Determining reinfection rates by hepatitis C testing interval among key populations: A systematic review and meta-analysis.

BACKGROUND & AIMS: Detecting hepatitis C virus (HCV) reinfection among key populations helps prevent ongoing transmission. This systematic review aims to determine the association between different testing intervals during post-SVR follow-up on the detection of HCV reinfection among highest risk populations. METHODS: We searched electronic databases between January 2014 and February 2023 for studies that tested individuals at risk for HCV reinfection at discrete testing intervals and reported HCV reinfection incidence among key populations. Pooled estimates of reinfection incidence were calculated by population and testing frequency using random-effects meta-analysis. RESULTS: Forty-one single-armed observational studies (9453 individuals) were included. Thirty-eight studies (8931 individuals) reported HCV reinfection incidence rate and were included in meta-analyses. The overall pooled estimate of HCV reinfection incidence rate was 4.13 per 100 per person-years (py) (95% confidence interval [CI]: 3.45-4.81). The pooled incidence estimate among people who inject drugs (PWID) was 2.84 per 100 py (95% CI: 2.19-3.50), among men who have sex with men (MSM) 7.37 per 100 py (95% CI: 5.09-9.65) and among people in custodial settings 7.23 per 100 py (95% CI: 2.13-16.59). The pooled incidence estimate for studies reporting a testing interval of ≤6 months (4.26 per 100 py; 95% CI: 2.86-5.65) was higher than studies reporting testing intervals >6 months (5.19 per 100 py; 95% CI: 3.92-6.46). CONCLUSIONS: HCV reinfection incidence was highest in studies of MSM and did not appear to change with retesting interval. Shorter testing intervals are likely to identify more reinfections, help prevent onward transmission where treatment is available and enable progress towards global HCV elimination, but additional comparative studies are required.

Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment.

Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29-14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni.

From nature to creation: Going around in circles, the art of peptide cyclization.

Cyclic peptides and cyclotides are becoming common identities within the present efforts seen in peptide engineering - as we seek approaches to achieve potent biological activity, pharmacological selectivity, structurally stability and oral bioavailability. Yet this unique family of peptides has faced uncommon hurdles in their discovery, synthesis and bioengineering, retaining to characteristics that truly deviate these from their linear counterparts. In this mini-review we take a board spectrum approach to introduce this novel family of biomolecules and the troubles that they face in their sequence and disulfide connectivity assignment, together highlighting the present combined strategies involved in cyclic peptide/cyclotide synthesis and modification. These efforts have circumvented otherwise impossible hurdles in their manipulation and production that are only now advancing cyclic peptides/cyclotides as research probes and future pharmaceutical templates.

Native chemical ligation: a boon to peptide chemistry.

The use of chemical ligation within the realm of peptide chemistry has opened various opportunities to expand the applications of peptides/proteins in biological sciences. Expansion and refinement of ligation chemistry has made it possible for the entry of peptides into the world of viable oral therapeutic drugs through peptide backbone cyclization. This progression has been a journey of chemical exploration and transition, leading to the dominance of native chemical ligation in the present advances of peptide/protein applications. Here we illustrate and explore the historical and current nature of peptide ligation, providing a clear indication to the possibilities and use of these novel methods to take peptides outside their typically defined boundaries.

Differential COVID-19 case ascertainment by age and vaccination status in Victoria, Australia: a serosurveillance and record linkage study.

Objectives: To compare serological evidence of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with linked coronavirus disease 2019 (COVID-19) case notification data in Victoria, Australia, and to determine in vitro SARS-CoV-2 neutralisation activity based on prior infection and vaccination history. Design, setting, participants: Four cross-sectional serological surveys were conducted between 30 June and 31 October 2022 (a period of Omicron BA.4/BA.5 dominance) using 1,974 residual serum samples obtained from the Victorian Infectious Diseases Reference Laboratory. Serological results were linked to COVID-19 case notification and vaccination data. Surrogate virus neutralisation testing was performed to obtain in vitro inhibition estimates by anti-nucleocapsid serostatus and COVID-19 vaccination history. Main outcome measures: Adjusted anti-SARS-CoV-2 spike and nucleocapsid seropositivity by sex, age and region of residence; adjusted proportion of cases notified by anti-nucleocapsid serostatus, age and number of COVID-19 vaccination doses received; adjusted percentage in vitro inhibition against wildtype and Omicron BA.4/BA.5 SARS-CoV-2 variants by anti-nucleocapsid serostatus and COVID-19 vaccination history. Results: The prevalence of anti-SARS-CoV-2 nucleocapsid antibodies was inversely proportional to age. In October 2022, prevalence was 84% (95% confidence interval [95% CI]: 75-93%) among 18-29-year-olds, compared to 39% (95% CI: 27-52%) among ≥ 80-year-olds. In most age groups, approximately 40% of COVID-19 cases appear to have been notified via existing surveillance mechanisms. Case notification was highest among individuals older than 80 years and people who had received COVID-19 vaccine booster doses. In vitro neutralisation of Omicron BA.4/BA.5 sub-variants was highest for individuals with evidence of both prior infection and booster vaccination. Conclusions: Under-notification of SARS-CoV-2 infections in the Victorian population is not uniform across age and vaccination strata. Seroprevalence data that give insights into case notification behaviour provide additional context for the interpretation of existing COVID-19 surveillance information.

Immediate treatment for recent hepatitis C infection in people with high-risk behaviors: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Direct-acting antivirals (DAAs) are almost exclusively approved for the treatment of chronic HCV. This poses a significant barrier to the treatment of recently acquired HCV because of the limited access to DAAs. This review seeks to address this issue by synthesizing evidence of the benefits and harms of immediate treatment after the detection of recently acquired HCV in people at higher risk of infection. APPROACH AND RESULTS: A systematic review and meta-analysis were conducted reporting on populations with recently acquired HCV at higher risk of infection. Studies were included if they assessed standard duration DAA treatment regimens and reported on the benefits and harms of immediate treatment (within one year of diagnosis). Outcomes included sustained virological response at 12 weeks post-treatment (SVR12), incidence, treatment initiation and adherence, overtreatment, engagement in care, and adverse events. Eight cohort studies, 3 open-label trials, and 1 case series study were included, reporting on 2085 participants with recently acquired HCV infection. No studies included a comparison group. Eight studies assessed DAA treatment in either men who have sex with men or men who have sex with men with HIV, 2 studies assessed treatment in people who inject drugs, and 2 among people living with HIV. Immediate treatment of HCV was associated with a pooled SVR12 of 95.9% (95% CI, 92.6%-99.3%). Three studies reported on hepatitis C incidence, where most participants were treated in the chronic phase of infection. A treatment completion rate of 100% was reported in 2 studies, and only 1 serious adverse event was described. CONCLUSIONS: High rates of cure were achieved with the treatment of recently acquired hepatitis C in people at higher risk of infection. Serious adverse events were rare, highlighting individual benefits consistent with the treatment of chronic hepatitis C. The impact of immediate treatment on HCV incidence requires further evaluation.

Simulation of a human circulatory system.

This article describes a mathematically based human circulatory model. The model consists of lumped elements made of venous, arterial, peripheral, pulmonary vein and artery segments. A heart model is simulated using 4 chambers (left and right atriums and ventricles). The heart pump mechanism is operated by a simple piston based models for each of the chambers. The simulation consists of 19 (states) first order differential equations. and simulated with Matlab and Simulink. The simulation computes volume, flow rate and pressures in each segment.

Genetic architecture of transmission stage production and virulence in schistosome parasites.

Both theory and experimental data from pathogens suggest that the production of transmission stages should be strongly associated with virulence, but the genetic bases of parasite transmission/virulence traits are poorly understood. The blood fluke Schistosoma mansoni shows extensive variation in numbers of cercariae larvae shed and in their virulence to infected snail hosts, consistent with expected trade-offs between parasite transmission and virulence. We crossed schistosomes from two populations that differ 8-fold in cercarial shedding and in their virulence to Biomphalaria glabrata snail hosts, and determined four-week cercarial shedding profiles in F0 parents, F1 parents and 376 F2 progeny from two independent crosses in inbred snails. Sequencing and linkage analysis revealed that cercarial production is polygenic and controlled by five QTLs (i.e. Quantitative Trait Loci). These QTLs act additively, explaining 28.56% of the phenotypic variation. These results demonstrate that the genetic architecture of key traits relevant to schistosome ecology can be dissected using classical linkage mapping approaches.

Assessment of Antibodies Induced by Multivalent Transmission-Blocking Malaria Vaccines.

A malaria transmission-blocking vaccine would be a critical tool in achieving malaria elimination and eradication. By using chimpanzee adenovirus serotype 63 and modified vaccinia virus Ankara viral vectored vaccines, we investigated whether incorporating two antigens into one vaccine would result in higher transmission-reducing activity than one antigen. We demonstrated that when Pfs25 was administered with other antigens Pfs28 or Pfs230C, either concurrently as a mixed vaccine or co-expressed as a dual-antigen vaccine, the antibody response in mice to each antigen was comparable to a monoantigen vaccine, without immunological interference. However, we found that the transmission-reducing activity (functional activity) of dual-antigen vaccines was not additive. Dual-antigen vaccines generally only elicited similar transmission-reducing activity to monoantigen vaccines and in one instance had lower transmission-reducing activity. We found that despite the lack of immunological interference of dual-antigen vaccines, they are still not as effective at blocking malaria transmission as Pfs25-IMX313, the current leading candidate for viral vectored vaccines. Pfs25-IMX313 elicited similar quality antibodies to dual-antigen vaccines, but higher antibody titers.

Development of a patient-specific surgical simulator for pediatric laparoscopic procedures.

The purpose of this study is to develop and evaluate a pediatric patient-specific surgical simulator for the planning, practice, and validation of laparoscopic surgical procedures prior to intervention, initially focusing on the choledochal cyst resection and reconstruction scenario. The simulator is comprised of software elements including a deformable body physics engine, virtual surgical tools, and abdominal organs. Hardware components such as haptics-enabled hand controllers and a representative endoscopic tool have also been integrated. The prototype is able to perform a number of surgical tasks and further development work is under way to simulate the complete procedure with acceptable fidelity and accuracy.

Children with otitis media mount a pneumococcal serotype specific serum IgG and IgA response comparable to healthy controls after pneumococcal conjugate vaccination.

It has been suggested that otitis-prone children have an impaired antibody response. To investigate this in the context of pneumococcal vaccination, we used a multiplex bead-based assay to measure serum IgG and IgA levels against pneumococcal serotypes included in the 7-valent pneumococcal conjugate vaccine (PCV7; serotypes 4, 6B, 9V, 14, 18C, 19F and 23F) and 4 non-PCV7 serotypes (1, 5, 7F and 19A) in healthy (n=43) and otitis-prone children (n=75) before, 6 weeks after and 1 year after vaccination with one dose of PCV7. Pre-vaccination, otitis-prone children had significantly higher serum IgG levels against serotypes 4, 9V and 23F and against all non-PCV7 serotypes. One year following vaccination, there was no difference in IgG or IgA levels between healthy and otitis-prone children. The effect of the administration of one or two doses of PCV7 was investigated in otitis-prone children. After a second dose of PCV7, pneumococcal serotype specific IgG levels, but not IgA titres, were higher compared to the levels measured after the initial dose of PCV7. One year post PCV7 vaccination there was no difference in either IgG or IgA antibody levels to any of the PCV7 serotypes between children who received either one or two doses of PCV7. The finding that otitis-prone children do not have an impaired pneumococcal serotype-specific serum IgG or IgA response suggests that new pneumococcal conjugate vaccines may be immunogenic in otitis-prone children, however, further investigations are necessary to determine the clinical impact of such vaccines against the development of recurrent acute otitis media.

Trace Element Studies on Tinospora cordifolia (Menispermaceae), Ocimum sanctum (Lamiaceae), Moringa oleifera (Moringaceae), and Phyllanthus niruri (Euphorbiaceae) Using PIXE.

Traditionally, Tinospora cordifolia (Willd.) Hook. F. & Thomson (Menispermaceae), Ocimum sanctum L. (Lamiaceae), Moringa oleifera Lam. (Moringaceae), and Phyllanthus niruri L. (Euphorbiaceae) are some of the commonly used medicinal plants in India for curing ailments ranging from common cold, skin diseases, and dental infections to major disorders like diabetes, hypertension, jaundice, rheumatism, etc. To understand and correlate their medicinal use, trace element studies on the aqueous extract of these medicinal plants have been carried out using particle-induced X-ray emission technique. A 2-MeV proton beam was used to identify and characterize major and minor elements namely Cl, K, Ca, Ti, Cr, Mn, Fe, Co, Ni, Cu, Zn, Br, and Sr in them. Results have revealed that these elements are present in varying concentrations in the selected plants. Notable results include very high concentrations of Cl, K, and Ca in all the leaf samples, appreciable levels of Mn in all plants, high Zn content in T. cordifolia, and the aqueous extract of Moringa leaves compared to others and relative higher concentrations of Cr in all the plants.