.3), but there was no evidence of effects from IYCF or WASH alone. There was no evidence that that any intervention impacted object permanence or self-control. Conclusions: Combining IYCF and WASH interventions significantly improved motor, language and cognitive development in HIV-exposed children. Trial registration number: NCT01824940.

Non-pharmaceutical strategies win coronavirus disease 2019 battle in New Zealand.

This literature-based article found that on 08 June 2020, New Zealand claimed victory over coronavirus disease 2019 (COVID-19) mainly because of effective non-pharmaceutical strategies and interventions that included a hard lockdown. The response was informed by the country's Influenza Pandemic Plan (although without criticism), which was updated in 2017, and the swift responses from political leadership and other key stakeholders. Strategies instituted included the proclamation of urgent precautionary measures leading to border closures, issuing of a 3-month-long COVID-19 notice under the Epidemic Preparedness Act 2006, the proclamation of the COVID-19 Elimination Strategy and the Initial COVID-19 Maori Response Action Plan, which incorporated COVID-19 Alert Levels that facilitated stepwise easing of the hard lockdown. The non-pharmaceutical strategies seem to have worked again, even as the second wave of COVID-19 infections returned in August 2020 through an Auckland cluster. Hence, the New Zealand case remains one that the world can draw lessons from, although not perfect.

Independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved complementary feeding on early neurodevelopment among children born to HIV-negative mothers in rural Zimbabwe: Substudy of a cluster-randomized trial.

BACKGROUND: Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IYCF) on early child development (ECD) among children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. METHODS AND FINDINGS: SHINE was a cluster-randomized community-based 2×2 factorial trial. A total of 5,280 pregnant women were enrolled from 211 clusters (defined as the catchment area of 1-4 village health workers [VHWs] employed by the Zimbabwean Ministry of Health and Child Care). Clusters were randomly allocated to standard of care, IYCF (20 g of small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counseling), WASH (ventilated improved pit latrine, handwashing stations, chlorine, liquid soap, and play yard), and WASH + IYCF. Primary outcomes were child length-for-age Z-score and hemoglobin concentration at 18 months of age. Children who completed the 18-month visit and turned 2 years (102-112 weeks) between March 1, 2016, and April 30, 2017, were eligible for the ECD substudy. We prespecified that primary inferences would be drawn from findings of children born to HIV-negative mothers; these results are presented in this paper. A total of 1,655 HIV-unexposed children (64% of those eligible) were recruited into the ECD substudy from 206 clusters and evaluated for ECD at 2 years of age using the Malawi Developmental Assessment Tool (MDAT) to assess gross motor, fine motor, language, and social skills; the MacArthur-Bates Communicative Development Inventories (CDI) to assess vocabulary and grammar; the A-not-B test to assess object permanence; and a self-control task. Outcomes were analyzed in the intention-to-treat population. For all ECD outcomes, there was not a statistical interaction between the IYCF and WASH interventions, so we estimated the effects of the interventions by comparing the 2 IYCF groups with the 2 non-IYCF groups and the 2 WASH groups with the 2 non-WASH groups. The mean (95% CI) total MDAT score was modestly higher in the IYCF groups compared to the non-IYCF groups in unadjusted analysis: 1.35 (0.24, 2.46; p = 0.017); this difference did not persist in adjusted analysis: 0.79 (-0.22, 1.68; p = 0.057). There was no evidence of impact of the IYCF intervention on the CDI, A-not-B, or self-control tests. Among children in the WASH groups compared to those in the non-WASH groups, mean scores were not different for the MDAT, A-not-B, or self-control tests; mean CDI score was not different in unadjusted analysis (0.99 [95% CI -1.18, 3.17]) but was higher in children in the WASH groups in adjusted analysis (1.81 [0.01, 3.61]). The main limitation of the study was the specific time window for substudy recruitment, meaning not all children from the main trial were enrolled. CONCLUSIONS: We found little evidence that the IYCF and WASH interventions implemented in SHINE caused clinically important improvements in child development at 2 years of age. Interventions that directly target neurodevelopment (e.g., early stimulation) or that more comprehensively address the multifactorial nature of neurodevelopment may be required to support healthy development of vulnerable children. TRIAL REGISTRATION: ClinicalTrials.gov NCT01824940.

Influence of Maternal Characteristics during Pregnancy on the Infant Early Life Immune Responses in a High HIV Burdened Setting in Harare, Zimbabwe.

This study aimed at investigating the maternal characteristics that in turn influence the immunological status of infants in asymptomatic enteric pathogen carriers in mother baby pairs (MBPs) in a high HIV burdened population in Harare, Zimbabwe. BIOPLEX immunoassay was used to analyse serum samples from 39 MBPs for 27 cytokines and 6 immunoglobulins. The MBP were purposively selected based on HIV infection and Entamoeba histolytica carriage. Logistic regression was used to identify any link between maternal demographic and clinical data with infant cytokine and immunoglobulin levels. Maternal E. histolytica carriers were more likely to have infants with low levels of IL-12p70, FGF-basic, GM-CSF and TNF-α cytokines (OR: 0.14; 95% CI: 0.03-0.79) and high levels of IgA immunoglobulin (OR: 8.1; 95% CI: 1.45-45.06). HIV infected mothers were more likely to have infants with low levels of IgG2 (OR: 0.24; 95% CI: 0.06-1.00) and IgA (OR: 0.22; 95% CI: 0.05-0.90) immunoglobulins. Notably, it was highly likely to deliver infants with low IgG4 levels (OR: 0.24; 95% CI: 0.06-1.02) for maternal mean age above 30.38 years (Standard deviation 6.09) though not significant (p=0.05). Maternal E. histolytica asymptomatic carriage, and HIV-infection status result in low levels of pro-inflammatory cytokines IL-12p70, FGF-basic, GM-CSF and TNF-α and immunoglobulins IgG2, IgG4 and IgA on their infants.

CCR2, CX3CR1, RANTES and SDF1 genetic polymorphisms influence HIV infection in a Zimbabwean pediatric population.

INTRODUCTION: There is growing evidence that polymorphisms in chemokine and chemokine receptor genes influence susceptibility to HIV infection and disease progression. However, not much is documented about the prevalence and effects of chemokine and chemokine receptor gene variations in the Zimbabwean population despite the high burden of HIV/AIDS in the country. This study therefore describes polymorphisms in CCR2, CX3CR1, SDF1 and RANTES genes in a Zimbabwean pediatric population and their effects on HIV infection in children born to HIV-infected mothers. METHODOLOGY: A total of 106 children between seven and nine years of age comprising 70 perinatally exposed to HIV (34 born infected [EI] and 36 born uninfected [EU]) and 36 unexposed and uninfected (UEUI) controls were recruited. Six allelic variants in four genes were genotyped using PCR-RFLP and sequencing. RESULTS: Frequencies for minor alleles in the HIV uninfected groups (EU and UEUI) were CCR2 190A (16%), SDF1 801A (2%), CX3CR1 745A (9%), CX3CR1 839T (0%), RANTES In 1.1C (20%), and RANTES -403A (44%). There were significant differences between the EI and EU groups in the distribution of CCR2 190G/A genotype (15% versus 39%, respectively, p = 0.02) and CCR2 190G/A-CX3CR1 745G/G genotype combination (0% versus 33%, respectively, p = 0.002). CONCLUSIONS: Our findings suggest that chemokine and chemokine receptor gene variants seem to play an important role in the dynamics of HIV infection and could be used as drug or vaccine targets.

Validation of a culturally modified short form of the McCarthy Scales of Children's Abilities in 6 to 8 year old Zimbabwean school children: a cross section study.

BACKGROUND: The burden of cognitive impairment among school children from developing communities is under reported due to lack of culturally appropriate screening tools. The objective of this study was to validate a culturally modified short form of the McCarthy Scales of Children Abilities (MSCA) in school children aged 6-8 years from varied backgrounds. METHODS: One hundred and one children aged 6-8 years attending mainstream classes were enrolled cross-sectionally from three schools: one rural and two urban. Two assessments were conducted on each child and the Short form MSCA was compared to an independent assessment by the educational psychologist. RESULTS: When comparing the results of the MSCA to local standard at -2SD, -1.5 SD and -1SD the sensitivity rates ranged from 17 to 50% with lower sensitivity at -2SD cut-off point. Specificity rates had less variation ranging from 95% to 100%. The number of children identified with cognitive impairment using -2SD, -1.5SD and -1SD below the mean for MSCA as a cut-off point were 3(3%), 7(7%) and 13(13%) respectively while the psychologist identified 18 (18%). The overall mean score on MSCA was 103 (SD 15). The rural children tended to score significantly lower marks compared to their peers from urban areas, mean (SD) 98(15) and 107(15) respectively, p=0.006. There was no difference in the mean (SD) scores between boys and girls, 103(17) and 103(15) respectively, p=0.995. CONCLUSION: The culturally modified short form MSCA showed high specificity but low sensitivity. Prevalence of cognitive impairment among 6 to 8 year children was 3%. This figure is high when compared to developed communities.

Neurodevelopmental impairment among infants born to mothers infected with human immunodeficiency virus and uninfected mothers from three peri-urban primary care clinics in Harare, Zimbabwe.

AIM: The aim of this article is to document the risk of neurodevelopmental impairment (NDI) among infants enrolled in a programme for the prevention of mother-to-child transmission of HIV (human immunodeficiency virus) in Zimbabwe using the Bayley Infant Neurodevelopmental Screener (BINS). METHOD: We prospectively followed up infants at three primary care clinics in Harare, Zimbabwe. Neurodevelopmental assessments using the BINS were conducted during the first 12 months of life. NDI risk category and associated risk factors were examined. RESULTS: Of the 598 infants assessed, 305 (51%) were female and 293 (49%) were male. Sixty-five infants (11%) were infected with HIV, 188 (31%) were exposed but uninfected, 287 (48%) were unexposed, and 58 (10%) were of unknown status. The prevalence of a high risk of NDI was 9.4% (95% confidence interval [CI] 7.1-11.1%): 9.2% in males and 9.6% in females. Of the 598 infants, 549 (92%) had ever been breastfed, 49% of whom had mothers infected with HIV. The risk of NDI was higher among infants infected early with HIV, i.e. by 3 months of age (p value <0.001). The NDI high-risk category included twice as many infants infected with HIV as uninfected infants (odds ratio [OR] 2.1; 95% CI 1.0-4.3). After adjusting for other factors, head circumference and family financial subsistence remained risk factors for NDI with an OR of 2.22 (1.04-4.82) and 2.55 (1.02-6.36) respectively. INTERPRETATION: The background prevalence of high-risk NDI category of 9.4% across groups seems high but is similar to that reported previously in developing countries. Integration of an early infant neurodevelopmental screening programme into child HIV management protocols will assist in the early referral of children exposed to HIV.

Reduced HIV transmission at subsequent pregnancy in a resource-poor setting.

Several studies indicate that HIV-infected women continue to have children. We set out to determine the trend in HIV transmission at subsequent pregnancies. From 2002-2003, pregnant women were enrolled in a single dose nevirapine-based Prevention of Mother-to-Child Transmission of HIV (PMTCT) programme. Six years later, women with subsequent children in this cohort were identified and their children's HIV status determined. From 330 identified HIV-infected mothers, 73 had second/subsequent children with HIV results. Of these, nine (12.3%, 95% confidence interval [CI]: 4.6-20.1%) children were HIV-infected. Of the 73 second children, 51 had older siblings who had been initially enrolled in the study with definitive HIV results with an infection rate of 17/51 (33.3%, 95% CI: 19.9-46.7). About 35% of the women had been on antiretroviral drugs. These results demonstrate lower subsequent HIV transmission rates in women on a national PMTCT programme in a resource-poor setting with the advent of antiretroviral therapy.

Randomized study of vaginal and neonatal cleansing with 1% chlorhexidine.

OBJECTIVE: To determine the safety, acceptability, and antimicrobial effect of 1% chlorhexidine (CHX) vaginal washing of women in labor and their neonates. METHODS: Randomized controlled trial of 1% CHX vaginal and neonatal washing compared with no washing (usual care [UC]). The study included 502 women (334 CHX, 168 UC) who delivered 508 liveborn neonates (335 CHX, 173 UC). Main outcome measures were the incidence of maternal adverse effects, the incidence of neonatal skin rash, the axillary temparature before and after neonatal wiping, and vaginal culture results. RESULTS: Maternal demographics did not differ between the groups. No case of maternal rash occurred; 4% of women experienced vaginal burning. An axillary temperature drop of more than 1 °C after CHX cleansing occurred in 8 neonates; 2 neonates had a minor rash. In the subset of women with positive vaginal cultures as baseline, 1% CHX eliminated culture growth in 56% after 1 wash, and in 86% after 2 washes. CONCLUSIONS: Use of 1% CHX is safe for neonates, well tolerated by laboring mothers, and effective in treating vaginal infections during labor. A randomized controlled trial using 1% CHX and powered for a reduction in neonatal septic mortality is justified based on these data.

Rising mother-to-child HIV transmission in a resource-limited breastfeeding population.

The objective of this study was to determine mother to child HIV transmission rates at different time points in a breastfeeding cohort enrolled in a single dose nevirapine program in Harare, Zimbabwe. Between 2002-2004, 434 HIV-positive mothers and their infants were recruited and followed up from delivery to 15 months. Infant blood specimens were collected for HIV testing at these time points. The majority of the patients (78%) received single dose nevirapine. The overall HIV transmission rate was 21.8% (17.8-25.8). Receiving single dose nevirapine was protective against HIV vertical transmission although statistically insignificant (relative risk: 0.76; 95% CI: 0.49-1.19). Breastfeeding was not found to be associated with HIV vertical transmission (P = 0.612). In this resource-limited setting, HIV transmission rates are high. Efforts to use more efficacious regimens to arrest HIV vertical transmission are required.