Acinic cell carcinoma of the salivary gland (ACC-SG) is characterized by a recurrent chromosomal rearrangement (t(4; 9)(q13; q31)) that upregulates the transcription factor NR4A3. Studies conducted ...on formalin-fixed paraffin-embedded (FFPE) tissue have found that nuclear expression of a monoclonal antibody NR4A3 (NOR-1) is a sensitive and specific diagnostic marker for ACC-SG. The aims of this study were to evaluate the performance of the NOR-1 antibody and to compare its utility in separating ACC-SG from its mimics on cytology cell block specimens. Cell blocks were obtained from 70 fine-needle aspiration specimens from multiple institutional archives over a 7-year period (2013–2019). These included 10 cases of conventional low-grade ACC-SG, 1 case of dedifferentiated high-grade ACC-SG, and 59 cases of non–ACC-SG. An automated immunohistochemistry system (Bond-III, Leica) was used for the detection of NR4A3, using the commercially available antibody NOR-1 (sc-393902 H-7, Santa Cruz Biotechnology Inc.). Optimization of the antibody on the cell blocks was successfully completed by increasing the titer from 1:100 (suggested titer for FFPE specimens) to 1:30. Distinct nuclear reactivity was observed in all 11 cases of ACC-SG (10 of 11 with 3+ diffuse nuclear positivity and 1 case with 2+ focal reactivity). Expression of NR4A3 was absent in all non–ACC-SG cases in the cell blocks. Application of the NOR-1 immunohistochemical staining in fine-needle aspirates of salivary gland tumors for which ACC-SG is a diagnostic consideration successfully distinguishes ACC-SG from its cytologic mimics and provides an early opportunity for oncologic intervention.
Tests for recent HIV infection (TRI) distinguish recent from long-term HIV infections using markers of antibody maturation. The limiting antigen avidity enzyme immunoassay (LAg EIA) is widely used ...with HIV viral load (VL) in a recent infection testing algorithm (RITA) to improve classification of recent infection status, estimate population-level HIV incidence, and monitor trends in HIV transmission. A novel rapid test for recent HIV infection (RTRI), Asanté™, can determine HIV serostatus and HIV recency within minutes on a lateral flow device through visual assessment of test strip or reader device. We conducted a field-based laboratory evaluation of the RTRI among pregnant adolescent girls and young women (AGYW) attending antenatal clinics (ANC) in Malawi.We enrolled pregnant AGYW aged <25 years testing HIV-positive for the first time at their first ANC visit from 121 ANCs in four high-HIV burden districts. Consenting participants provided blood for recency testing using LAg EIA and RTRI, which were tested in central laboratories. Specimens with LAg EIA normalized optical density values ≤2.0 were classified as probable recent infections. RTRI results were based on: (1) visual assessment: presence of a long-term line (LT) indicating non-recent infection and absence of the line indicating recent infection; or (2) a reader; specimens with LT line intensity units <3.0 were classified as probable recent infections. VL was measured for specimens classified as a probable recent infections by either assay; those with HIV-1 RNA ≥1,000 copies/mL were classified as confirmed recent infections. We evaluated the performance of the RTRI by calculating correlation between RTRI and LAg EIA results, and percent agreement and kappa between RTRI and LAg EIA RITA results.Between November 2017 to June 2018, 380 specimens were available for RTRI evaluation; 376 (98.9%) were confirmed HIV-positive on RTRI. Spearman's rho between RTRI and LAg EIA was 0.72 indicating strong correlation. Percent agreement and kappa between RTRI- and LAg EIA-based RITAs were >90% and >0.65 respectively indicating substantial agreement between the RITAs.This was the first field evaluation of an RTRI in sub-Saharan Africa, which demonstrated good performance of the assay and feasibility of integrating RTRI into routine HIV testing services for real-time surveillance of recent HIV infection.
Age-mixing (age-disparate 5-9 years difference and intergenerational ≥ 10 years difference) partnerships are hypothesized drivers of HIV in adolescent girls and young women (AGYW; 15-24 years). These ...partnerships are often associated with increased gender inequities which undermine women's agency and assertiveness. We assessed whether age-mixing partnerships were associated with HIV in Malawi and if endorsement of inequitable gender norms modifies this relationship.
We analyzed data from the Malawi Population-based HIV Impact Assessment, a nationally representative household survey conducted in 2015-2016. Participants underwent HIV testing and completed questionnaires related to actively endorsed gender norms and sexual risk behavior. We used multivariate logistic regression and multiplicative interaction to assess associations among AGYW who reported the age of their primary sex partner from the last year.
The analysis included 1,958 AGYW (mean age = 19.9 years, SD = 0.1), 459 (23.4%) and 131 (6.7%) of whom reported age-disparate and intergenerational partnerships, respectively. AGYW in age-mixing partnerships accounted for 13% of all AGYW and were older, more likely to reside in urban areas, to be married or cohabitating with a partner, and to have engaged in riskier sexual behavior compared with AGYW in age-concordant partnerships (p < 0.05). HIV prevalence among AGYW in age-disparate and intergenerational partnerships was 6.1% and 11.9%, respectively, compared with 3.2% in age-concordant partnerships (p < 0.001). After adjusting for residence, age, education, employment, wealth quintile, and ever been married or cohabitated as married, AGYW in age-disparate and intergenerational partnerships had 1.9 (95% CI: 1.1-3.5) and 3.4 (95% CI: 1.6-7.2) greater odds of HIV, respectively, compared with AGYW in age-concordant partnerships. Among the 614 (31% of the study group) who endorsed inequitable gender norms, AGYW in age-disparate and intergenerational partnerships had 3.5 (95% CI: 1.1-11.8) and 6.4 (95% CI: 1.5-27.8) greater odds of HIV, respectively, compared with AGYW in age-concordant partnerships.
In this Malawi general population survey, age-mixing partnerships were associated with increased odds of HIV among AGYW. These findings highlight inequitable gender norms as a potential focus for HIV prevention and could inform interventions targeting structural, cultural, and social constraints of this key group.
Malawi spearheaded the development and implementation of Option B+ for prevention of mother-to-child transmission of HIV (PMTCT), providing life-long ART for all HIV-positive pregnant and ...breastfeeding women. We used data from the 2015-2016 Malawi Population-based HIV Impact Assessment (MPHIA) to estimate progress toward 90-90-90 targets (90% of those with HIV know their HIV-positive status; of these, 90% are receiving ART; and of these, 90% have viral load suppression VLS) for HIV-positive women reporting a live birth in the previous 3 years. MPHIA was a nationally representative household survey; consenting eligible women aged 15-64 years were interviewed on pregnancies and outcomes, including HIV status during their most recent pregnancy, PMTCT uptake, and early infant diagnosis (EID) testing. Descriptive analyses were weighted to account for the complex survey design. Viral load (VL) results were categorized by VLS (<1,000 copies/mL) and undetectable VL (target not detected/below the limit of detection). Of the 3,153 women included in our analysis, 371 (10.1%, 95% confidence interval CI: 8.8%-11.3%) tested HIV positive in the survey. Most HIV-positive women (84.2%, 95% CI: 79.9%-88.6%) reported knowing their HIV-positive status; of these, 94.9% (95% CI: 91.7%-98.2%) were receiving ART; and of these, 91.2% (95% CI: 87.4%-95.0%) had VLS. Among the 371 HIV-positive women, 76.0% (95% CI: 70.4%-81.7%) had VLS and 66.5% (95% CI: 59.8%-73.2%) had undetectable VL. Among 262 HIV-exposed children, 50.8% (95% CI: 42.8%-58.8%) received EID testing within 2 months of birth, whereas 17.9% (95% CI: 11.9%-23.8%) did not receive EID testing. Of 190 HIV-exposed children with a reported HIV test result, 2.1% (95% CI: 0.0%-4.6%) had positive results. MPHIA data demonstrate high PMTCT uptake at a population level. However, our results identify some gaps in VLS in postpartum women and EID testing.
To determine early COVID-19 burden in Malawi, we conducted a multistage cluster survey in 5 districts. During October-December 2020, we recruited 5,010 community members (median age 32 years, ...interquartile range 21-43 years) and 1,021 health facility staff (HFS) (median age 35 years, interquartile range 28-43 years). Real-time PCR-confirmed SARS-CoV-2 infection prevalence was 0.3% (95% CI 0.2%-0.5%) among community and 0.5% (95% CI 0.1%-1.2%) among HFS participants; seroprevalence was 7.8% (95% CI 6.3%-9.6%) among community and 9.7% (95% CI 6.4%-14.5%) among HFS participants. Most seropositive community (84.7%) and HFS (76.0%) participants were asymptomatic. Seroprevalence was higher among urban community (12.6% vs. 3.1%) and HFS (14.5% vs. 7.4%) than among rural community participants. Cumulative infection findings 113-fold higher from this survey than national statistics (486,771 vs. 4,319) and predominantly asymptomatic infections highlight a need to identify alternative surveillance approaches and predictors of severe disease to inform national response.
Few studies have been conducted in Africa to assess prevalence of sexually transmitted infections (STIs) and risk factors among men who have sex with men (MSM). We report findings from the first ...behavioural survey to include STI testing among MSM in Kampala, Uganda.
Respondent-driven sampling (RDS) was used to recruit MSM for a biobehavioural survey. Eligible participants were men who reported anal sex with another man in the previous 3 months, were 18 years or older, and resided in Kampala. Information was collected on demographics, sexual behaviour, alcohol and drug use, and STI symptoms. Blood, urine and rectal specimens were tested for syphilis, HIV, rectal and urethral gonorrhoea, and chlamydia. Analyses weighted for RDS were conducted to assess associations with STI diagnosis.
A total of 295 MSM participated in the survey. Almost half (weighted percentage: 47.3%) reported STI symptoms in the last 6 months and 12.9% tested HIV-positive. Prevalence of non-HIV STI was 13.5%; syphilis prevalence was 9.0%. Adjusting for age and education, STI was associated with HIV (adjusted OR (AOR)=3.46, 95% CI 1.03 to 11.64), alcohol use before sex (AOR=4.99, 95% CI 1.86 to 13.38) and having sold sex in the last 3 months (AOR=3.17, 95% CI 1.25 to 8.07), and inversely associated with having anonymous sex partners (AOR=0.20, 95% CI 0.07 to 0.61).
We observed high levels of self-reported STI symptoms and STI prevalence associated with alcohol use and HIV among MSM in Kampala. Public health interventions supporting MSM are needed to address STI risk and facilitate access to diagnosis and treatment services.
We used publicly available data to describe epidemiology, genomic surveillance, and public health and social measures from the first 3 COVID-19 pandemic waves in southern Africa during April 6, ...2020-September 19, 2021. South Africa detected regional waves on average 7.2 weeks before other countries. Average testing volume 244 tests/million/day) increased across waves and was highest in upper-middle-income countries. Across the 3 waves, average reported regional incidence increased (17.4, 51.9, 123.3 cases/1 million population/day), as did positivity of diagnostic tests (8.8%, 12.2%, 14.5%); mortality (0.3, 1.5, 2.7 deaths/1 million populaiton/day); and case-fatality ratios (1.9%, 2.1%, 2.5%). Beta variant (B.1.351) drove the second wave and Delta (B.1.617.2) the third. Stringent implementation of safety measures declined across waves. As of September 19, 2021, completed vaccination coverage remained low (8.1% of total population). Our findings highlight opportunities for strengthening surveillance, health systems, and access to realistically available therapeutics, and scaling up risk-based vaccination.
Evidence suggests that disclosure of HIV status between partners may influence prevention of maternal-to-child transmission of HIV (PMTCT) outcomes. We report partner disclosure in relation to ...maternal antiretroviral therapy (ART) uptake and adherence, and MTCT among postpartum HIV-infected Malawian women.
A cross-sectional mixed-method study was conducted as part of a nationally representative longitudinal cohort study. Between 2014-2016, all (34,637) mothers attending 54 under-5 clinics with their 4-26 week-old infants were approached, of which 98% (33,980) were screened for HIV; infants received HIV-1 DNA testing. HIV-exposure was confirmed in 3,566/33,980 (10.5%). Baseline data from mothers who were known to be HIV-infected at time of screening were included in the current analysis. Guardians (n = 17), newly diagnosed HIV-infected mothers (n = 256) and mothers or infants with undetermined HIV status (n = 30) were excluded. Data collected included socio-demographics, partner disclosure, maternal ART uptake, and adherence. Between 2016-2017, in-depth interviews and focus group discussions were conducted with adult mothers (n = 53) and their spouse/cohabiting partners (n = 19), adolescent mothers (n = 13), lost-to-follow up (LTFU) mothers (n = 22), community leaders (n = 23) and healthcare workers (n = 154).
Of 3153 known HIV-infected mothers, 2882 (91.4%) reported having a spouse/cohabiting partner. Among 2882 couples, both partners, one partner, and neither partner disclosed to each other in 2090 (72.5%), 622 (21.6%), and 169 (5.9%), respectively. In multivariable models, neither partner disclosing was associated with no maternal ART (aOR 4.7; 95%CI 2.5-8.8), suboptimal treatment adherence (aOR 1.8; 95%CI 1.1-2.8) and MTCT (aOR 2.1; 95%CI 1.1-4.1). Women's fear of blame by partners was central to decisions not to disclose within couples and when starting new relationships. LTFU mothers struggled to accept and disclose their status, hindering treatment initiation; some were unable to hide ART and feared involuntary disclosure.
Partner disclosure seems to play an important role in women's decisions regarding ART initiation and adherence. Inter-partner non-disclosure was associated with no ART uptake, suboptimal treatment adherence and MTCT.
Although human congenital cerebellar malformations are common, their molecular and developmental basis is still poorly understood. Recently, cilia-related gene deficiencies have been implicated in ...several congenital disorders that exhibit cerebellar abnormalities such as Joubert syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome, and Orofaciodigital syndrome. The association of cilia gene mutations with these syndromes suggests that cilia may be important for cerebellar development, but the nature of cilia involvement has not been elucidated. To assess the importance of cilia-related proteins during cerebellar development, we studied the effects of CNS-specific inactivation of two mouse genes whose protein products are critical for cilia formation and maintenance, IFT88, (also known as polaris or Tg737), which encodes intraflagellar transport 88 homolog, and Kif3a, which encodes kinesin family member 3a. We showed that loss of either of these genes caused severe cerebellar hypoplasia and foliation abnormalities, primarily attributable to a failure of expansion of the neonatal granule cell progenitor population. In addition, granule cell progenitor proliferation was sensitive to partial loss of IFT function in a hypomorphic mutant of IFT88 (IFT88(orpk)), an effect that was modified by genetic background. IFT88 and Kif3a were not required for the specification and differentiation of most other cerebellar cell types, including Purkinje cells. Together, our observations constitute the first demonstration that cilia proteins are essential for normal cerebellar development and suggest that granule cell proliferation defects may be central to the cerebellar pathology in human cilia-related disorders.
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