Case Report-Progressive immobilising back and joint pain

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Effects of coronavirus disease pandemic on tuberculosis notifications, Malawi

The coronavirus disease (COVID-19) pandemic might affect tuberculosis (TB) diagnosis and patient care. We analyzed a citywide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi did not have an official COVID-19 lockdown but closed schools and borders on March 23, 2020. In an interrupted time series analysis, we noted an immediate 35.9% reduction in TB notifications in April 2020; notifications recovered to near prepandemic numbers by December 2020. However, 333 fewer cumulative TB notifications were received than anticipated. Women and girls were affected more (30.7% fewer cases) than men and boys (20.9% fewer cases). Fear of COVID-19 infection, temporary facility closures, inadequate personal protective equipment, and COVID-19 stigma because of similar symptoms to TB were mentioned as reasons for fewer people being diagnosed with TB. Public health measures could benefit control of both TB and COVID-19, but only if TB diagnostic services remain accessible and are considered safe to attend.Peer reviewe

Computer-aided X-ray screening for tuberculosis and HIV testing among adults with cough in Malawi (the PROSPECT study): A randomised trial and cost-effectiveness analysis.

BACKGROUND: Suboptimal tuberculosis (TB) diagnostics and HIV contribute to the high global burden of TB. We investigated costs and yield from systematic HIV-TB screening, including computer-aided digital chest X-ray (DCXR-CAD). METHODS AND FINDINGS: In this open, three-arm randomised trial, adults (≥18 years) with cough attending acute primary services in Malawi were randomised (1:1:1) to standard of care (SOC); oral HIV testing (HIV screening) and linkage to care; or HIV testing and linkage to care plus DCXR-CAD with sputum Xpert for high CAD4TBv5 scores (HIV-TB screening). Participants and study staff were not blinded to intervention allocation, but investigator blinding was maintained until final analysis. The primary outcome was time to TB treatment. Secondary outcomes included proportion with same-day TB treatment; prevalence of undiagnosed/untreated bacteriologically confirmed TB on day 56; and undiagnosed/untreated HIV. Analysis was done on an intention-to-treat basis. Cost-effectiveness analysis used a health-provider perspective. Between 15 November 2018 and 27 November 2019, 8,236 were screened for eligibility, with 473, 492, and 497 randomly allocated to SOC, HIV, and HIV-TB screening arms; 53 (11%), 52 (9%), and 47 (9%) were lost to follow-up, respectively. At 56 days, TB treatment had been started in 5 (1.1%) SOC, 8 (1.6%) HIV screening, and 15 (3.0%) HIV-TB screening participants. Median (IQR) time to TB treatment was 11 (6.5 to 38), 6 (1 to 22), and 1 (0 to 3) days (hazard ratio for HIV-TB versus SOC: 2.86, 1.04 to 7.87), with same-day treatment of 0/5 (0%) SOC, 1/8 (12.5%) HIV, and 6/15 (40.0%) HIV-TB screening arm TB patients (p = 0.03). At day 56, 2 SOC (0.5%), 4 HIV (1.0%), and 2 HIV-TB (0.5%) participants had undiagnosed microbiologically confirmed TB. HIV screening reduced the proportion with undiagnosed or untreated HIV from 10 (2.7%) in the SOC arm to 2 (0.5%) in the HIV screening arm (risk ratio [RR]: 0.18, 0.04 to 0.83), and 1 (0.2%) in the HIV-TB screening arm (RR: 0.09, 0.01 to 0.71). Incremental costs were US$3.58 and US$19.92 per participant screened for HIV and HIV-TB; the probability of cost-effectiveness at a US$1,200/quality-adjusted life year (QALY) threshold was 83.9% and 0%. Main limitations were the lower than anticipated prevalence of TB and short participant follow-up period; cost and quality of life benefits of this screening approach may accrue over a longer time horizon. CONCLUSIONS: DCXR-CAD with universal HIV screening significantly increased the timeliness and completeness of HIV and TB diagnosis. If implemented at scale, this has potential to rapidly and efficiently improve TB and HIV diagnosis and treatment. TRIAL REGISTRATION: clinicaltrials.gov NCT03519425

Impact of COVID-19 on tuberculosis notifications in Blantyre Malawi: an interrupted time series analysis and qualitative study with healthcare workers.

COVID-19 may impact on tuberculosis (TB) diagnosis and care. We analysed a city-wide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi had no official “lockdown” but closed schools and borders on 23 March 2020. In interrupted time series analysis, there was an immediate 35.9% reduction in TB notifications (95% CI 22.0 to 47.3%) in April, which recovered to near pre-pandemic numbers by December 2020, but with 333 (95% CI 291 to 375) fewer cumulative notifications than anticipated. Women and girls were impacted (30.7% fewer cases, 95% CI 28.4 to 33.0%) more than men and boys (20.9% fewer, 95% CI 18.5 to 23.3). Fear of COVID-19 infection, temporary facility closure, inadequate protective equipment and COVID-19 stigma with similar presenting symptoms to TB were mentioned. Public health measures could benefit both TB and COVID-19, but only if diagnostic services remain accessible and are considered safe to attend

The choice of reference chart affects the strength of the association between malaria in pregnancy and small for gestational age: an individual participant data meta-analysis comparing the Intergrowth-21 with a Tanzanian birthweight chart

Background: The prevalence of small for gestational age (SGA) may vary depending on the chosen weight-for-gestational-age reference chart. An individual participant data meta-analysis was conducted to assess the implications of using a local reference (STOPPAM) instead of a universal reference (Intergrowth-21) on the association between malaria in pregnancy and SGA. Methods: Individual participant data of 6,236 newborns were pooled from seven conveniently identified studies conducted in Tanzania and Malawi from 2003–2018 with data on malaria in pregnancy, birthweight, and ultrasound estimated gestational age. Mixed-effects regression models were used to compare the association between malaria in pregnancy and SGA when using the STOPPAM and the Intergrowth-21 references, respectively. Results: The 10th percentile for birthweights-for-gestational age was lower for STOPPAM than for Intergrowth-21, leading to a prevalence of SGASTOPPAM of 14.2% and SGAIG21 of 18.0%, p < 0.001. The association between malaria in pregnancy and SGA was stronger for STOPPAM (adjusted odds ratio (aOR) 1.30 [1.09–1.56], p < 0.01) than for Intergrowth-21 (aOR 1.19 [1.00–1.40], p = 0.04), particularly among paucigravidae (SGASTOPPAM aOR 1.36 [1.09–1.71], p < 0.01 vs SGAIG21 aOR 1.21 [0.97–1.50], p = 0.08). Conclusions: The prevalence of SGA may be overestimated and the impact of malaria in pregnancy underestimated when using Intergrowth-21. Comparing local reference charts to global references when assessing and interpreting the impact of malaria in pregnancy may be appropriate

Group B Streptococcus vaccine development: present status and future considerations, with emphasis on perspectives for low and middle income countries.

Globally, group B Streptococcus (GBS) remains the leading cause of sepsis and meningitis in young infants, with its greatest burden in the first 90 days of life. Intrapartum antibiotic prophylaxis (IAP) for women at risk of transmitting GBS to their newborns has been effective in reducing, but not eliminating, the young infant GBS disease burden in many high income countries. However, identification of women at risk and administration of IAP is very difficult in many low and middle income country (LMIC) settings, and is not possible for home deliveries. Immunization of pregnant women with a GBS vaccine represents an alternate pathway to protecting newborns from GBS disease, through the transplacental antibody transfer to the fetus in utero. This approach to prevent GBS disease in young infants is currently under development, and is approaching late stage clinical evaluation. This manuscript includes a review of the natural history of the disease, global disease burden estimates, diagnosis and existing control options in different settings, the biological rationale for a vaccine including previous supportive studies, analysis of current candidates in development, possible correlates of protection and current status of immunogenicity assays. Future potential vaccine development pathways to licensure and use in LMICs, trial design and implementation options are discussed, with the objective to provide a basis for reflection, rather than recommendations

Systemic governance, public accountability and institutional autonomy

University autonomy remains as controversial an issue in South African higher education as it was during the apartheid era. Before 1994, liberal universities1 in South Africa declared support for the principles of academic freedom and university autonomy, in opposing State education policies and State interference, in particular. Their stance was captured in T.B. Davie’s wellknown definition of academic freedom as ‘our freedom from external interference in who shall teach, what we teach, how we teach and whom we teach’ (quoted in Jansen, 2005a:297). In examining the relationship between the State and the higher education sector in South African since 1994, the chosen starting point is a tension reflected in the Higher Education Act (Republic of South Africa 1997:2): ‘it is desirable for higher education institutions to enjoy freedom and autonomy in their relationships with the State within the context of accountability and the national need for advanced skills and scientific knowledge’. The tension at stake may be captured in the question of whether the interpretation of accountability and the measures taken to meet the need for skills and knowledge threaten to undermine academic freedom and university autonomy

LB-2112-24 Diagnostic accuracy, clinical impact and antimicrobial resistance consequences of using trial-of-antibiotics for tuberculosis diagnosis: a randomised controlled trial in Malawi (ACT-TB study)

Background: Tuberculosis (TB) diagnostic algorithms often include ‘trial-of-antibiotics’— empirical antibiotics for mycobacteriology-negative individuals to treat infectious causes other than tuberculosis, as a ‘rule- out’ diagnostic test for tuberculosis. We investigated the effect of trial-of-antibiotics among adults being investigated for TB on diagnostic accuracy, clinical outcomes, and antimicrobial resistance (AMR). Methods: We randomised (1:1:1) Malawian adults (≥18 years) attending primary care for illness ≥2 weeks in- cluding cough not previously treated with antibiotics to receive: azithromycin (500mg once daily, 3 days), amoxi- cillin (1g three times/day, 5 days), or standard-of-care (SOC, no immediate antibiotic). Sputum taken at enrol- ment and day 8 was tested using mycobacteriology (mi- croscopy, Xpert MTB/RIF, and TB culture). Nasopha- ryngeal swabs at enrolment and day 29 were cultured onto blood agar. Primary outcomes were specificity, de- fined as proportion reporting symptom improvement on audio computer-assisted self-interview at day 8 among those with negative mycobacteriology, and proportion with composite day 29 endpoint of death, hospitalisa- tion or missed tuberculosis diagnosis (clinical impact). The secondary outcome was the proportion with newly resistant nasopharyngeal Streptococcus pneumoniae on day 29. (NCT03545373). Results: Between 02/2019-03/2020, we screened 2452 adults with cough and randomised 1583 (40% male, median age 32 years, 11.9% HIV-positive) to SOC (530), azithromycin (527), or amoxicillin (526). Overall 3.79% (60/1583) had positive mycobacteriology by day 8. Com- pared to SOC (79.1%), trial-of-antibiotics improved specificity of TB diagnosis: azithromycin vs. SOC (dif- ference +7.40% [3.6%-11.2%]); amoxicillin vs. SOC (difference +6.70% [2.8%-10.6%]). Proportions with day 29 poor clinical outcomes (SOC 1.13%) or new AMR (SOC 5.28%) were similar (Table) including when antibiotic arms were combined. Conclusions: Immediate trial-of-antibiotic during TB diagnosis investigations resulted in modestly increased but still suboptimal specificity, with no impact on early clinical outcomes or AMR generation. National pro- grams can consider omitting routine trial-of-antibiotics from diagnostic algorithms, but more effective strategies to minimise unnecessary TB treatment are needed

Age-related changes in PD-1 expression coincide with increased cytotoxic potential in V\u3b42 T cells during infancy

Human V\u3b39V\u3b42 T cells respond to several diverse pathogens by sensing microbial cholesterol intermediates. Unlike CD4 T cells, they are poised for rapid Th1-like responses even before birth, which allows them to play a key role in the first line of defense against pathogens in early life. However, their regulation and functional maturation during infancy (in particular the acquisition of cytotoxic potential) remain understudied. We thus characterized their responses to cholesterol intermediates and Bacille Calmette-Gu\ue9rin in a cohort of African neonates and 12-month-old infants. Infant V\u3b42 lymphocytes exhibited intermediate or adult-like expression of markers associated with differentiation or function, intermediate proliferative responses, and adult-like cytotoxic potential. The enhancement of V\u3b42 cell cytotoxic potential coincided with decreasing PD-1 and increasing NKG2A expression. Our results are consistent with the hypothesis that switching from a PD-1+ to a NKG2A+ phenotype during infancy indicates a shift in mechanisms regulating V\u3b42 T cell function