SARS-CoV-2 Variants and Vaccines.

Viral variants of concern may emerge with dangerous resistance to the immunity generated by the current vaccines to prevent coronavirus disease 2019 (Covid-19). Moreover, if some variants of concern have increased transmissibility or virulence, the importance of efficient public health measures and vaccination programs will increase. The global response must be both timely and science based.

National advisory panels for childhood cancer in the United Kingdom: An evaluation of current practice and a best practice statement for the future.

BACKGROUND: National advisory panels (NAPs) have been established for the care of children and young people (CYP) with cancer in the United Kingdom since 2011, with an increase in panel number in recent years. Their practice has not previously been reviewed; therefore, we sought to evaluate the role, practice and impact of six selected NAPs offering expertise in ependymoma, histiocytosis, leukaemia, neuroblastoma, renal tumours and sarcoma. PROCEDURE: This service evaluation used mixed methodology, including review of NAP documentation, semi-structured interviews with the NAP chairs and an analysis of the cases referred for discussion. RESULTS: Total 1110 referrals were analysed. Results demonstrated the significant scope and amount of work undertaken by the NAPs, largely testament to the commitment of the panel members. Specific roles fulfilled have been highlighted, and NAP recommendations have been shown to influence clinical decision-making and be implemented in the majority of cases. Despite widespread good practice, areas to address have been identified; these include clarity regarding NAP membership, consistency in recommendations, the consideration of holistic information to promote personalised management and the exploration of wider multidisciplinary team roles. CONCLUSIONS: In the context of increasing demand and the escalating number of NAPs, it is timely to consider how service improvement can be facilitated. Best practice guidelines have been formulated as a product of this study, to promote a sustainable and effective model for NAPs. Review and benchmarking national panel performance against these guidelines will drive high standards of care going forward and they should be embedded as standard practice.

The Practical Role of Induced Resistance for Crop Protection.

Plants have evolved a highly sophisticated immune system to resist pathogen attack comprising both preformed and inducible mechanisms. Over the last 50 years, various biological and chemical inducers have been used to artificially trigger the defense response in plants, thereby promoting an induced resistance (IR) to subsequent pathogen attack. IR has proven effective for disease control in laboratory and glasshouse conditions but has seldom equalled the level of protection offered by synthetic pesticides in the field. However, renewed interest in IR for crop protection is being driven by legislation to reduce the use of synthetic chemicals in agriculture. Inducers can contribute to integrated crop management strategies when used in combination with fungicides, bactericides, and with other biological control options. Integrating inducers in this way can reduce chemical inputs without loss of efficacy. Moreover, advances in our understanding of plant defense are informing the development of new inducers and guiding new strategies for their implementation in sustainable crop protection. This review will discuss the use of IR in selected cropping systems and describe opportunities for optimizing its potential, including the development of more effective inducers and their integration with conventional and cultural control options.

Incidence of Herpes Simplex Virus Type 2 Infection Among African Women Using Depot Medroxyprogesterone Acetate, a Copper Intrauterine Device, or a Levonorgestrel Implant for Contraception: A Nested Randomized Trial.

BACKGROUND: Globally, women have higher herpes simplex virus type 2 (HSV-2) prevalence than men; data from observational studies suggest a possible association of HSV-2 acquisition with use of intramuscular depot medroxyprogesterone acetate (DMPA-IM). METHODS: Within a randomized trial of the effect of 3 contraceptive methods-DMPA-IM, a copper intrauterine device (IUD), and a levonorgestrel (LNG) implant-on human immunodeficiency virus (HIV) acquisition, we assessed HSV-2 acquisition. HSV-2 and HIV seronegative women, aged 16-35 years, and seeking effective contraception were followed for 12-18 months at 12 sites in Eswatini, Kenya, South Africa, and Zambia from 2015 to 2018. HSV-2 serologic testing was done at enrollment and final study visits. Intention-to-treat analysis using Poisson regression with robust standard errors compared HSV-2 incidence by contraceptive method. RESULTS: At baseline, 4062 randomized women were HSV-2 seronegative, of whom 3898 (96.0%) had a conclusive HSV-2 result at their final study visit. Of these, 614 (15.8%) acquired HSV-2, at an incidence of 12.4/100 person-years (p-y): 10.9/100 p-y among women assigned DMPA-IM, 13.7/100 p-y the copper IUD, and 12.7/100 p-y the LNG implant. Incidence rate ratios (IRR) for HSV-2 acquisition were 0.80 (95% confidence interval [CI], .65-.97) for DMPA-IM compared with copper IUD, 0.86 (95% CI, .71-1.05) for DMPA-IM compared with LNG implant, and 1.08 (95% CI, .89-1.30) for copper IUD compared with LNG implant. HSV-2 acquisition risk was significantly increased among women who also acquired HIV during follow-up (IRR 3.55; 95% CI, 2.78-4.48). CONCLUSIONS: In a randomized trial, we found no association between HSV-2 acquisition and use of 3 contraceptive methods. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02550067.

COVID-19 vaccination rollout in the World Health Organization African region: status at end June 2022 and way forward.

In October 2021, the WHO published an ambitious strategy to ensure that all countries had vaccinated 40% of their population by the end of 2021 and 70% by mid-2022. The end of June 2022 marks 18 months of implementation of coronavirus disease 2019 (COVID-19) vaccination in the African region and provides an opportunity to look back and think ahead about COVID-19 vaccine set targets, demand and delivery strategies. As of 26 June 2022 two countries in the WHO African region have achieved this target (Mauritius and Seychelles) and seven are on track, having vaccinated between 40% and 69% of their population. By the 26 June 2022, seven among the 20 countries that had less than 10% of people fully vaccinated at the end of January 2022, have surpassed 15% of people fully vaccinated at the end of June 2022. This includes five targeted countries, which are being supported by the WHO Regional Office for Africa through the Multi-Partners' Country Support Team Initiative. As we enter the second semester of 2022, a window of opportunity has opened to provide new impetus to COVID-19 vaccination rollout in the African region guided by the four principles: Scale-up, Transition, Consolidation and Communication. Member States need to build on progress made to ensure that this impetus is not lost and that the African region does not remain the least vaccinated global region, as economies open up and world priorities change.

Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis.

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers.

Sexually transmitted infections among women randomised to depot medroxyprogesterone acetate, a copper intrauterine device or a levonorgestrel implant.

OBJECTIVES: Reproductive aged women are at risk of pregnancy and sexually transmitted infections (STI). Understanding drivers of STI acquisition, including any association with widely used contraceptives, could help us to reduce STI prevalence and comorbidities. We compared the risk of STI among women randomised to three contraceptive methods. METHODS: We conducted a secondary analysis to assess the risk of chlamydia and gonorrhoea in a clinical trial evaluating HIV risk among 7829 women aged 16-35 randomised to intramuscular depot medroxyprogesterone acetate (DMPA-IM), a copper intrauterine device (IUD) or a levonorgestrel (LNG) implant. We estimated chlamydia and gonorrhoea prevalences by contraceptive group and prevalence ratios (PR) using log-binomial regression. RESULTS: At baseline, chlamydia and gonorrhoea prevalences were 18% and 5%, respectively. Final visit chlamydia prevalence did not differ significantly between DMPA-IM and copper IUD groups or between copper IUD and LNG implant groups. The DMPA-IM group had significantly lower risk of chlamydia compared with the LNG implant group (PR 0.83, 95% CI 0.72 to 0.95). Final visit gonorrhoea prevalence differed significantly only between the DMPA-IM and the copper IUD groups (PR 0.67, 95% CI 0.52 to 0.87). CONCLUSIONS: The findings suggest that chlamydia and gonorrhoea risk may vary with contraceptive method use. Further investigation is warranted to better understand the mechanisms of chlamydia and gonorrhoea susceptibility in the context of contraceptive use.

Trajectories of fertility intentions among women living with HIV in South Africa.

Fertility intentions are thought to be dynamic among women of reproductive age, yet few studies have assessed fertility intentions over time among women with HIV. We examine temporal patterns of fertility intentions in women with HIV to assess the extent to which fertility intentions - and the corresponding need for safer conception and judicious antiretroviral therapy (ART) regimen selection - vary over time. 850 non-pregnant HIV-positive women aged 18-35 on or being initiated onto ART in Johannesburg, South Africa were enrolled into a prospective cohort study (2009-2010). Fertility intentions were assessed at enrollment and at 30-day intervals via an interviewer-administered questionnaire. We used group-based trajectory modelling to identify longitudinal patterns of fertility intentions over 12 months. We identified four patterns of fertility intentions, which we labelled "consistently low" (representing ∼60% of the population), "low and increasing" (∼23%), "high and increasing" (∼12%), and "high and decreasing" (∼5%). Our findings suggest that a single family-planning assessment at one time point is insufficient to fully identify and meet the reproductive needs of women with HIV. As HIV testing and treatment evolve in South Africa, routine screening for fertility intentions can offer important opportunities to optimize HIV treatment, prevention, and maternal and child health.

Comparisons of Human Immunodeficiency Virus Type 1 Envelope Variants in Blood and Genital Fluids near the Time of Male-to-Female Transmission.

To better understand the transmission of human immunodeficiency virus type 1 (HIV-1), the genetic characteristics of blood and genital viruses from males were compared to those of the imputed founding virus population in their female partners. Initially serodiscordant heterosexual African couples with sequence-confirmed male-to-female HIV-1 transmission and blood and genital specimens collected near the time of transmission were studied. Single viral templates from blood plasma and genital tract RNA and DNA were sequenced across HIV-1 env gp160. Eight of 29 couples examined yielded viral sequences from both tissues. Analysis of these couples' sequences demonstrated, with one exception, that the women's founding viral populations arose from a single viral variant and were CCR5 tropic, even though CXCR4 variants were detected within four males. The median genetic distance of the imputed most recent common ancestor of the women's founder viruses showed that they were closer to the semen viruses than to the blood viruses of their transmitting male partner, but this finding was biased by detection of a greater number of viral clades in the blood. Using multiple assays, the blood and genital viruses were consistently found to be compartmentalized in only two of eight men. No distinct amino acid signatures in the men's viruses were found to link to the women's founders, nor did the women's env sequences have shorter variable loops or fewer N-linked glycosylation sites. The lack of selective factors, except for coreceptor tropism, is consistent with others' findings in male-to-female and high-risk transmissions. The infrequent compartmentalization between the transmitters' blood and semen viruses suggests that cell-free blood virus likely includes HIV-1 sequences representative of those of viruses in semen.IMPORTANCE Mucosal transmissions account for the majority of HIV-1 infections. Identification of the viral characteristics associated with transmission would facilitate vaccine design. This study of HIV strains from transmitting males and their seroconverting female partners found that the males' genital tract viruses were rarely distinct from the blood variants. The imputed founder viruses in women were genetically similar to both the blood and genital tract variants of their male partners, indicating a lack of evidence for genital tract-specific lineages. These findings suggest that targeting vaccine responses to variants found in blood are likely to also protect from genital tract variants.

Fertility Intentions and Clinical Care Attendance Among Women Living with HIV in South Africa.

Poor HIV care retention impedes optimal treatment outcomes in persons living with HIV. Women trying to become pregnant may be motivated by periconception horizontal and vertical transmission concerns and thus more likely to attend HIV care visits than women not trying to conceive. We estimated the effect of fertility intentions on HIV care attendance over 12 months among non-pregnant, HIV-positive women aged 18-35 years who were on or initiating antiretroviral therapy in Johannesburg, South Africa. The percentage of women attending an HIV care visit decreased from 93.4% in the first quarter to 82.8% in the fourth quarter. Fertility intentions were not strongly associated with care attendance in this cohort of reproductive-aged women; however, attendance declined over time irrespective of childbearing plans. These findings suggest a need for reinforced efforts to support care engagement and risk reduction, including safer conception practices for women wishing to conceive.

COVID-19 in Africa: care and protection for frontline healthcare workers.

Medical staff caring for COVID-19 patients face mental stress, physical exhaustion, separation from families, stigma, and the pain of losing patients and colleagues. Many of them have acquired SARS-CoV-2 and some have died. In Africa, where the pandemic is escalating, there are major gaps in response capacity, especially in human resources and protective equipment. We examine these challenges and propose interventions to protect healthcare workers on the continent, drawing on articles identified on Medline (Pubmed) in a search on 24 March 2020. Global jostling means that supplies of personal protective equipment are limited in Africa. Even low-cost interventions such as facemasks for patients with a cough and water supplies for handwashing may be challenging, as is 'physical distancing' in overcrowded primary health care clinics. Without adequate protection, COVID-19 mortality may be high among healthcare workers and their family in Africa given limited critical care beds and difficulties in transporting ill healthcare workers from rural to urban care centres. Much can be done to protect healthcare workers, however. The continent has learnt invaluable lessons from Ebola and HIV control. HIV counselors and community healthcare workers are key resources, and could promote social distancing and related interventions, dispel myths, support healthcare workers, perform symptom screening and trace contacts. Staff motivation and retention may be enhanced through carefully managed risk 'allowances' or compensation. International support with personnel and protective equipment, especially from China, could turn the pandemic's trajectory in Africa around. Telemedicine holds promise as it rationalises human resources and reduces patient contact and thus infection risks. Importantly, healthcare workers, using their authoritative voice, can promote effective COVID-19 policies and prioritization of their safety. Prioritizing healthcare workers for SARS-CoV-2 testing, hospital beds and targeted research, as well as ensuring that public figures and the population acknowledge the commitment of healthcare workers may help to maintain morale. Clearly there are multiple ways that international support and national commitment could help safeguard healthcare workers in Africa, essential for limiting the pandemic's potentially devastating heath, socio-economic and security impacts on the continent.

Integrating Cervical Cancer Screening Into Safer Conception Services to Improve Women's Health Outcomes: A Pilot Study at a Primary Care Clinic in South Africa.

BACKGROUND: Sub-optimal cervical cancer screening in low- and middle-income countries contributes to preventable cervical cancer deaths, particularly among human immunodeficiency virus (HIV)-positive women. We assessed feasibility and outcomes of integrating cervical cancer screening into safer conception services for HIV-affected women. METHODS: At a safer conception service in Johannesburg, South Africa, HIV-affected women desiring pregnancy received a standard package of care designed to minimize HIV transmission risks while optimizing prepregnancy health. All eligible women were offered Papanicolaou smear, and those with significant pathology were referred for colposcopy before attempting pregnancy. Multivariable analyses identified associations between patient characteristics and abnormal pathology. RESULTS: In total, 454 women were enrolled between June 2015 and April 2017. At enrolment, 91% were HIV-positive, 92% were on antiretroviral therapy (ART) and 82% virally suppressed. Eighty-three percent (376 of 454) of clients were eligible for cervical cancer screening and 85% (321 of 376) of these completed screening. More than half had abnormal cervical pathology (185 of 321) and 20% required colposcopy for possible high-grade or persistently atypical lesions (64 of 321). Compared with HIV-negative women, abnormal pathology was more likely among HIV-positive women, both those on ART <2 years (adjusted prevalence ratio, 2.5; 95% confidence interval, 1.2-5.0) and those on ART 2 years or longer (adjusted prevalence ratio, 2.1; 95% confidence interval, 1.0-4.2). CONCLUSIONS: Integrating cervical cancer screening into safer conception care was feasible with high coverage, including for HIV-positive women. Significant pathology, requiring colposcopy, was common, even among healthy women on ART. Safer conception services present an opportunity for integration of cervical cancer screening to avert preventable cancer-related deaths among HIV-affected women planning pregnancy.

Pre-exposure prophylaxis (PrEP) in an era of stalled HIV prevention: Can it change the game?

Pre-exposure prophylaxis (PrEP) for HIV prevention has evolved significantly over the years where clinical trials have now demonstrated the efficacy of oral PrEP, and the field is scaling-up implementation. The WHO and UNAIDS have made PrEP implementation a priority for populations at highest risk, and several countries have developed guidelines and national plans accordingly, largely based on evidence generated by demonstration projects. PrEP presents the opportunity to change the face of HIV prevention by offering a new option for protection against HIV and disrupting current HIV prevention systems. Nevertheless, as with all new technologies, both practical and social requirements for implementation must be taken into account if there is to be sustained and widespread adoption, which will also apply to forthcoming prevention technologies. Defining and building success for PrEP within the scope of scale-up requires careful consideration. This review summarises where the PrEP field is today, lessons learned from the past, the philosophy and practicalities of how successful programming may be defined, and provides perspectives of costs and affordability. We argue that a successful PrEP programme is about effective intervention integration and ultimately keeping people HIV negative.

"It Was Not My Aim to Sleep There": The Impact of Timing and Location of Sex on Adherence to Coitally-Dependent HIV Pre-exposure Prophylaxis.

The FACTS 001 trial found that vaginal pre- and post-coital application of 1% tenofovir gel did not prevent HIV-1 infection amongst young South African women. The trial included a multi-faceted approach to adherence support and collected objective and self-reported adherence measures. Using qualitative data collected from a random sub-set of FACTS 001 participants (135 in-depth interviews at product discontinuation and 13 focus group discussions at dissemination of trial results), we explore the importance of 'place' and 'timing' in shaping acts of sexual intimacy and product adherence. Demographically, this qualitative sub-sample is similar to the trial cohort of predominantly young, unemployed women living with parents or other family members. Sexual intimacy was largely unpredictable and happened across multiple locations in which women had limited privacy, autonomy, or control over the timing of sex. This made adherence to the dosing strategy challenging. Findings may inform the development of future event-driven pre-exposure prophylaxis regimens or products.

Advancing STI priorities in the SDG era: priorities for action.

The Sustainable Development Goals present an opportunity to reimagine and then reconfigure the approach to controlling sexually transmitted infections (STIs). The predilection of STIs for women and for vulnerable populations means that services that ameliorate STIs, by their nature, enhance equity, a key focus of the goals. Given the considerable breadth and depth of the goals, it is important to locate points of convergence between the SDGs and STIs, further craft synergies with HIV and select a few population groups and settings to prioritise. There are many opportunities for STI aficionados in this era to advance the field and global control of these infections.

Expanding global access to essential medicines: investment priorities for sustainably strengthening medical product regulatory systems.

Access to quality-assured medical products improves health and save lives. However, one third of the world's population lacks timely access to quality-assured medicines while estimates indicate that at least 10% of medicine in low- and middle-income countries (LMICs) are substandard or falsified (SF), costing approximately US$ 31 billion annually. National regulatory authorities are the key government institutions that promote access to quality-assured medicines and combat SF medical products but despite progress, regulatory capacity in LMICs is still insufficient. Continued and increased investment in regulatory system strengthening (RSS) is needed. We have therefore reviewed existing global normative documents and resources and engaged with our networks of global partners and stakeholders to identify three critical challenges being faced by NRAs in LMICs that are limiting access to medical products and impeding detection of and response to SF medicines. The challenges are; implementing value-added regulatory practices that best utilize available resources, a lack of timely access to new, quality medical products, and limited evidence-based data to support post-marketing regulatory actions. To address these challenges, we have identified seven focused strategies; advancing and leveraging convergence and reliance initiatives, institutionalizing sustainability, utilizing risk-based approaches for resource allocation, strengthening registration efficiency and timeliness, strengthening inspection capacity and effectiveness, developing and implementing risk-based post-marketing quality surveillance systems, and strengthening regulatory management of manufacturing variations. These proposed solutions are underpinned by 13 focused recommendations, which we believe, if financed, technically supported and implemented, will lead to stronger health system and as a consequence, positive health outcomes.

HIV pre-exposure prophylaxis and early antiretroviral treatment among female sex workers in South Africa: Results from a prospective observational demonstration project.

BACKGROUND: Operational research is required to design delivery of pre-exposure prophylaxis (PrEP) and early antiretroviral treatment (ART). This paper presents the primary analysis of programmatic data, as well as demographic, behavioural, and clinical data, from the TAPS Demonstration Project, which offered both interventions to female sex workers (FSWs) at 2 urban clinic sites in South Africa. METHODS AND FINDINGS: The TAPS study was conducted between 30 March 2015 and 30 June 2017, with the enrolment period ending on 31 July 2016. TAPS was a prospective observational cohort study with 2 groups receiving interventions delivered in existing service settings: (1) PrEP as part of combination prevention for HIV-negative FSWs and (2) early ART for HIV-positive FSWs. The main outcome was programme retention at 12 months of follow-up. Of the 947 FSWs initially seen in clinic, 692 were HIV tested. HIV prevalence was 49%. Among those returning to clinic after HIV testing and clinical screening, 93% of the women who were HIV-negative were confirmed as clinically eligible for PrEP (n = 224/241), and 41% (n = 110/270) of the women who were HIV-positive had CD4 counts within National Department of Health ART initiation guidelines at assessment. Of the remaining women who were HIV-positive, 93% were eligible for early ART (n = 148/160). From those eligible, 98% (n = 219/224) and 94% (n = 139/148) took up PrEP and early ART, respectively. At baseline, a substantial fraction of women had a steady partner, worked in brothels, and were born in Zimbabwe. Of those enrolled, 22% on PrEP (n = 49/219) and 60% on early ART (n = 83/139) were seen at 12 months; we observed high rates of loss to follow-up: 71% (n = 156/219) and 30% (n = 42/139) in the PrEP and early ART groups, respectively. Little change over time was reported in consistent condom use or the number of sexual partners in the last 7 days, with high levels of consistent condom use with clients and low use with steady partners in both study groups. There were no seroconversions on PrEP and 7 virological failures on early ART among women remaining in the study. Reported adherence to PrEP varied over time between 70% and 85%, whereas over 90% of participants reported taking pills daily while on early ART. Data on provider-side costs were also collected and analysed. The total cost of service delivery was approximately US$126 for PrEP and US$406 for early ART per person-year. The main limitations of this study include the lack of a control group, which was not included due to ethical considerations; clinical study requirements imposed when PrEP was not approved through the regulatory system, which could have affected uptake; and the timing of the implementation of a national sex worker HIV programme, which could have also affected uptake and retention. CONCLUSIONS: PrEP and early ART services can be implemented within FSW routine services in high prevalence, urban settings. We observed good uptake for both PrEP and early ART; however, retention rates for PrEP were low. Retention rates for early ART were similar to retention rates for the current standard of care. While the cost of the interventions was higher than previously published, there is potential for cost reduction at scale. The TAPS Demonstration Project results provided the basis for the first government PrEP and early ART guidelines and the rollout of the national sex worker HIV programme in South Africa.