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Background: Adolescent girls and young women (AGYW) account for 25% of incident HIV infections in sub-Saharan Africa. Human papillomavirus (HPV) infection is common among AGYW, but its role in HIV [...]

We report on an 11-year-old girl with cystic fibrosis who presented with thoracic pain and an extensive subcutaneous emphysema and subsequently developed progressive respiratory distress. The chest computed tomography revealed a huge pneumomediastinum. Due to the development of severe respiratory failure, urgent needle thoracocentesis was necessary that resulted in only temporary improvement. Therefore, under general anesthesia two mediastinal drains were introduced. Using active suction, the size of the pneumomediastinum decreased gradually and the drains were removed after 3 weeks. Here, we describe an extremely rare situation, when acute surgical intervention was necessary in a child with spontaneous pneumomediastinum.

Background: Febrile encephalopathy, defined as fever, seizures and/or altered consciousness, is a common presentation in children in tropical developing countries. Outcomes range from complete recovery through varying degrees of neurological disability which slowly resolve or remain permanent to death from either the acute illness or complications. Whilst bacterial meningitis accounts for a proportion of children affected, the aetiology in many remains unclear but includes malaria and probably viral encephalitis. Aim: To understand the aetiology, presentation and outcome of febrile encephalopathy in children in Papua New Guinea. Methods: Children aged between 1 month and 12 years presenting to Port Moresby General Hospital with febrile encephalopathy were studied prospectively. A detailed history and examination and the following laboratory investigations were undertaken as appropriate: cerebrospinal fluid (CSF) microscopy and bacterial culture, gram stain, measurement of protein and glucose and latex agglutination testing for Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitides; Ziehl—Neelsen staining and india ink examination on selected samples; IgM for Japanese encephalitis, dengue, rubella and measles; PCR testing and mycobacterial culture for Mycobacterium tuberculosis. Blood was tested for flavivirus, measles and rubella IgM and IgG. Results: 149 children were enrolled in the study. 129 had a lumbar puncture and CSF examination; 66 had a normal CSF white cell count. A clinical or laboratory-based diagnosis was possible for 140 children, but a definite pathogen was identifiable for only 55 (37%). The diagnoses included bacterial meningitis in 33 (S. pneumonia 16, H. influenza 13 and N. meningitides 4), tuberculous meningitis (5), probable tuberculous meningitis (18), malaria (10), cryptococcal meningitis (1), flavivirus encephalitis (5), rubella encephalitis (1), hepatic encephalopathy (1) and HIV encephalopathy (1). There were 28 cases of meningitis of unspecified aetiology. Of the five children with IgM-confirmed flavivirus encephalitis, one had dengue serotype 1 and two had Japanese encephalitis. Twenty-five children (including three of the five children with CSF flavivirus IgM) had serological IgG evidence of previous flavivirus infection. A history of multiple convulsions, the presence of neck stiffness and use of the Glasgow coma score (GCS) and TB score chart helped to identify children with bacterial meningitis and an adverse outcome and those with febrile convulsions. Conclusion: The study confirms the importance of S. pneumonia and H. influenza as major causes of febrile encephalopathy in children in Papua New Guinea. Flaviviruses including Japanese encephalitis are a cause of the febrile encephalopathy syndrome, as is Mycobacterium tuberculosis. All children with febrile encephalopathy should have their GCS and TB scores recorded and should be examined for neck stiffness, and a history of the frequency of convulsions should be recorded. These basic clinical data can help to discriminate aetiology, to guide treatment and monitoring and to identify the children at highest risk of adverse outcome. [ABSTRACT FROM AUTHOR]

In previous research, it was determined that the altitude of origin altered the parameters of photic entrainment and free-running rhythmicity of adult locomotor activity of the high-altitude Himalayan (haH) strain (Hemkund-Sahib, 4121 m above sea level) of Drosophila helvetica compared to the low-altitude Himalayan (laH) strain (Birahi, 1132 m above sea level) of the same species. The present study investigated whether the altitude of origin also affects the parameters of the light pulse phase response curve (PRC) of the adult locomotor activity rhythm of the haH strain. Light pulse PRCs were determined for both strains against the background of constant darkness. Although both were "weak" or type 1 PRCs, the PRC for the haH strain differed from that of the laH strain in three basic parameters. The PRC for the haH strain was of low amplitude, had a protracted dead zone, and showed a ratio of the advance to delay region (A/D>1), while the PRC of the laH strain was characterized by high amplitude, absence of dead zone, and a A/D ratio<1. The asymmetric PRCs of these strains might explain the process of photic entrainment to 24 h light-dark cycles, as the long period of the free-running rhythm (τ) of the haH strain is complemented with a larger advance portion of its PRC (A/D>1), whereas the short τ of the laH strain is matched with a larger delay portion of its PRC (A/D<1). Prolonged dead zone and low amplitude in the PRC of the haH strain imply that the photic sensitivity of this strain has been drastically diminished as an adaptation to environmental conditions at the altitude of its origin. While adults of this strain begin activity in very bright light in the forenoon due to non-permissible low temperature in the morning, the converse is true for the laH strain. [ABSTRACT FROM AUTHOR]

The properties of the pacemaker controlling the adult locomotor activity rhythm of the high-altitude Himalayan (haH) strain (Hemkund Sahib, 4121 m above sea level) of Drosophila helvetica are strikingly different from those of the low-altitude Himalayan (laH) strain (Birahi, 1132 m above sea level) of the same species. The haH strain has a unimodal activity pattern with a delayed peak occurring about 4.5 h after lights-on of the entraining light-dark (LD) cycle, while the laH strain has a bimodal activity pattern with the morning and evening peaks. It is rather unusual for a wild type strain of any Drosophila species to have a unimodal activity pattern during entrainment as observed in the haH strain. The single activity peak of the haH strain is regarded as a consequence of delayed morning peak merging with the evening one. Three experiments were performed to test this hypothesis. The first experiment examined whether the single activity peak could be dissociated into two components by LD cycles in which photoperiods varied from 10 to 16 h per 24 h. The haH strain again exhibited a unimodal activity pattern with a delayed peak in 10, 12, and 14 h photoperiods but a bimodal activity pattern in 16 h photoperiod. The laH strain had bimodality in 10 and 12 h photoperiods, unimodality in a 14 h photoperiod, but complete arrhythmicity in a 16 h photoperiod. In the second experiment, the haH flies were transferred from LD 16:8 to LL at 5 lux to confirm whether the bimodality of this strain in LD 16:8 cycles was not the result of masking by the long photoperiod of 16 h. Bimodality of the haH strain persisted in LL too; moreover, the morning component free-ran with period (τ) <24 h, while the evening component free-ran with τ>24 h. The third experiment examined the LL-induced splitting of activity peak of the haH strain. Flies were transferred from LD 12:12 cycles to LL at 0, 1, 5, and 15 lux. The haH strain was rhythmic in LL at 0 and 1 lux with a unimodal activity pattern. It was also rhythmic in LL at 5 lux, but the single activity peak was split into two discrete components; the morning component free-ran with τ<24 h, while the evening component free-ran with τ>24 h. This strain, however, was completely arrhythmic in LL at 15 lux. The laH strain was uniformly arrhythmic in LL at all levels of light intensity. These results suggest that the single but late activity component of the haH strain during entrainment appears to be the consequence of merging the delayed morning peak with the evening one as an adaptation to the environmental conditions at the altitude of origin of this strain, where these flies begin activity in the forenoon owing to non-permissible low temperature in the morning. [ABSTRACT FROM AUTHOR]

Phase III trials have demonstrated the efficacy of human papillomavirus (HPV) vaccines in preventing transient and persistent high-risk (hr) HPV infection and precancerous lesions. A mathematical model of HPV type 16 infection and progression to cervical cancer, parameterised to represent the infection in Finland, was used to explore the optimal age at vaccination and pattern of vaccine introduction. In the long term, the annual proportion of cervical cancer cases prevented is much higher when early adolescents are targeted. Vaccinating against hr HPV generates greater long-term benefits if vaccine is delivered before the age at first sexual intercourse. However, vaccinating 12 year olds delays the predicted decrease in cervical cancer, compared to vaccinating older adolescents or young adults. Vaccinating males as well as females has more impact on the proportion of cases prevented when vaccinating at younger ages. Implementing catch-up vaccination at the start of a vaccination programme would increase the speed with which a decrease in HPV and cervical cancer incidence is observed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare alternative methods to vital registration systems for estimating adult mortality, and describe patterns of mortality in Manicaland, Zimbabwe, which has been severely affected by HIV. METHODS: We compared estimates of adult mortality from (1) a single question on household mortality, (2) repeated household censuses, and (3) an adult cohort study with linked HIV testing from Manicaland, with a mathematical model fitted to local age-specific HIV prevalence (1998 -2000). FINDINGS: The crude death rate from the single question (29 per 1000 person-years) was roughly consistent with that from the mathematical model (22 -25 per 1000 person-years), but much higher than that from the household censuses (12 per 1000 person-years). Adult mortality in the household censuses (males 0.65; females 0.51) was lower than in the cohort study (males 0.77; females 0.57), while mathematical models gave a much higher estimate, especially for females (males 0.80 -0.83; females 0.75 -0.80). The population attributable fraction of adult deaths due to HIV was 0.61 for men and 0.70 for women, with life expectancy estimated to be 34.3 years for males and 38.2 years for females. CONCLUSION: Each method for estimating adult mortality had limitations in terms of loss to follow-up (cohort study), under-ascertainment (household censuses), transparency of underlying processes (single question), and sensitivity to parameterization (mathematical model). However, these analyses make clear the advantages of longitudinal cohort data, which provide more complete ascertainment than household censuses, highlight possible inaccuracies in model assumptions, and allow direct quantification of the impact of HIV. Copyright © 2006 World Health Organization [ABSTRACT FROM AUTHOR]

The effect of altitude on four basic properties of the pacemaker controlling the circadian rhythm of oviposition in two strains of Drosophila ananassae was determined. The high altitude (HA) strain from Badrinath (5,123 m above sea level) had a low amplitude peak in the forenoon while the low altitude (LA) strain from Firozpur (179 m a. s.l.) had a high amplitude peak after the lights-off of LD 12:12 cycles. Free running periods in continuous darkness were about 22.6 and 27.4 h in the HA and LA strains, respectively. The light pulse phase response curve (PRC) for the HA strain showed a low amplitude and a dead zone of 8 h; the ratio for the advance to delay region (A/D) was less than 1, while the PRC for the LA strain had a high amplitude, which was devoid of a dead zone and showed a ratio of A/D>1. The magnitude of the delay phase shifts at CT 18 evoked by light pulses of 1 h duration, but varying light intensity was significantly different in the HA and LA strain, which suggests that the photic sensitivity of the clock photoreceptors mediating the phase shifts had been affected by the altitude. [ABSTRACT FROM AUTHOR]

In 2003, the National Health Service Cervical Screening Programme (NHSCSP) announced that its screening interval would be reduced to 3 years in women aged 25-49 and fixed at 5 years in those aged 50-64, and that women under 25 years will no longer be invited for screening. In order to assess these and possible further changes to cervical screening practice in the UK, we constructed a mathematical model of cervical HPV infection, cervical intraepithelial neoplasia and invasive cervical cancer, and of UK age-specific screening coverage rates, screening intervals and treatment efficacy. The predicted cumulative lifetime incidence of invasive cervical cancer in the UK is 1.70% in the absence of screening and 0.77% with pre-2003 screening practice. A reduction in lifetime incidence to 0.63% is predicted following the implementation of the 2003 NHSCSP recommendations, which represents a 63% reduction compared to incidence rates in the UK population if it were unscreened. The model suggests that, after the implementation of the 2003 recommendations, increasing the sensitivity of the screening test regime from its current average value of 56 to 90% would further reduce the cumulative lifetime incidence of invasive cervical cancer to 0.46%. Alternatively, extending screening to women aged 65-79 years would further reduce the lifetime incidence to 0.56%. Screening women aged 20-25 years would have minimal impact, with the cumulative lifetime incidence decreasing from 0.63 to 0.61%. In conclusion, the study supports the 2003 recommendations for changes to cervical screening intervals. [ABSTRACT FROM AUTHOR]

Eclosion rhythm of the high-altitude Himalayan strain of Drosophila ananassae from Badrinath (altitude 5123 m) was temperature-dependent and at 21°C, it was entrained by cycles of 12 h light: 12 h darkness (LD 12:12) and free-ran in constant darkness, however, it was arrhythmic at 13°C or 17°C under identical experimental conditions (Khare, P. V., Barnabas, R. J., Kanojiya, M., Kulkarni, A. D., Joshi, D. S. (2002). Temperature dependent eclosion rhythmicity in the high altitude Himalayan strains of Drosophila ananassae. Chronobiol. Int. 19:1041–1052). The present studies were designed to see whether or not these strains could be entrained at 13°C, 17°C, and 21°C by two types of LD cycles in which the photoperiod at 100 lux intensity varied from 6 h to 18 h, and the light intensity of LD 14:10 cycles varied from 0.001 lux to 1000 lux. All LD cycles entrained this strain at 21°C but not at 13°C or 17°C. These results demonstrate that the entrainment of eclosion rhythm depends on the ambient temperature and not on the photoperiod or light intensity of LD cycles. Thus the temperature has taken precedence over the light in the entrainment process of eclosion rhythm of the high altitude Himalayan strain of D. ananassae. This may be the result of natural selection in response to the environmental temperature at Badrinath that resembles that of the sub-Arctic region but the photoperiod or light intensity are of the subtropical region. [ABSTRACT FROM AUTHOR]

The Psi-mutations affected the circadian rhythm of locomotor activity in the early and late strains of Drosophila rajasekari (Joshi, 1999a). The present study was designed to determine the effects of psi-mutations on the oviposition rhythm of the early and late strains. Oviposition rhythms were studied in light-dark cycles of 12:12h in which the light intensity of photophase was 0.001, 0.1, 1, 10, 100 or 1000 lux. The oviposition rhythm of wild type was unimodal at or above 10 lux with a peak before lights-off, while it was bimodal at lower light intensities. The early strain was unimodal at all light intensities with a peak after lights-on at or above 10 lux, and around the mid-day at or below 1 lux. The late strain was rhythmic at 100 and 1000 lux with a peak after the lights-off, weakly rhythmic at 10 lux and arrhythmic at or below 1 lux. Free running period in constant darkness was shortest in the early and longest in the late strain. Threshold lightntensityof constant lightto generate arrhythmicity was lowest in the early and highest in the late strain, apparently the photic sensitivity of the clock photoreceptors was differentially altered by these mutations. Thus the psi-mutations for locomotor rhythmicity affected the oviposition rhythm too, suggesting that the same circadian oscillator might be controlling these both rhythms. [ABSTRACT FROM AUTHOR]

The circadian pacemaker controlling the eclosion rhythm of the high altitude Himalayan strains of Drosophila ananassae captured at Badrinath (5123 m) required ambient temperature at 21°C for the entrainment and free-running processes. At this temperature, their eclosion rhythms entrained to 12h light, 12h dark (LD 12:12) cycles and free-ran when transferred from constant light (LL) to constant darkness (DD) or upon transfer to constant temperature at 21°C following entrainment to temperature cycles in DD. These strains, however, were arrhythmic at 13 or 17°C under identical experimental conditions. Eclosion medians always occurred in the thermophase of temperature cycles whether they were imposed in LL or DD; or whether the thermophase coincided with the photophase or scotophase of the concurrent LD 12:12 cycles. The temperature dependent rhythmicity in the Himalayan strains of D. ananassae is a rare phenotypic plasticity that might have been acquired through natural selection by accentuating the coupling sensing mechanism of the pacemaker to temperature, while simultaneously suppressing the effects of light on the pacemaker. [ABSTRACT FROM AUTHOR]

Asymptomatic bacterial colonization of the urinary bladder (asymptomatic bacteriuria, ABU) can prevent bladder colonization by uropathogens and thus symptomatic urinary tract infection (UTI). Deliberate bladder colonization with Escherichia coli ABU isolate 83972 has been shown to outcompete uropathogens and prevent symptomatic UTI by bacterial interference. Many ABU isolates evolved from uropathogenic ancestors and, although attenuated, may still be able to express virulence-associated factors. Our aim was to screen for efficient and safe candidate strains that could be used as alternatives to E. coli 83972 for preventive and therapeutic bladder colonization. To identify ABU E. coli strains with minimal virulence potential but maximal interference efficiency, we compared nine ABU isolates from diabetic patients regarding their virulence- and fitness-associated phenotypes in vitro, their virulence in a murine model of sepsis and their genome content. We identified strains in competitive growth experiments, which successfully interfere with colonization of ABU isolate 83972 or uropathogenic E. coli strain 536. Six isolates were able to outcompete E. coli 83972 and two of them also outcompeted UPEC 536 during growth in urine. Superior competitiveness was not simply a result of better growth abilities in urine, but seems also to involve expression of antagonistic factors. Competitiveness in urine did not correlate with the prevalence of determinants coding for adhesins, iron uptake, toxins, and antagonistic factors. Three ABU strains (isolates 61, 106, and 123) with superior competitiveness relative to ABU model strain 83972 display low in vivo virulence in a murine sepsis model, and susceptibility to antibiotics. They belong to different phylogroups and differ in the presence of ExPEC virulence- and fitness-associated genes. Importantly, they all lack marked cytotoxic activity and exhibit a high LD50 value in the sepsis model. These strains represent promising candidates for a more detailed assessment of relevant fitness traits in urine and their suitability for therapeutic bladder colonization.

In the post–communist transitional era, Hungarian elections show diverse results among various areas, raising the question if there are firmly embedded differences between some parts of the country. In the light of the election returns between 1985–2006, it appears that there is a more or less definite pattern. This study will examine the 2006 legislative returns and compare the results with the previous trends and especially the 2002 data, testing the validity of the findings indicating the presence of some fairly constant regional standards of voting. As a main indicator of past trends we use mostly the territorial (party) lists which provide more accurate picture of voting preferences that individual districts which in runoffs carry an indirect distortion of voters’ primary preferences by other considerations.2 For a deeper analysis of the recent 2002 and 2006 elections, we will compare the first run individual district voting outcomes, as they give the more accurate picture of the voters’ real preferences.

Background: Combined antiretroviral therapy (cART) has been associated with significant decrease in the mortality and morbidity in patients with HIV/AIDS. However, there has been increased recognition of immune dysregulation syndromes related to recovery of immunity on cART. HIV-mediated CD8 encephalitis is a rare neurological syndrome due to perivascular inflammation caused by infiltration of CD8+ cells. Methods & Materials: We report the clinical and pathological features of three cases of CD8 encephalitis which will sensitise the clinicians to have high index of suspicion to recognize this entity early. Results: All three patients were men with a mean age of 42.3 years. The mean duration of HIV was 10 years. The patient's mean CD4 at presentation was 392 cells/microL and blood HIV viral load was 11,588.3 copies/ml. All patients presented with an average duration of 4 months with cognitive decline, especially memory disturbances and tremors. The mean cerebrospinal fluid (CSF) cell count was 65 cells/ml, lymphocyte predominant (mean - 97%), and protein was 171.3 mg/dl. The CSF lymphocyte subset analysis showed a median CD8 cell proportion of 54.7%. CSF was tested negative for viral infections (HSV1, HSV2, CMV, JC virus and VZV) and VDRL. The CSF cultures were sterile and GeneXpert was negative. MRI brain revealed diffuse hyper intensities involving the deep grey and white matter and typical perivascular hyperintensities were present in one patient. All patients were started on steroids after excluding other etiologies. Two patients made a complete recovery while one patient in whom the diagnosis was delayed succumbed to the illness. Postmortom brain biopsy of the patient who had a fatal outcome demonstrated perivascular cuffing with lymphocytes positive for CD8 and negative for CD4 and CD20 markers on immunohistochemistry, consistent with CD8 encephalitis. Conclusion: CD8 encephalitis is a rare but potentially treatable cause of cognitive decline in patients with HIV on cART. The typical presentation includes memory impairment with extrapyramidal symptoms like tremors with lymphocytosis in CSF and predominant CD8 cells in CSF. MRI may show the typical perivascular hyperintensities in the deep brain tissue. Aggressive early steroid treatment after excluding opportunistic infections is likely to result in complete recovery. [ABSTRACT FROM AUTHOR]

Abstract Background Only four out of 31 completed randomized controlled trials (RCTs) of HIV prevention strategies against sexual transmission have shown significant efficacy. Poor adherence may have contributed to the lack of effect in some of these trials. In this paper we explore the impact of various levels of adherence on measured efficacy within an RCT. Analysis We used simple quantitative methods to illustrate the impact of various levels of adherence on measured efficacy by assuming a uniform population in terms of sexual behavior and the binomial model for the transmission probability per partnership. At 100% adherence the measured efficacy within an RCT is a reasonable approximation of the true biological efficacy. However, as adherence levels fall, the efficacy measured within a trial substantially under-estimates the true biological efficacy. For example, at 60% adherence, the measured efficacy can be less than half of the true biological efficacy. Conclusion Poor adherence during a trial can substantially reduce the power to detect an effect, and improved methods of achieving and maintaining high adherence within trials are needed. There are currently 12 ongoing HIV prevention trials, all but one of which require ongoing user-adherence. Attention must be given to methods of maximizing adherence when piloting and designing RCTs and HIV prevention programmes.

Abstract Background We assessed the cost-effectiveness of adding a quadrivalent (6/11/16/18) human papillomavirus (HPV) vaccine to the current screening programme in the UK compared to screening alone. Methods A Markov model of the natural history of HPV infection incorporating screening and vaccination was developed. A vaccine that prevents 98% of HPV 6, 11, 16 and 18-associated disease, with a lifetime duration and 85% coverage, in conjunction with current screening was considered. Results Vaccination with screening, compared to screening alone, was associated with an incremental cost-effectiveness ratio of £21,059 per quality adjusted life year (QALY) and £34,687 per life year saved (LYS). More than 400 cases of cervical cancer, 6700 cases of cervical intraepithelial neoplasia and 4750 cases of genital warts could be avoided per 100,000 vaccinated girls. Results were sensitive to assumptions about the need for a booster, the duration of vaccine efficacy and discount rate. Conclusion These analyses suggest that adding a quadrivalent HPV vaccine to current screening in the UK could be a cost-effective method for further reducing the burden of cervical cancer.

Background: REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown.Methods: We randomly assigned, in a 1:1 ratio, participants (≥12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-COV-2 infection (as measured by reverse-transcriptase-quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity).Results: Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P<0.001). In weeks 2 to 4, a total of 2 of 753 participants in the REGEN-COV group (0.3%) and 27 of 752 participants in the placebo group (3.6%) had symptomatic SARS-CoV-2 infection (relative risk reduction, 92.6%). REGEN-COV also prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%). Among symptomatic infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV than with placebo (1.2 weeks and 3.2 weeks, respectively), and the duration of a high viral load (>104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted.Conclusions: Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04452318.). [ABSTRACT FROM AUTHOR]

Purpose: Data on the polar vessel sign (enlarged feeding vessel terminating in parathyroid lesions) on four-dimensional computed tomography (4D-CT) is limited. We performed a retrospective analysis to determine the prevalence, predictors, and adjunctive utility of polar vessel sign in pre-operative 4D-CT of patients with primary hyperparathyroidism (PHPT)., Methods: One radiologist blinded to the patients' details reported the 4D-CT of eighty-four operated patients with histopathology-proven single-gland PHPT. Two protocols were used to obtain arterial-phase images: timed via bolus tracking (n = 41) or fixed at 20 s after contrast injection (n = 43)., Results: Seventy-one patients were symptomatic for PHPT, with median serum calcium 12.1 mg/dL. On the arterial phase of 4D-CT, 88.1% of lesions had the polar vessel sign, including 7/9 asymptomatic patients, 6/6 parathyroid carcinomas, and 3/4 ectopic(1:mediastinum, 2:thyro-thymic ligament). Predictors of polar vessel sign were maximum lesion dimension (2.2 vs. 1.4 cm; P = 0.03), solid-cystic CT morphology (47.3% vs. none; P = 0.004), and bolus tracking-timed arterial phase (55.4% vs. none; P = 0.001). Of these, bolus tracking improved the polar vessel's visualization (100% vs. 76.7%; P = 0.001) independent of lesion dimension and solid-cystic morphology. The latter two predicted polar vessel sign in images obtained at a fixed interval (20 s). A significantly lower proportion of bolus tracking-timed scans had lesion percentage arterial enhancement (PAE) < 128.9% (2/41 vs. 9/43; P = 0.04). Even with suboptimal PAE, the polar vessel helped identify 9/11 lesions., Conclusion: The polar vessel sign demonstrated an additive role to PAE during CT reporting. Bolus tracking is valuable in optimizing vessel and tumor arterial enhancement and is easily incorporated into parathyroid 4D-CT protocol., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To describe the genotype-phenotype characteristics of patients with 21-hydroxylase deficiency from western India and ascertain the prevalence of various phenotypes of 21-hydroxylase deficiency., Methods: Patients with 21-hydroxylase deficiency, diagnosed clinically and biochemically, were prospectively enrolled and classified into salt wasting (SW), simple virilizing (SV), and non-classic (NC) phenotypes and were subjected to genetic testing of CYP21A2 by targeted sequencing and multiplex ligation-dependent probe amplification (MLPA)., Results: Eighty (64; 46, XX) probands with 21-hydroxylase deficiency were analyzed. 41 had SW, 34 had SV, and 5 had NC phenotype. Disease-causing mutations were identified in 158/160 alleles. The common mutations were Deletions/Large Gene Conversions (Del/LGC, 25.6%), p.293-13A/C>G (22.5%), and p.Ile173Asn(18.75%). Exon 6 cluster mutations (Ile236Asn, Val237Glu, Met238Lys) and p.Val282Leu were absent. c.-113G>A+p.Pro31Leu (6.87%) and p.Phe405Ser (2.5%) were rare recurrent mutations with a possible founder effect. Two novel variants (Exon 1, p.Leu49Arg, Exon 8, p.Leu362Ter) were identified and were estimated to have low enzyme activity (<2%)., Conclusion: Del/LGC were the most common mutations identified. The c.-113G>A+p.Pro31Leu and p.Phe405Ser were recurrent variants with possible founder effect. This study also reiterates the low prevalence of NC CAH in Indian cohorts.

Background: The data on Leydig cell hypoplasia (LCH) resulting from biallelic Luteinizing hormone/chorionic gonadotropin receptor (LHCGR) inactivating variants is limited to case series., Methods: We aim to describe our patients and perform systematic review of the patients with LHCGR inactivating variants in the literature. Detailed phenotype and genotype data of three patients from our centre and 85 (46,XY: 67; 46,XX: 18) patients from 59 families with LHCGR-inactivating variants from literature were described., Results: Three 46,XY patients (age 6-18 years) from our center, with two reared as females, had two novel variants in LHCGR. Systematic review (including our patients) revealed 72 variants in 88 patients. 46,XY patients (n = 70, 56 raised as females) presented with pubertal delay (n = 41) or atypical genitalia (n = 17). Sinnecker score ≥3 (suggesting antenatal human chorionic gonadotropin (hCG) inaction) was seen in 80% (56/70), and hCG-stimulated testosterone was low (<1.1 ng/mL) in 77.4% (24/31), whereas puberty/postpubertal age, high luteinizing hormone (LH) (97.6%, 41/42) and low (<1.0 ng/mL) basal testosterone (94.9%, 37/39) was observed in most. Follicle stimulating hormone was elevated in 21/51 of these patients. Variants with <10% receptor function were exclusively seen in cohorts with Sinnecker 4/5 (10/15 vs 0/5, P = 0.033). 46,XX patients (n = 18) presented with oligo/amenorrhea and/or anovulatory infertility and had polycystic ovaries (7/9) with median LH of 10 IU/L (1.2-38)., Conclusion: In summary, this study comprehensively characterizes LHCGR variants, revealing genotype-phenotype correlations and informing clinical management of LCH. In 46,XY LCH patients, pubertal LH inaction is uniform with variable severity of antenatal hCG inaction. Few mutant LHCGR have differential actions for LH and hCG.

Introduction: Pituitary apoplexy (PA) is a rare clinical syndrome due to acute/subacute pituitary hemorrhage and/or infarction; data on PA in functioning pituitary adenoma (FPA) is scarce., Methods: A retrospective record-review of details of PA in non-functioning (NFPA) and FPA managed at tertiary endocrine center., Results: 93 patients [56 males; 33.3% FPA: 5 acromegaly, 14 prolactinoma, and 12 Cushing's Disease (CD)] diagnosed with PA were included. Median age was 40 years, with younger age of presentation in FPA. Type A (acute) [49.5%] and headache (78.5%) were the commonest presentations, with PA being the initial manifestation in 98.4% of NFPA. Median (range) Pituitary Apoplexy Score (PAS) was 2 (0-8). Median tumor diameter was 2.5 cm, with larger tumors in FPA (3.2 cm vs. 2.3 cm). 29 (46.7%) NFPA-PA and 14 (45.2%) FPA-PA patients [71% prolactinoma, 33% in CD, and none in acromegaly] were conservatively managed. In the NFPA cohort, those managed surgically had significantly higher PAS (4 vs. 1) and larger tumor size (2.6 vs. 1.8 cm); however, both arms had comparable recovery of neuro-visual, radiological, and hormonal outcomes. In FPA cohort, CD and acromegaly required definitive treatment, whereas prolactinomas were effectively managed (clinical and biochemical recovery) with oral cabergoline and glucocorticoids. Matching PAS cohorts (to overcome allocation bias for management approach) in macroadenomas (excluding prolactinoma) showed comparable neuro-deficit and hormonal recovery between surgical and conservative approaches., Conclusion: PA in FPA has distinct features and management issues. Carefully selected patients (PAS guided) in NFPA with PA for conservative management have comparable outcomes to surgery., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Data on radiofrequency ablation (RFA) in tumor-induced osteomalacia (TIO) are restricted to case reports (~ 11 patients) and long-term follow-up data are further scarce. We describe our experience on managing TIO from a tertiary care center in India. Retrospective study of patients with localized TIO was performed and clinical, biochemical, treatment and follow-up details were retrieved. Normalization of serum phosphorus in absence of phosphate supplementation was defined as remission. Of 33 patients (23 males), 24 patients underwent surgery as first-line treatment, and early remission, delayed remission (> 1 month for phosphorus normalization) and persistence were observed 12, 3, and 9 patients at a median follow-up of 5 (4-9) years. The gender, age, tumor size, location of tumors and FGF23 levels were not statistically different in patients who were in remission after surgery versus those with persistent disease. Second/third line treatment included conventional medical treatment and/or repeat surgery (n = 3), radiotherapy (n = 3), peptide receptor radionuclide therapy (n = 1), RFA (n = 1). Two patients had transient worsening (weeks) of weakness post-surgery. 10 patients underwent RFA (first-line n = 9); at the last follow-up 5 (4-10) years, 7 are in remission. Two of three persistent disease patients had large tumors (5.6 and 3.6 cm). There were no RFA-related complications except local ulcer in one. Although persistent disease was present in a few patients in both arms, there was no recurrence in either RFA or surgical cohort. RFA provide durable response similar to surgery, persistence requires multi-modality treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To elucidate the role of various imaging modalities for tumor localization in ectopic ACTH Cushing's syndrome (EAS)., Design and Method: Systematic review of the literature published between January 2015-2024 was performed. Patients (290 EAS patients, 23.8% Occult) who underwent contrast enhanced CT (CECT) and at least one PET/CT-scan ( 68 Ga-SSTR, FDG and/or F-DOPA) were included., Results: The sensitivity for identifying EAS tumor was comparable across CECT (63.1%, n=290), SSTR-PET/CT (58.2%, n=187), and FDG-PET/CT (57.6%, n=191), but was poor for DOPA-PET/CT (30.8%, n=26). Sensitivity for detecting metastasis was also comparable across CECT (78%, n=73), SSTR-PET/CT (85.3%, n=41), and FDG-PET (73.7%, n=38). For localised lesions, sensitivity as per etiology and grade of NET were similar for three scans, with exception of Thymic NET and grade 1 NET where CECT was better than FDG PET/CT. In patients not localised on CECT, sensitivity of SSTR PET/CT was 33.3% (vs. 18.9% FDG-PET/CT) whereas for patients negative on CECT and FDG-PET, sensitivity of SSTR-PET/CT was 15%. In cases where CECT and SSTR-PET/CT failed to localize, the sensitivities of FDG-PET/CT and DOPA-PET/CT were only 5.7% (2/35) and 0% (0/9), respectively. SSTR-PET/CT has a distinct advantage with significantly lesser false positive (FP) lesions (2.6%, mostly in thyroid/or pancreas). In comparison, CECT and FDG-PET/CT had FP ∼11% (mostly in lung and/or mediastinum), most of which were negative on SSTR-PET/CT., Conclusions: As per the current evidence, SSTR-PET/CT can be considered as the scan of choice in EAS evaluation, and further research is needed as one-fourth of the lesions remain occult., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction: Pituitary apoplexy (PA) in Cushing's disease (CD) is rare with data limited to case reports/series., Methods: We retrospectively reviewed case records of PA in CD managed at our center from 1987 to 2023 and performed a systematic literature review., Results: We identified 58 patients (44 females), including twelve from our center (12/315 CD, yielding a PA prevalence in CD of 3.8%) and forty six from systematic review. The median age at PA diagnosis was 35 years. The most common presentation was type A (79.3%) and symptom was headache (89.6%), with a median Pituitary Apoplexy Score (PAS) of 2. Median cortisol and ACTH levels were 24.9 µg/dl and 94.1 pg/ml, respectively. Apoplexy was the first manifestation of underlying CD in 55.2% of cases, with 31.1% (14/45) presenting with hypocortisolemia (serum cortisol ≤ 5.0 µg/dl), underscoring the importance of recognizing clinical signs/symptoms of hypercortisolism. The median largest tumor dimension was 1.7 cm (53/58 were macroadenomas). PA was managed surgically in 57.8% of cases, with the remainder conservatively managed. All five PA cases in CD with microadenoma achieved remission through conservative management, though two later relapsed. Among treatment-naïve CD patients with macroadenoma, PA-related neuro-deficit improvement was comparable between surgical and conservative groups. However, a greater proportion of surgically managed patients remained in remission longer (70% vs. 38.5%; p = 0.07), for an average of 31 vs. 10.5 months., Conclusion: PA in CD is more commonly associated with macroadenomas, may present with hypocortisolemia, and surgical treatment tends towards higher and longer-lasting remission rates., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Healthcare-associated infections (HAI) and antimicrobial use (AMU) are drivers for antimicrobial resistance, and robust data are required to inform interventions and track changes. We aimed to estimate the prevalence of HAI and AMU at Port Moresby General Hospital (PMGH), the largest hospital in Papua New Guinea., Methods: We did a point prevalence survey (PPS) on HAI and AMU at PMGH in May 2023 using the European Centre for Disease Prevention and Control (ECDC) PPS protocol. We included all critical care patients and randomly sampled half of the patients in other acute-care wards. We calculated weighted HAI and AMU prevalence estimates to account for this sampling strategy. Weighted HAI estimates were also calculated for an expanded definition that included physician diagnosis., Findings: Of 361 patients surveyed in 18 wards, the ECDC protocol identified 28 HAIs in 26 patients, resulting in a weighted HAI prevalence of 6.7% (95% CI: 4.6, 9.8). Surgical site infections (9/28, 32%) were the most common HAI. When adding physician diagnosis to the ECDC definitions, more skin and soft tissue, respiratory, and bloodstream HAIs were detected, and the weighted HAI prevalence was 12.4% (95% CI: 9.4, 16.3). The prevalence of AMU was 66.5% (95%CI: 61.3, 71.2), and 73.2% (263/359) of antibiotics were from the World Health Organization Access group., Interpretation: This is the first reported hospital PPS of HAI and AMU in Papua New Guinea. These results can be used to prioritise interventions, and as a baseline against which future point prevalence surveys can be compared., Funding: Australian Government Department of Foreign Affairs and Trade and Therapeutic Guidelines Limited Australia., Competing Interests: There are none to declare relevant to this work. TP is the recipient of a Medical Research Future Fund grant [GNT2014635] and is a Board Director for the Australasian Clinical Trial Alliance. KC receives royalties from UpToDate as co-author of chapter “Daptomycin: An overview”, and their workplace has been paid Honoraria for presentations., (© 2024 The Author(s).)

Understanding the levels of power that adolescent girls and young women exercise in their sexual and reproductive lives is imperative to inform interventions to help them meet their goals. We implemented an adapted version of the Sexual and Reproductive Health Empowerment (SRE) Scale for Adolescents and Young Adults among 500 adolescent girls and young women aged 15-20 in Kisumu, Kenya. We used confirmatory factor analysis (CFA) to assess factor structure, and logistic regression to examine construct validity through the relationship between empowerment scores and ability to mitigate risk of undesired pregnancy through consistent contraceptive use. Participants had a mean age of 17.5, and most were students (61 percent), were currently partnered (94 percent), and reported having sex in the past 3 months (70 percent). The final, 26-item CFA model had acceptable fit. All subscales had Cronbach's alpha scores >0.7, and all items had rotated factor loadings >0.5, indicating good internal consistency and robust factor-variable associations. The total SRE-Kenya (SRE-K) score was associated with increased odds of the consistent method used in the past three months (adjusted odds ratio: 1.98, 95 percent CI: 1.29-3.10). The SRE-K scale is a newly adapted and valid measure of sexual and reproductive empowerment specific to adolescent girls and young women in an East African setting., (© 2024 The Population Council, Inc.)

Burosumab, a monoclonal antibody directed against the fibroblast growth factor 23 (FGF23), has been approved for the treatment of X-linked hypophosphatemia (XLH). We conducted a systematic review to compare the efficacy and safety of burosumab versus conventional therapy (phosphorus and calcitriol) on XLH treatment. After a comprehensive literature search on MEDLINE/PubMed and Embase, we found nine studies for inclusion in the analysis. Risk of bias was assessed, and a random-effects model was used to determine the effect size. Clinical, biochemical, and radiological parameters of disease severity before and after treatment were analyzed and expressed in standardized mean difference (SMD). Burosumab resulted in normalization of phosphate homeostasis with an increase in renal tubular phosphate reabsorption and significant resolution of skeletal lesions (change in Thacher's total rickets severity score SMD: -1.46, 95% confidence interval [CI]: -1.76 to -1.17, p < 0.001, improvement in deformities, and decline in serum alkaline phosphatase levels [SMD: 130.68, 95% CI: 125.26-136.1, p < 0.001)]. Conventional therapy led to similar improvements in all these parameters but to a lower degree. In adults, burosumab normalized phosphorus levels (SMD: 1.23, 95% CI: 0.98-1.47, p < 0.001) with resultant clinical improvement. Burosumab treatment was well tolerated, with only mild treatment-related adverse effects. The present review indicates a potential role for burosumab in improving rickets, deformities, and growth in children with XLH. Given its superior efficacy and safety profile, burosumab could be an effective therapeutic option in children. We suggest further studies comparing burosumab versus conventional therapy in children and adults with XLH.

Introduction: In 2018, the Mozambique Ministry of Health launched guidelines for implementing differentiated service delivery models (DSDMs) to optimize HIV service delivery, improve retention in care, and ultimately reduce HIV-associated mortality. The models were fast-track, 3-month antiretrovirals dispensing, community antiretroviral therapy groups, adherence clubs, family approach and three one-stop shop models: adolescent-friendly health services, maternal and child health, and tuberculosis. We conducted a cost-effectiveness analysis and budget impact analysis to compare these models to conventional services., Methods: We constructed a decision tree model based on the percentage of enrolment in each model and the probability of the outcome (12-month retention in treatment) for each year of the study period-three for the cost-effectiveness analysis (2019-2021) and three for the budget impact analysis (2022-2024). Costs for these analyses were primarily estimated per client-year from the health system perspective. A secondary cost-effectiveness analysis was conducted from the societal perspective. Budget impact analysis costs included antiretrovirals, laboratory tests and service provision interactions. Cost-effectiveness analysis additionally included start-up, training and clients' opportunity costs. Effectiveness was estimated using an uncontrolled interrupted time series analysis comparing the outcome before and after the implementation of the differentiated models. A one-way sensitivity analysis was conducted to identify drivers of uncertainty., Results: After implementation of the DSDMs, there was a mean increase of 14.9 percentage points (95% CI: 12.2, 17.8) in 12-month retention, from 47.6% (95% CI, 44.9-50.2) to 62.5% (95% CI, 60.9-64.1). The mean cost difference comparing DSDMs and conventional care was US$ -6 million (173,391,277 vs. 179,461,668) and -32.5 million (394,705,618 vs. 433,232,289) from the health system and the societal perspective, respectively. Therefore, DSDMs dominated conventional care. Results were most sensitive to conventional care interaction costs in the one-way sensitivity analysis. For a population of 1.5 million, the base-case 3-year financial costs associated with the DSDMs was US$550 million, compared with US$564 million for conventional care., Conclusions: DSDMs were less expensive and more effective in retaining clients 12 months after antiretroviral therapy initiation and were estimated to save approximately US$14 million for the health system from 2022 to 2024., (© 2024 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background: Identifying spatial variation in TB burden can help national TB programs effectively allocate resources to reach and treat all people with TB. However, data limitations pose challenges for subnational TB burden estimation., Methods: We developed a small-area modeling approach using geo-positioned prevalence survey data, case notifications, and geospatial covariates to simultaneously estimate spatial variation in TB incidence and case notification completeness across districts in Uganda from 2016-2019. TB incidence was estimated using 1) cluster-level data from the national 2014-2015 TB prevalence survey transformed to incidence, and 2) case notifications adjusted for geospatial covariates of health system access. The case notification completeness surface was fit jointly using observed case notifications and estimated incidence., Results: Estimated pulmonary TB incidence among adults varied >10-fold across Ugandan districts in 2019. Case detection increased nationwide from 2016 to 2019, and the number of districts with case detection rates >70% quadrupled. District-level estimates of TB incidence were five times more precise than a model using TB prevalence survey data alone., Conclusion: A joint spatial modeling approach provides useful insights for TB program operation, outlining areas where TB incidence estimates are highest and health programs should concentrate their efforts. This approach can be applied in many countries with high TB burden., (© 2024 The Authors.)

Objectives: This study systematically reviewed the published literature from clinical trials on the efficacy and immunogenicity of single-dose HPV vaccination compared to multidose schedules or no HPV vaccination., Methods: Four databases were searched for relevant articles published from Jan-1999 to Feb-2023. Articles were assessed for eligibility for inclusion using pre-defined criteria. Relevant data were extracted from eligible articles and a descriptive quality assessment was performed for each study. A narrative data synthesis was conducted, examining HPV infection, other clinical outcomes and immunogenicity responses by dose schedule., Results: Fifteen articles reporting data from six studies (all in healthy young females) were included. One article was included from each of three studies that prospectively randomised participants to receive a single HPV vaccine dose versus one or more comparator schedule(s). The other 12 articles reported data from three studies that randomised participants to receive multidose HPV vaccine (or control vaccine) schedules; in those studies, some participants failed to complete their allocated schedule, and evaluations were conducted to compare participants who actually received one, two or three doses. Across all efficacy studies, the incidence or prevalence of HPV16/18 infection was very low among HPV-vaccinated participants, regardless of the number of doses received; with no evidence for a difference between dose groups. In immunogenicity studies, HPV16/18 antibody seropositivity rates were high among all HPV-vaccinated participants. Antibody levels were significantly lower with one dose compared to two or three doses, but levels with one dose were stable and sustained to 11 years post-vaccination., Conclusions: Results from this review support recent World Health Organization recommendations allowing either one- or two-dose HPV vaccination in healthy young females. Longer-term efficacy and immunogenicity data from ongoing studies are awaited. Randomised trials of single-dose HPV-vaccination are urgently needed in other populations, e.g. boys, older females and people with HIV., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DWJ has received research funding and HPV vaccine donations from MSD and GlaxoSmithKline Biologicals. Regeneron Pharmaceuticals covered RVB’s cost of conference abstract and manuscript writing, outside the submitted work. RVB serves on a Gilead Sciences DMC, for which she is paid an honorarium. HSW, ARK, PB, RB and DWJ are investigators in ongoing studies and clinical trials evaluating the efficacy and/or immunogenicity of single- dose HPV vaccination: the IARC India vaccine trial (PB), CVT (ARK), the DoRIS trial (DWJ, HSW), the ESCUDDO trial (ARK), the Primavera trial (ARK), the KEN-SHE trial (RVB) and the Add-Vacc trial (DWJ, HSW). HSW, SMJ, ARK, PB, RVB, MD, MB and DWJ are members of the PATH-convened Single-Dose HPV Vaccine Evaluation Consortium. SMJ is funded by the National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Vaccines and Immunization (NIHR200929)., (© 2024 The Authors.)

Background: Aromatase deficiency is a rare disorder, with only a few cases reported in India. We describe a single-center experience in western India, with a systematic review of genetically proven 46,XX aromatase deficiency patients to evaluate hormonal parameters., Methods: Retrospective review of case records, collating phenotypic and genotypic data and molecular modeling. Systematic review of 46,XX aromatase deficiency, analyzing data on gonadotropins, estrogen and androgens., Results: In the seven patients from our center, presentation was frequent in childhood or adolescence (4/7: delayed puberty or hyperandrogenism), with maternal virilization (4/7), predominance of Prader III/IV (5/7), and initial rearing as females (6/7). Three patients had hypoplastic ovaries. One patient had spontaneous regular menses. We report three novel (p.Arg115Pro, p.Arg192Pro, and c.145+1&#95;145+4delins) and two recurrent variants (p.Val370Met, and c.145+1&#95;145+4delins) in western and northern India, respectively. On systematic review (n=43), gonadotropins were elevated (FSH>LH) across ages (except preterm infants), androgens were elevated in about one-third of cases during childhood and puberty, and estradiol was lower than in controls in mini-puberty and puberty. Spontaneous thelarche and streak ovaries were significantly more frequent in patients with non-truncating and truncating variants, respectively., Conclusion: We report uncommon presentations with possible founder variants, and highlight hormonal parameters across ages. Serum FSH levels were elevated except in preterms, and can be used as a diagnostic marker., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Introduction: Significant progress has been made in the HIV response in South Africa; however, gaps remain in ensuring engagement in care to support life-long medication adherence and viral suppression. The National Department of Health (NDoH) has introduced community-based and clinic-based HIV differentiated service delivery (DSD) models to tackle suboptimal adherence and retention in care. Nevertheless, differentiated care models require adaptation to better serve clients who struggle with adherence. There is limited research on the acceptability of fee for home delivery of ART in resource-constrained settings. The current study investigates the acceptability of fee for home delivery of ART among people living with HIV in South Africa., Methods: Two mixed-gender focus group discussions (FGDs) took place between June and November 2019, consisting of 10 participants in each group. A purposive sampling strategy was employed to identify and select 10 people living with HIV who were ART-eligible but not in care, and 10 people living with HIV who were currently taking ART and in care. Participants were grouped according to their treatment status. A coding framework, informed by a priori categories and derived from topics in the interview guide, was developed and utilized to facilitate analysis., Results: Participants expressed enthusiasm for having ART home-delivered, as it would save the time spent waiting in long queues at the clinic. However, some participants raised concerns about potential payment difficulties due to high unemployment rates in the community. Some participants believed this would be acceptable, as patients already incur costs for travel and food when visiting the clinic. Participants in both FGDs expressed strong concerns about home delivery of their ART based on fear of accidental disclosure, especially for those who have not disclosed to their immediate families and partners., Conclusion: Our study suggests that charging a fee for home delivery is an acceptable and innovative approach to supporting PLHIV in maintaining adherence to their medication and remaining in care., (© 2024. The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a global pandemic of coronavirus disease 2019 (COVID-19). Early in the pandemic, efforts were made to test the SARS-CoV-2 antiviral efficacy of repurposed medications that were already approved and available for other indications, including hydroxychloroquine (HCQ) and azithromycin (AZI). To reduce the risk of SARS-CoV-2 exposure for clinical-trial study participants and to conform with lockdowns and social distancing guidelines, biospecimen collection for HCQ and AZI included at-home dried blood spot (DBS) collection rather than standard venipuncture by trained clinicians. In this study, we developed and validated the first sensitive and selective simultaneous LC-MS/MS method to accurately quantitate the concentration of HCQ, HCQ metabolites (Desethylchloroquine [DCQ], Bisdesethylchloroquine [BDCQ], Monodesethylhydroxychloroquine [DHCQ]) and AZI extracted from DBS. The validated method was successfully applied for the quantification of over 2000 DBS specimens to evaluate the pharmacokinetic profile of AZI, HQC, and its metabolites. This new method has a small sample volume requirement (~ 10 µL), results in high sensitivity (1 ng/mL), and would facilitate remotely conducted therapeutic drug monitoring., (© 2023. Springer Nature Limited.)

Minimally invasive parathyroidectomy (MIP) is the standard of care for primary hyperparathyroidism (PHPT). Four dimensional computed tomography(4DCT) and F-18 Fluorocholine positron emission tomography/computed tomography (FCH PET/CT) localize adenomas accurately to perform MIP. We aimed to conduct a systematic review and metanalysis to evaluate the diagnostic performance of 4DCT and FCH PET/CT scan for quadrant wise localisation in PHPT patients and to do head-to-head comparison between these two modalities. DESIGN, PATIENTS AND MEASUREMENT : After searching through PubMed and EMBASE databases, 46 studies (using histology as a gold standard) of 4DCT and FCH PET/CT were included. RESULTS: Total number of patients included were 1651 and 952 for 4DCT scan (studies n = 26) and FCH PET/CT scan (studies n = 24) respectively. In per patient analysis, FCH PET/CT and 4DCT had pooled sensitivities of 92% (88-94) and 85% (73-92) respectively and in per lesion analysis, 90% (86-93) and 79% (71-84), respectively. In the subgroup with negative conventional imaging/persistent PHPT, FCH PET/CT had comparable sensitivity to 4DCT (84% [74-90] vs. 72% [46-88]). As per patient wise analysis, FCH PET/CT had better detection rates than 4DCT ([92.4 vs. 76.85], odds ratio -3.89 [1.6-9.36] p = .0024) in the subpopulation where both FCH PET/CT and 4DCT were reported. CONCLUSION: Both 4DCT and FCH PET/CT scan performed well in newly diagnosed patients, patients with persistent disease and in those with inconclusive conventional imaging results. FCH PET/CT scan had a higher pooled sensitivity than 4DCT in detecting patients with PHPT in head to head comparison., (© 2023 John Wiley & Sons Ltd.)

The burden of cervical cancer is disproportionately distributed globally, with the vast majority of cases occurring in low- and middle-income countries. Women with human immunodeficiency virus (HIV) (WWH) are at increased risk of human papillomavirus (HPV) infection and cervical cancer as compared to HIV-negative individuals. HPV vaccination remains a priority in regions with a high burden of cervical cancer and high HIV prevalence. With HPV vaccines becoming more accessible, optimal use beyond the initial World Health Organization-recommended target population of 9 to 14-year-old girls is an important question. In March 2022, a group of experts in epidemiology, immunology, and vaccinology convened to discuss the state-of-the-science of HPV vaccination in WWH. This report summarizes the proceedings: review of HIV epidemiology and its intersection with cervical cancer burden, immunology, HPV vaccination including reduced-dose schedules and experience with other vaccines in people with HIV (PWH), HPV vaccination strategies and knowledge gaps, and outstanding research questions. Studies of HPV vaccine effectiveness among WWH, including duration of protection, are limited. Until data from ongoing research is available, the current recommendation for WWH remains for a multi-dose HPV vaccination regimen. A focus of the discussion included the potential impact of HIV acquisition following HPV vaccination. With no data currently existing for HPV vaccines and limited information from non-HPV vaccines, this question requires further research. Implementation research on optimal HPV vaccine delivery approaches for WWH and other priority populations is also urgently needed., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AMD reports participation in advisory boards for Sanofi, Bioaster, Speranza and ACM Biolabs, and research grants from GlaxoSmithKline, Moderna, and Roche, outside the submitted work. ABM reports personal fees from Merck & Co. global advisory board honorarium, outside the submitted work. GL is an employee of Merck & Co. NM is a recipient of an Investigator Initiated Grant evaluating ‘Immunogenicity of HPV vaccine among HIV infected adolescents’, outside the submitted work. JMP reports grants and personal fees from Merck & Co., from Vir Biotechnologies, from Antiva Biosciences, from Roche Diagnostics, and other from Virion Therapeutics, outside the submitted work. JS reports participation to DSMB for NCT04508309 and the India/IARC Gardasil trial. SAM reports grants from Bill & Melinda Gates Foundation, Pfizer, GlaxoSmithKline, Minervax and Sanofi, outside the submitted work. SP reports personal fees from Merck & Co. global advisory board honorarium, and personal fees from Sanofi, Inovio, Merck & Co., Janssen, Moderna, Valneva, Codagenix, Pfizer, VaxArt, Meissa, Vaxinnity, Rational, and AstraZeneca, outside the submitted work. RB reports grants from National Institutes of Health and Bill & Melinda Gates Foundation and non-financial support from Regeneron Pharmaceutical, outside the submitted work. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Introduction: Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) in the HPTN 083/084 trials. We compared the potential impact of expanding PrEP coverage by offering CAB-LA to men who have sex with men (MSM) in Atlanta (US), Montreal (Canada) and the Netherlands, settings with different HIV epidemics., Methods: Three risk-stratified HIV transmission models were independently parameterized and calibrated to local data. In Atlanta, Montreal and the Netherlands, the models, respectively, estimated mean TDF/FTC coverage starting at 29%, 7% and 4% in 2022, and projected HIV incidence per 100 person-years (PY), respectively, decreasing from 2.06 to 1.62, 0.08 to 0.03 and 0.07 to 0.001 by 2042. Expansion of PrEP coverage was simulated by recruiting new CAB-LA users and by switching different proportions of TDF/FTC users to CAB-LA. Population effectiveness and efficiency of PrEP expansions were evaluated over 20 years in comparison to baseline scenarios with TDF/FTC only., Results: Increasing PrEP coverage by 11 percentage points (pp) from 29% to 40% by 2032 was expected to avert a median 36% of new HIV acquisitions in Atlanta. Substantially larger increases (by 33 or 26 pp) in PrEP coverage (to 40% or 30%) were needed to achieve comparable reductions in Montreal and the Netherlands, respectively. A median 17 additional PYs on PrEP were needed to prevent one acquisition in Atlanta with 40% PrEP coverage, compared to 1000+ in Montreal and 4000+ in the Netherlands. Reaching 50% PrEP coverage by 2032 by recruiting CAB-LA users among PrEP-eligible MSM could avert >45% of new HIV acquisitions in all settings. Achieving targeted coverage 5 years earlier increased the impact by 5-10 pp. In the Atlanta model, PrEP expansions achieving 40% and 50% coverage reduced differences in PrEP access between PrEP-indicated White and Black MSM from 23 to 9 pp and 4 pp, respectively., Conclusions: Achieving high PrEP coverage by offering CAB-LA can impact the HIV epidemic substantially if rolled out without delays. These PrEP expansions may be efficient in settings with high HIV incidence (like Atlanta) but not in settings with low HIV incidence (like Montreal and the Netherlands)., (© 2023 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Context: Selective deficiency of β-subunit of luteinizing hormone (LHB) is a rare disease with scarce data on its characteristics., Objectives: To describe a male with LHB deficiency and systematically review the literature., Design and Patients: Description of a male patient with LHB deficiency and a systematic review of LHB deficiency patients published to date (10 males and 3 females) as per PRISMA guidelines., Results: A 36-year-old Asian Indian male presented with infertility. On evaluation, he had sexual maturity of Tanner's stage 3, low testosterone (0.23 ng/ml), low LH (0.44 mIU/ml), high follicle-stimulating hormone (FSH, 22.4 mIU/ml), and a novel homozygous missense likely pathogenic variant (p.Cys46Arg) in LHB. In the molecular dynamics simulation study, this variant interferes with heterodimerization of alpha-beta subunits. Eleven males with pathogenic variants in LHB reported to date, presented at a median age of 29 (17-38) years, most commonly with delayed puberty. Clinical and biochemical profiles were similar to those of our patient. In the majority, testosterone monotherapy modestly increased testicular volume whereas human chorionic gonadotropin (hCG) monotherapy also improved spermatogenesis. In females, oligomenorrhoea after spontaneous menarche was the most common manifestation. Ten pathogenic/likely pathogenic variants (three in-frame deletions, three missense, two splice-site, one nonsense, and one frameshift variants) have been reported in nine index patients., Conclusion: We report a novel likely pathogenic LHB variant in an Asian Indian patient. The typical phenotype in male patients with LHB deficiency is delayed puberty with low testosterone, low LH, and normal to high FSH and hCG monotherapy being the best therapeutic option., (© 2022 John Wiley & Sons Ltd.)

Background: Of the 8 million people in South Africa living with HIV, 74% of persons living with HIV are on antiretroviral therapy (ART) and 65% are virally suppressed. Detectable viral load results in HIV-associated morbidity and mortality and HIV transmission. Patient barriers to care, such as missed wages, transport costs, and long wait times for clinic visits and ART refills, are associated with detectable viral load. HIV differentiated service delivery (DSD) has simplified ART delivery for clients who achieve viral suppression and engage in care. However, DSD needs adaptation to serve clients who are not engaged in care., Methods: A Sequential Multiple Assignment Randomized Trial will be undertaken in KwaZulu-Natal, South Africa, to test adaptive ART delivery for persons with detectable viral load and/or who are not engaged in care. The types of differentiated service delivery (DSD) which will be examined in this study are clinic-based incentives, community-based smart lockers, and home delivery. The study plans to enroll up to 900 participants-people living with HIV, eligible for ART, and who are not engaged in care. The study aims to assess the proportion of ART-eligible persons living with HIV who achieve viral suppression at 18 months. The study will also evaluate the preferences of clients and providers for differentiated service delivery and evaluate the cost-effectiveness of adaptive HIV treatment for those who are not engaged in care., Discussion: To increase population-level viral suppression, persons with detectable viral load need responsive DSD interventions. A Sequential Multiple Assignment Randomized Trial (SMART) design facilitates the evaluation of a stepped, adaptive approach to achieving viral suppression with "right-sized" interventions for patients most in need of effective and efficient HIV care delivery strategies., Trial Registration: ClinicalTrials.gov NCT05090150. Registered on October 22, 2021., (© 2023. The Author(s).)

Background: HIV testing rates in sub-Saharan Africa remain below the targeted threshold, and primary care facilities struggle to provide adequate services. Innovative approaches that leverage digital technologies could improve HIV testing and access to treatment., Objective: This study aimed to examine the feasibility and acceptability of Nolwazi&#95;bot. It is an isiZulu-speaking conversational agent designed to support HIV self-testing (HIVST) in KwaZulu-Natal, South Africa., Methods: Nolwazi&#95;bot was designed with 4 different personalities that users could choose when selecting a counselor for their HIVST session. We recruited a convenience sample of 120 consenting adults and invited them to undertake an HIV self-test facilitated by the Nolwazi&#95;bot. After testing, participants completed an interviewer-led posttest structured survey to assess their experience with the chatbot-supported HIVST., Results: Participants (N=120) ranged in age from 18 to 47 years, with half of them being men (61/120, 50.8%). Of the 120 participants, 111 (92.5%) had tested with a human counselor more than once. Of the 120 participants, 45 (37.5%) chose to be counseled by the female Nolwazi&#95;bot personality aged between 18 and 25 years. Approximately one-fifth (21/120, 17.5%) of the participants who underwent an HIV self-test guided by the chatbot tested positive. Most participants (95/120, 79.2%) indicated that their HIV testing experience with a chatbot was much better than that with a human counselor. Many participants (93/120, 77.5%) reported that they felt as if they were talking to a real person, stating that the response tone and word choice of Nolwazi&#95;bot reminded them of how they speak in daily conversations., Conclusions: The study provides insights into the potential of digital technology interventions to support HIVST in low-income and middle-income countries. Although we wait to see the full benefits of mobile health, technological interventions including conversational agents or chatbots provide us with an excellent opportunity to improve HIVST by addressing the barriers associated with clinic-based HIV testing., (©Xolani Ntinga, Franco Musiello, Alfred Kipyegon Keter, Ruanne Barnabas, Alastair van Heerden. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 12.12.2022.)

Background: Community health workers (CHWs) are essential field-based personnel and increasingly used to deliver priority interventions to achieve universal health coverage. Existing literature allude to the potential for detrimental effects of multi-tasking CHWs. This study objective was to assess the impact of integrating cervical cancer screening and prevention therapy (CCSPT) with family planning (FP) on time utilization among CHWs., Methods: A time and motion study was conducted in 7 health facilities in Malawi. Data was collected at baseline between October-July 2019, and 12 months after CCSPT implementation between July and August 2021. CHWs trained to deliver CCSPT were continuously observed in real time while their activities were timed by independent observers. We used paired sample t-test to assess pre-post differences in average hours CHWs spent on the following key activities, before and after CCSPT implementation: clinical and preventive care; administration; FP; and non-work-related tasks. Regression models were used to ascertain impact of CCSPT on average durations CHWs spent on key activities., Results: Thirty-seven (n = 37) CHWs were observed. Their mean age and years of experience were 42 and 17, respectively. Overall, CHWs were observed for 323 hours (inter quartile range: 2.8-5.5). Compared with the period before CCSPT, the proportion of hours CHWs spent on clinical and preventive care, administration and non-work-related activities were reduced by 13.7, 8.7 and 34.6%, respectively. CHWs spent 75% more time on FP services after CCSPT integration relative to the period before CCSPT. The provision of CCSPT resulted in less time that CHWs devoted towards clinical and preventive care but this reduction was not significant. Following CCPST, CHWs spent significantly few hours on non-work-related activities., Conclusion: Introduction of CCSPT was not very detrimental to pre-existing community services. CHWs managed their time ensuring additional efforts required for CCSPT were not at the expense of essential activities. The programming and policy implications are that multi-tasking CHWs with CCSPT will not have substantial opportunity costs., (© 2022. The Author(s).)

While detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by diagnostic reverse-transcription polymerase chain reaction (RT-PCR) is highly sensitive for viral RNA, the nucleic acid amplification of subgenomic RNAs (sgRNAs) that are the product of viral replication may more accurately identify replication. We characterized the diagnostic RNA and sgRNA detection by RT-PCR from nasal swab samples collected daily by participants in postexposure prophylaxis or treatment studies for SARS-CoV-2. Among 1932 RT-PCR-positive swab samples with sgRNA tests, 40% (767) had detectable sgRNA. Above a diagnostic RNA viral load (VL) threshold of 5.1 log10 copies/mL, 96% of samples had detectable sgRNA with VLs that followed a linear trend. The trajectories of diagnostic RNA and sgRNA VLs differed, with 80% peaking on the same day but duration of sgRNA detection being shorter (8 vs 14 days). With a large sample of daily swab samples we provide comparative sgRNA kinetics and a diagnostic RNA threshold that correlates with replicating virus independent of symptoms or duration of illness., Competing Interests: Potential conflicts of interest. M. E. D. is funded by the Infectious Diseases Clinical Research Consortium through the National Institute for Allergy and Infectious Diseases, National Institutes of Health (NIH; award UM1AI148684), outside the submitted work. M. L. W. H. and M. H. W. report funding from the BMGF, outside the submitted work. A. B. reports personal fees from Gates Ventures and grant funding from the NIH, the BMGF, and the New York City Department of Health and Mental Hygiene, outside the submitted work. H. Y. C. reports consulting with Ellume, Pfizer, the BMGF, GlaxoSmithKline, and Merck; she has also received research funding from Gates Ventures and Sanofi Pasteur and support and reagents from Ellume and Cepheid, outside the submitted work. H. C. S. K. is funded by the Research Supplement to Promote Diversity in Health-Related Research Program, the National Cancer Institute, NIH (grant R01 CA213130-S) and a Department of Medicine Diversity Academic Development Scholar Award from the University of Washington. C. M. J. reports consulting with AbbVie and Gilead, outside the submitted work. R. B. reports funding from BMGF and the NIH, outside the submitted work, and support for abstract and manuscript writing from Regeneron Pharmaceuticals, also outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: Key populations, including sex workers, men who have sex with men, and people who inject drugs, have a high risk of HIV and sexually transmitted infections. We assessed the health and economic impacts of different HIV and syphilis testing strategies among three key populations in Viet Nam using a dual HIV/syphilis rapid diagnostic test (RDT)., Setting: We used the spectrum AIDS impact model to simulate the HIV epidemic in Viet Nam and evaluated five testing scenarios among key populations. We used a 15-year time horizon and a provider perspective for costs., Participants: We simulate the entire population of Viet Nam in the model., Interventions: We modelled five testing scenarios among key populations: (1) annual testing with an HIV RDT, (2) annual testing with a dual RDT, (3) biannual testing using dual RDT and HIV RDT, (4) biannual testing using HIV RDT and (5) biannual testing using dual RDT., Primary and Secondary Outcome Measures: The primary outcome is incremental cost-effectiveness ratios. Secondary outcomes include HIV and syphilis cases., Results: Annual testing using a dual HIV/syphilis RDT was cost-effective (US$10 per disability-adjusted life year (DALY)) and averted 3206 HIV cases and treated 27 727 syphilis cases compared with baseline over 15 years. Biannual testing using one dual test and one HIV RDT (US$1166 per DALY), or two dual tests (US$5672 per DALY) both averted an additional 875 HIV cases, although only the former scenario was cost-effective. Annual or biannual HIV testing using HIV RDTs and separate syphilis tests were more costly and less effective than using one or two dual RDTs., Conclusions: Annual HIV and syphilis testing using dual RDT among key populations is cost-effective in Vietnam and similar settings to reach global reduction goals for HIV and syphilis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)