Disease-Associated Mutations in CEP120 Destabilize the Protein and Impair Ciliogenesis.

Ciliopathies are a group of genetic disorders caused by a failure to form functional cilia. Due to a lack of structural information, it is currently poorly understood how ciliopathic mutations affect protein functionality to give rise to the underlying disease. Using X-ray crystallography, we show that the ciliopathy-associated centriolar protein CEP120 contains three C2 domains. The point mutations V194A and A199P, which cause Joubert syndrome (JS) and Jeune asphyxiating thoracic dystrophy (JATD), respectively, both reduce the thermostability of the second C2 domain by targeting residues that point toward its hydrophobic core. Genome-engineered cells homozygous for these mutations have largely normal centriole numbers but show reduced CEP120 levels, compromised recruitment of distal centriole markers, and deficient cilia formation. Our results provide insight into the disease mechanism of two ciliopathic mutations in CEP120, identify putative binding partners of CEP120 C2B, and suggest a complex genotype-phenotype relation of the CEP120 ciliopathy alleles

Author Correction: A consensus-based transparency checklist.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

CCDC61/VFL3 Is a Paralog of SAS6 and Promotes Ciliary Functions.

Centrioles are cylindrical assemblies whose peripheral microtubule array displays a 9-fold rotational symmetry that is established by the scaffolding protein SAS6. Centriole symmetry can be broken by centriole-associated structures, such as the striated fibers in Chlamydomonas that are important for ciliary function. The conserved protein CCDC61/VFL3 is involved in this process, but its exact role is unclear. Here, we show that CCDC61 is a paralog of SAS6. Crystal structures of CCDC61 demonstrate that it contains two homodimerization interfaces that are similar to those found in SAS6, but result in the formation of linear filaments rather than rings. Furthermore, we show that CCDC61 binds microtubules and that residues involved in CCDC61 microtubule binding are important for ciliary function in Chlamydomonas. Together, our findings suggest that CCDC61 and SAS6 functionally diverged from a common ancestor while retaining the ability to scaffold the assembly of basal body-associated structures or centrioles, respectively

Cost-per-diagnosis as a metric for monitoring cost effectiveness of HIV testing programmes in low income settings in southern Africa : health economic and modelling analysis

Introduction: As prevalence of undiagnosed HIV declines, it is unclear whether testing programmes will be cost effective. To guide their HIV testing programmes,countries require appropriatemetrics that can be measured. The cost-per-diagnosisis potentially a useful metric. Methods:We simulated a series of setting-scenarios for adult HIV epidemics and ART programmes typical of settings in southern Africa using an individual-based model and projected forward from 2018 under two policies: (i) a minimum package of “core” testing (i.e. testing in pregnant women, for diagnosis of symptoms, in sex workers, and in men coming forward for circumcision) is conducted, and (ii) “core” testing as above plus “additional-testing”, for which we specify different rates of testing and various degrees to which those with HIV are more likely to test than thosewithout HIV. We also considered a plausible range of unit test costs. The aim was to assess the relationship between cost-per-diagnosisand the incremental cost-effectiveness ratio(ICER) of the additional-testingpolicy. Discount rate 3%; costs in 2018 $US. Results:There was a strong graded relationship between the cost-per-diagnosisand the ICER. Overall, the ICERwas below$500 per-DALY-averted (the cost effectiveness threshold used in primary analysis) so long as thecost-per-diagnosiswas below $315. This thresholdcost-per-diagnosiswas similar according to epidemic and programmatic features including the prevalence of undiagnosed HIV, the HIV incidence and a measure of HIV programme quality (the proportion of HIV diagnosed people having a viral load <1000 copies/mL). However, restrictingto women, additional-testingdid not appear cost-effective even at acost-per-diagnosisof below$50, while restrictingto men additional-testingwas cost effective up to a cost-per-diagnosisof $585. Thethreshold cost for testing in men fell to$256 when the cost effectiveness threshold was $300instead of$500, and to $81 when considering a discount rate of 10% perannum.Conclusions:For testing programmesin low income settings in southern African there is an extremely strong relationship between the cost-per-diagnosisand the cost per DALY averted, indicating that the cost-per-diagnosiscan be used to monitor the cost effectiveness of testing programmes

Optimizing HIV retesting during pregnancy and postpartum in four countries: a cost-effectiveness analysis.

INTRODUCTION: HIV retesting during late pregnancy and breastfeeding can help detect new maternal infections and prevent mother-to-child HIV transmission (MTCT), but the optimal timing and cost-effectiveness of maternal retesting remain uncertain. METHODS: We constructed deterministic models to assess the health and economic impact of maternal HIV retesting on a hypothetical population of pregnant women, following initial testing in pregnancy, on MTCT in four countries: South Africa and Kenya (high/intermediate HIV prevalence), and Colombia and Ukraine (low HIV prevalence). We evaluated six scenarios with varying retesting frequencies from late in antenatal care (ANC) through nine months postpartum. We compared strategies using incremental cost-effectiveness ratios (ICERs) over a 20-year time horizon using country-specific thresholds. RESULTS: We found maternal retesting once in late ANC with catch-up testing through six weeks postpartum was cost-effective in Kenya (ICER = $166 per DALY averted) and South Africa (ICER=$289 per DALY averted). This strategy prevented 19% (Kenya) and 12% (South Africa) of infant HIV infections. Adding one or two additional retests postpartum provided smaller benefits (1 to 2 percentage point increase in infections averted versus one retest). Adding three retests during the postpartum period averted additional infections (1 to 3 percentage point increase in infections averted versus one retest) but ICERs ($7639 and in Kenya and$11 985 in South Africa) greatly exceeded the cost-effectiveness thresholds. In Colombia and Ukraine, all retesting strategies exceeded the cost-effectiveness threshold and prevented few infant infections (up to 31 and 5 infections, respectively). CONCLUSIONS: In high HIV burden settings with MTCT rates similar to those seen in Kenya and South Africa, HIV retesting once in late ANC, with subsequent intervention, is the most cost-effective strategy for preventing infant HIV infections. In these settings, two HIV retests postpartum marginally reduced MTCT and were less costly than adding three retests. Retesting in low-burden settings with MTCT rates similar to Colombia and Ukraine was not cost-effective at any time point due to very low HIV prevalence and limited breastfeeding

Cost-effectiveness of dual maternal HIV and syphilis testing strategies in high and low HIV prevalence countries: a modelling study.

BACKGROUND: Dual HIV and syphilis testing might help to prevent mother-to-child transmission (MTCT) of HIV and syphilis through increased case detection and treatment. We aimed to model and assess the cost-effectiveness of dual testing during antenatal care in four countries with varying HIV and syphilis prevalence. METHODS: In this modelling study, we developed Markov models of HIV and syphilis in pregnant women to estimate costs and infant health outcomes of maternal testing at the first antenatal care visit with individual HIV and syphilis tests (base case) and at the first antenatal care visit with a dual rapid diagnostic test (scenario one). We additionally evaluated retesting during late antenatal care and at delivery with either individual tests (scenario two) or a dual rapid diagnosis test (scenario three). We modelled four countries: South Africa, Kenya, Colombia, and Ukraine. Strategies with an incremental cost-effectiveness ratio (ICER) less than the country-specific cost-effectiveness threshold (US$500 in Kenya,$750 in South Africa, $3000 in Colombia, and$1000 in Ukraine) per disability-adjusted life-year averted were considered cost-effective. FINDINGS: Routinely offering testing at the first antenatal care visit with a dual rapid diagnosis test was cost-saving compared with the base case in all four countries (ICER: -$26 in Kenya,-$559 in South Africa, -$844 in Colombia, and -$454 in Ukraine). Retesting during late antenatal care with a dual rapid diagnostic test (scenario three) was cost-effective compared with scenario one in all four countries (ICER: $270 in Kenya,$260 in South Africa, $2207 in Colombia, and$205 in Ukraine). INTERPRETATION: Incorporating dual rapid diagnostic tests in antenatal care can be cost-saving across countries with varying HIV prevalence. Countries should consider incorporating dual HIV and syphilis rapid diagnostic tests as the first test in antenatal care to support efforts to eliminate MTCT of HIV and syphilis. FUNDING: WHO, US Agency for International Development, and the Bill & Melinda Gates Foundation

A consensus-based transparency checklist

We present a consensus-based checklist to improve and document the transparency of research reports in social and behavioural research. An accompanying online application allows users to complete the form and generate a report that they can submit with their manuscript or post to a public repository

Optimal Uses of Antiretrovirals for Prevention in HIV-1 Serodiscordant Heterosexual Couples in South Africa: A Modelling Study

Hallett et al use a mathematical model to examine the long-term impact and cost-effectiveness of different pre-exposure prophylaxis (PrEP) strategies for HIV prevention in serodiscordant couples

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially