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Background: Given that South Africa has one of the highest rates of pregnancy amongst adolescent girls and young women (AGYW) globally, the provision of contraceptives to this group has been a key focus in recent years. Pregnancy prevention involves an on-going continuum of decision-making around contraceptive method choice, uptake, use, experience, continuation, and discontinuation., Methods: This paper presents analysis of data from a cross-sectional survey with 2376 AGYW, as well as qualitative in-depth interviews (IDIs) with 54 AGYW, inclusive of contraceptive journey narratives. We examine the preferences, valued characteristics, choices, beliefs, understandings and experiences of choosing and using contraceptives amongst AGYW in two South African communities characterised by high rates of pregnancy., Results: These findings shed light on the preferences towards, beliefs about, and experiences of choosing, using and discontinuing contraceptive methods amongst this population, with survey data suggesting that the most popular methods were the injection, followed by the implant, and then the oral pill. Findings illustrate the complexity and dynamic nature of contraceptive decision-making and the varied embodied and lived experiences of contraceptive use, and how these are impacted by contraception service provision., Conclusions: Our findings show that contraception experiences of each individual are cumulative, and comprise a continuum of method initiation, use, discontinuation, method switching and on-going circular decision-making influenced by multiple social, structural, contextual and interpersonal factors, combined with shifting preferences, values and needs. To maximise the use of contraceptives amongst South African AGYW, it is necessary to provide responsive contraception service provision to reflect the changing contexts and preferences of users, in order to ensure that pregnancy prevention needs are catered for throughout their reproductive life course., (© 2024. The Author(s).)

Persistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI. Here, we used genome sequencing to search for novel large (>1 Mb) deletions in 180 probands with HI of unknown cause and replicated our findings in a large cohort of 883 genetically unsolved individuals with HI using off-target copy number variant calling from targeted gene panels. We identified overlapping heterozygous deletions in five individuals (range 3-8 Mb) spanning chromosome 20p11.2. The pancreatic beta-cell transcription factor gene, FOXA2, a known cause of HI was deleted in two of the five individuals. In the remaining three, we found a minimal deleted region of 2.4 Mb adjacent to FOXA2 that encompasses multiple non-coding regulatory elements that are in conformational contact with FOXA2. Our data suggests that the deletions in these three children may cause disease through the dysregulation of FOXA2 expression. These findings provide new insights into the regulation of FOXA2 in the beta-cell and confirm an aetiological role for chromosome 20p11.2 deletions in syndromic HI., (© 2024. The Author(s).)

Aims/hypothesis: In pregnancies where the mother has glucokinase-MODY (GCK-MODY), fetal growth is determined by fetal genotype. When the fetus inherits a maternal pathogenic GCK variant, normal fetal growth is anticipated, and insulin treatment of maternal hyperglycaemia is not recommended. At present, fetal genotype is estimated from measurement of fetal abdominal circumference on ultrasound. Non-invasive prenatal testing of fetal GCK genotype (NIPT-GCK) using cell-free DNA in maternal blood has recently been developed. We aimed to compare the diagnostic accuracy of NIPT-GCK with that of ultrasound, and determine the feasibility of using NIPT-GCK to guide pregnancy management., Methods: We studied an international cohort of pregnant women with hyperglycaemia due to GCK-MODY. We compared the diagnostic accuracy of NIPT-GCK with that of measurement of fetal abdominal circumference at 28 weeks' gestation (n=38) using a directly genotyped offspring sample as the reference standard. In a feasibility study, we assessed the time to result given to clinicians in 43 consecutive pregnancies affected by GCK-MODY between July 2019 and September 2021., Results: In terms of diagnostic accuracy, NIPT-GCK was more sensitive and specific than ultrasound in predicting fetal genotype (sensitivity 100% and specificity 96% for NIPT-GCK vs sensitivity 53% and specificity 61% for fetal abdominal circumference 75th percentile). In terms of feasibility, a valid NIPT-GCK fetal genotype (≥95% probability) was reported in all 38 pregnancies with an amenable variant and repeated samples when needed. The median time to report was 5 weeks (IQR 3-8 weeks). For the 25 samples received before 20 weeks' gestation, results were reported at a median gestational age of 20 weeks (IQR 18-24), with 23/25 (92%) reported before 28 weeks., Conclusions/interpretation: Non-invasive prenatal testing of fetal genotype in GCK-MODY pregnancies is highly accurate and is capable of providing a result before the last trimester for most patients. This means that non-invasive prenatal testing of fetal genotype is the optimal approach to management of GCK-MODY pregnancies., (© 2023. The Author(s).)

We examined power and decision-making in heterosexual relationships amongst South African adolescents and young people. A survey conducted with 515 adolescent girls and young women (AGYW) included items from the Sexual Relationship Power Scale (SRPS) adapted for South African women. Qualitative interviews with fifty AGYW aged between 15 and 24, and nine males aged 18 years and above, explored decision-making in heterosexual relationships, particularly relating to timing of sex and condom use. Theories of gendered power, sexual relationship power and sexual scripting were used in interpreting the data. Findings showed that the power AGYW have in sexual relationships determines their ability to use condoms, and that males generally control condom use and timing of sex. Both survey and interview data suggest that male control over female partners' behaviour also extends beyond the sexual domain. Although while male power is pervasive and enduring, it is simultaneously contested and negotiated. Despite some young people believing that gendered power in decision-making should be equal, it is not always possible for AGYW to enact agency in the dyadic context of heterosexual relationships. Whilst adolescents and young people in South Africa move away from traditional cultural gendered expectations, relationship power inequity and hegemonic masculinities continue to legitimise men's power over women, constraining the sexual agency of adolescent girls and young women and discouraging them from taking control of their own sexual interests and sexual health., (© 2022. The Author(s).)

Daily oral pre-exposure prophylaxis (PrEP) is highly efficacious for HIV prevention. Adolescent girls and young women (AGYW) have been prioritised for PrEP delivery in South Africa. A combination HIV prevention intervention providing integrated biomedical, behavioural and structural interventions for AGYW aged 15-24 in twelve districts in South Africa characterised by high HIV prevalence, was implemented 2019-2022. We conducted qualitative interviews to explore PrEP implementation experiences with 38 individuals involved in the implementation of the combination HIV prevention programme, including programme managers and project coordinators, health care providers / nurses, social workers, counsellors, peer group trainers and outreach workers. Narratives included various challenges associated with PrEP uptake, adherence and acceptability experienced by implementers. Barriers to PrEP acceptability included AGYW fears of side effects and preference for injectable versus daily oral PrEP; resistance towards PrEP from AGYW, communities and parents due to a lack of accurate information; PrEP stigma linked to associations with antiretrovirals and assumptions of promiscuity; and issues pertaining to parental consent. Additionally, implementers faced logistical challenges related to procurement, stockouts, and supply of PrEP. Findings highlighted the critical role of parental and community acceptability of PrEP for successful implementation. Overall, PrEP was perceived by implementers as a valuable HIV prevention tool. In order to ensure the accessibility of PrEP for AGYW in South Africa, efforts to reduce stigma and foster social support for PrEP use, campaigns to raise awareness, ensure positive framing of PrEP, and build community acceptability of PrEP, are needed., (© 2022. The Author(s).)

The COVID-19 pandemic has been associated with reduced access to health services and worsening health outcomes for HIV and sexual and reproductive health (SRH). Through the analysis of data from an evaluation study of a combination intervention for adolescent girls and young women (AGYW) in South Africa, we sought to examine the way in which implementation and service provision were impacted by the COVID-19 pandemic and related restrictions, describing the adaptation implementers made to respond to this context. The intervention was implemented from 2019 in South African districts identified as high priority, given the high rates of HIV and teenage pregnancy amongst AGYW. The South African government introduced the first COVID-19 lockdown in March 2020. We conducted in-depth interviews with 38 intervention implementers in the period from November 2020 to March 2021. Respondents described various ways in which the COVID-19 pandemic and related restrictions had limited their ability to implement the intervention and provide services as planned. As a result, AGYW intervention beneficiary access to SRH and psychosocial services was disrupted. Implementers described several ways in which they attempted to adapt to the pandemic context, such as offering services remotely or door-to-door. Despite attempts to respond to the context and adapt services, overall COVID-19 negatively affected implementation and service provision, and heightened issues around community acceptability of the programs. Our findings can help to inform efforts to reduce health service disruption, increase health system resilience, and ensure continuous SRH service provision to AGYW in times of pandemics and other crises., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Duby, Bunce, Fowler, Jonas, Govindasamy, Wagner, Mangoale, Ambrose and Mathews.)

Background: Safe Spaces are a feature of combination HIV prevention interventions for adolescent girls and young women (AGYW) in South Africa. We investigated whether AGYW at risk for adverse sexual and reproductive health (SRH) outcomes accessed Safe Spaces that were part of an intervention, as well as their feasibility and acceptability., Methods: In December 2020 to February 2021, as part of a process evaluation of a combination HIV prevention intervention, we randomly sampled 2160 AGYW intervention beneficiaries aged 15-24 years from 6 of the 12 intervention districts. We invited them to participate in a phone survey, with questions about their vulnerability to adverse SRH outcomes, and participation in intervention components including Safe Spaces. We examined factors associated with use of Safe Spaces using bivariate analyses and Pearson's chi squared tests. We also conducted in-depth interviews with 50 AGYW beneficiaries, 27 intervention implementers, 4 health workers, 7 social workers, and 12 community stakeholders, to explore perceptions and experiences of the intervention. Thematic analysis of the qualitative data was performed., Results: At least 30 Safe Spaces were established across 6 districts. Five hundred fifteen of two thousand one hundred sixty sampled AGYW participated in the survey of whom 22.6% visited a Safe Space, accessing HIV testing (52.2%), mobile health services (21.2%) and counselling for distress (24.8%) while there. Beneficiaries of lower socioeconomic status (SES) were less likely to have visited a Safe Space, compared with those of higher SES (13.6% versus 25.3%; p < 0.01). Implementers described political, structural and financial challenges in identifying and setting up Safe Spaces that were safe, accessible and adequately-resourced, and challenges with AGYW not utilising them as expected. AGYW shared positive views of Safe Spaces, describing benefits such as access to computers and the internet, support with homework and job and education applications, and a space in which to connect with peers., Conclusion: AGYW are attracted to Safe Spaces by educational and employment promoting interventions and recreational activities, and many will take up the offer of SRH services while there. The poorest AGYW are more likely to be excluded, therefore, an understanding of the obstacles to, and enablers of their inclusion should inform Safe Space intervention design., (© 2022. The Author(s).)

Background: In contexts where poverty and mental health stressors already interact to negatively impact the most vulnerable populations, COVID-19 is likely to have worsened these impacts. Before the COVID-19 pandemic, adolescent girls and young women (AGYW) in South Africa already faced intersecting mental health stressors and vulnerabilities. It is critical to understand how additional challenges brought on by COVID-19 have intersected with existing vulnerabilities and mental health risks AGYW faced, particularly given the intersections between psychological distress and increased risk behaviours that impact sexual and reproductive health. We aimed to examine socio-economic and mental health impacts of COVID-19 on South African AGYW in order to understand how additional challenges brought on by COVID-19 have intersected with existing challenges, compounding AGYW vulnerabilities., Methods: Using qualitative and quantitative methods, framed by the syndemic theory, we examined the intersections between mental health and the COVID-19 epidemic amongst AGYW in six districts of South Africa characterised by high rates of HIV, teenage pregnancy and socio-economic hardship. Between November 2020 and March 2021 we conducted a cross-sectional telephone survey with 515 AGYW, and in-depth interviews with 50 AGYW, aged 15 to 24 years., Results: Our findings reveal how COVID-19 restrictions led to increased experiences of stress and anxiety. Poor mental health was compounded by strained family relationships, increased fear of domestic violence, household unemployment, economic stress and food insecurity. Respondents described feelings of boredom, frustration, isolation, loneliness, fear and hopelessness. However, despite the multitude of challenges, some AGYW articulated emotional resilience, describing ways in which they coped and retained hope., Conclusion: Various psycho-social risk factors already disproportionally affect the mental health of AGYW in these communities; the COVID-19 pandemic intersects with these pre-existing social and environmental factors. Understanding strategies AGYW have used to positively cope with the uncertainty of COVID-19 amongst an array of pre-existing mental health stressors, is key in informing efforts to respond to their needs. Multisectoral interventions are needed to address the drivers of poor mental health among AGYW, and bolster healthy coping mechanisms; interventions seeking to mitigate the mental health impacts on this vulnerable population need to be responsive to the unpredictable pandemic environment., (© 2022. The Author(s).)

Objectives: This study aimed to evaluate the associations between COVID-19 severity and active viral load, and to characterize the dynamics of active SARS-CoV-2 clearance in a series of archival samples taken from patients in the first wave of COVID-19 infection in the South West of the UK., Methods: Subgenomic RNA (sgRNA) and E-gene genomic sequences were measured in a retrospective collection of PCR-confirmed SARS-CoV-2-positive samples from 176 individuals, and related to disease severity. Viral clearance dynamics were then assessed in relation to symptom onset and last positive test., Results: Whilst E-gene sgRNAs declined before E-gene genomic sequences, some individuals retained sgRNA positivity for up to 68 days. 13% of sgRNA-positive cases still exhibited clinically relevant levels of virus after 10 days, with no clinical features previously associated with prolonged viral clearance times., Conclusions: Our results suggest that potentially active virus can sometimes persist beyond a 10-day period, and could pose a potential risk of onward transmission. Where this would pose a serious public health threat, additional mitigation strategies may be necessary to reduce the risk of secondary cases in vulnerable settings., (Copyright © 2021. Published by Elsevier Ltd.)

Heterozygous mutations of the HNF1B gene are the commonest known monogenic cause of developmental kidney disease. Half of patients have a deletion (approximately 1.3 Mb) of chromosome 17q12, encompassing HNF1B plus 14 additional genes. This 17q12 deletion has been linked with an increased risk of neurodevelopmental disorders, such as autism. Here we compared the neurodevelopmental phenotype of 38 patients with HNF1B-associated renal disease due to an intragenic mutation in 18 patients or due to 17q12 deletion in 20 patients to determine whether haploinsufficiency of HNF1B is responsible for the neurodevelopmental phenotype. Significantly, brief behavioral screening in children with the deletion showed high levels of psychopathology and its impact. Eight individuals (40%) with a deletion had a clinical diagnosis of a neurodevelopmental disorder compared to none with an intragenic mutation. The 17q12 deletions were also associated with more autistic traits. Two independent clinical geneticists were able to predict the presence of a deletion with a sensitivity of 83% and specificity of 79% when assessing facial dysmorphic features as a whole. Thus, the 17q12 deletions but not HNF1B intragenic mutations are associated with neurodevelopmental disorders. Hence, the HNF1B gene is not involved in the neurodevelopmental phenotype of these patients. Nephrologists need to be aware of this association to ensure appropriate referral to psychiatric services., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.

Context: Recent reports have proposed that sporadic or familial germline Xq26.3 microduplications involving the GPR101 gene are associated with early-onset X-linked acrogigantism (XLAG) with a female preponderance., Case Description: A 4-year-old boy presented with rapid growth over the previous 2 years. He complained of sporadic headaches and had coarse facial features. His height Z-score was +4.89, and weight Z-score was +5.57. Laboratory testing revealed elevated serum prolactin (185 μg/L; normal, <18 μg/L), IGF-1 (745 μg/L; normal, 64-369 μg/L), and fasting GH > 35.0 μg/L. Magnetic resonance imaging demonstrated a homogenous bulky pituitary gland (18 × 15 × 13 mm) without obvious adenoma. A pituitary biopsy showed hyperplastic pituitary tissue with enlarged cords of GH and prolactin cells. Germline PRKAR1A, MEN1, AIP, DICER1, CDKN1B, and somatic GNAS mutations were negative. Medical management was challenging until institution of continuous sc infusion of short-acting octreotide combined with sc pegvisomant and oral cabergoline. The patient remains well controlled with minimal side effects 7 years after presentation. His phenotype suggested XLAG, but his peripheral leukocyte-, saliva-, and buccal cell-derived DNA tested negative for microduplication in Xq26.3 or GPR101. However, DNA isolated from the pituitary tissue and forearm skin showed duplicated dosage of GPR101, suggesting that he is mosaic for this genetic abnormality., Conclusions: Our patient is the first to be described with somatic microduplication leading to typical XLAG phenotype. This patient demonstrates that a negative test for Xq26.3 microduplication or GPR101 duplication on peripheral blood DNA does not exclude the diagnosis of XLAG because it can result from a mosaic mutation affecting the pituitary.

The effectiveness of training referential communication skills with learning-disabled (LD) students was investigated. Forty-two upper elementary-aged children were divided equally into three groups: (a) an LD training group, (b) an LD control group, and (c) a normally achieving training group. The normal group was included as a check on training procedures. All subjects were administered pretests. The measures were a listening task and two speaking tasks. The two training groups were trained in dyads on a referential communication task. Posttests were administered 1 week after training. Results indicated that on the listening task the groups were not significantly different. On both speaking measures, the LD trained group achieved significantly higher scores than did the LD control group. The LD and normally achieving training groups were not significantly different. Follow-up testing 7 months later indicated that significant differences remained between the two LD groups on one of the speaking measures. It is concluded that LD students can benefit from training on referential communication tasks.

These cases reports describe the rationale and procedures for structuring an articulation therapy program on the basis of distinctive feature analysis of the child's articulation problems. Results of the speech therapy program described in these case reports illustrate the effectiveness and efficiency of using distinctive feature analysis to structure and guide articulation therapy. The report further points out that a therapist need not greatly alter the traditional approach to utilize distinctive feature analysis as an integral part of the overall articulation therapy program.

Two language-delayed children received comprehension instruction on preposition-object phrases using a miniature linguistic system format to structure generalization. Results indicated generalization not only to untreated two-word combinations, but also to comprehension of four-word phrases. In addition, there was some generalization of production of two- and four-word structures.