Efficacy and safety of GST-HG171 in adult patients with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trial.

Background: GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed to evaluate the efficacy and safety of orally administered GST-HG171 plus Ritonavir in patients with coronavirus disease 2019 (COVID-19) infected with emerging XBB and non-XBB variants. Methods: This randomised, double-blind, placebo-controlled phase 2/3 trial was conducted in 47 sites in China among adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Eligible patients were randomised 1:1 to receive GST-HG171 (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 days, with stratification factors including the risk level of disease progression and vaccination status. The primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days, defined as a score of 0 for 11 COVID-19-related target symptoms for 2 consecutive days, assessed in the modified intention-to-treat (mITT) population. This trial was registered at ClinicalTrials.gov (NCT05656443) and Chinese Clinical Trial Registry (ChiCTR2200067088). Findings: Between Dec 19, 2022, and May 4, 2023, 1525 patients were screened. Among 1246 patients who underwent randomisation, most completed basic (21.2%) or booster (74.9%) COVID-19 immunization, and most had a low risk of disease progression at baseline. 610 of 617 who received GST-HG171 plus Ritonavir and 603 of 610 who received placebo were included in the mITT population. Patients who received GST-HG171 plus Ritonavir showed shortened median time to sustained recovery of clinical symptoms compared to the placebo group (13.0 days [95.45% confidence interval 12.0-15.0] vs. 15.0 days [14.0-15.0], P = 0.031). Consistent results were observed in both SARS-CoV-2 XBB (45.7%, 481/1053 of mITT population) and non-XBB variants (54.3%, 572/1053 of mITT population) subgroups. Incidence of adverse events was similar in the GST-HG171 plus Ritonavir (320/617, 51.9%) and placebo group (298/610, 48.9%). The most common adverse events in both placebo and treatment groups were hypertriglyceridaemia (10.0% vs. 14.7%). No deaths occurred. Interpretation: Treatment with GST-HG171 plus Ritonavir has demonstrated benefits in symptom recovery and viral clearance among low-risk vaccinated adult patients with COVID-19, without apparent safety concerns. As most patients were treated within 2 days after symptom onset in our study, confirming the potential benefits of symptom recovery for patients with a longer duration between symptom onset and treatment initiation will require real-world studies. Funding: Fujian Akeylink Biotechnology Co., Ltd.

FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States.

BACKGROUND: Population screening for FMR1 mutations has been a topic of considerable discussion since the FMR1 gene was identified in 1991. Advances in understanding the molecular basis of fragile X syndrome (FXS) and in genetic testing methods have led to new, less expensive methodology to use for large screening endeavors. A core criterion for newborn screening is an accurate understanding of the public health burden of a disease, considering both disease severity and prevalence rate. This article addresses this need by reporting prevalence rates observed in a pilot newborn screening study for FXS in the US. METHODS: Blood spot screening of 14,207 newborns (7,312 males and 6,895 females) was conducted in three birthing hospitals across the United States beginning in November 2008, using a PCR-based approach. RESULTS: The prevalence of gray zone alleles was 1:66 females and 1:112 males, while the prevalence of a premutation was 1:209 females and 1:430 males. Differences in prevalence rates were observed among the various ethnic groups; specifically higher frequency for gray zone alleles in males was observed in the White group compared to the Hispanic and African-American groups. One full mutation male was identified (>200 CGG repeats). CONCLUSIONS: The presented pilot study shows that newborn screening in fragile X is technically feasible and provides overall prevalence of the premutation and gray zone alleles in the USA, suggesting that the prevalence of the premutation, particularly in males, is higher than has been previously reported.

A reference genetic map of C. clementina hort. ex Tan.; citrus evolution inferences from comparative mapping.

BACKGROUND: Most modern citrus cultivars have an interspecific origin. As a foundational step towards deciphering the interspecific genome structures, a reference whole genome sequence was produced by the International Citrus Genome Consortium from a haploid derived from Clementine mandarin. The availability of a saturated genetic map of Clementine was identified as an essential prerequisite to assist the whole genome sequence assembly. Clementine is believed to be a 'Mediterranean' mandarin × sweet orange hybrid, and sweet orange likely arose from interspecific hybridizations between mandarin and pummelo gene pools. The primary goals of the present study were to establish a Clementine reference map using codominant markers, and to perform comparative mapping of pummelo, sweet orange, and Clementine. RESULTS: Five parental genetic maps were established from three segregating populations, which were genotyped with Single Nucleotide Polymorphism (SNP), Simple Sequence Repeats (SSR) and Insertion-Deletion (Indel) markers. An initial medium density reference map (961 markers for 1084.1 cM) of the Clementine was established by combining male and female Clementine segregation data. This Clementine map was compared with two pummelo maps and a sweet orange map. The linear order of markers was highly conserved in the different species. However, significant differences in map size were observed, which suggests a variation in the recombination rates. Skewed segregations were much higher in the male than female Clementine mapping data. The mapping data confirmed that Clementine arose from hybridization between 'Mediterranean' mandarin and sweet orange. The results identified nine recombination break points for the sweet orange gamete that contributed to the Clementine genome. CONCLUSIONS: A reference genetic map of citrus, used to facilitate the chromosome assembly of the first citrus reference genome sequence, was established. The high conservation of marker order observed at the interspecific level should allow reasonable inferences of most citrus genome sequences by mapping next-generation sequencing (NGS) data in the reference genome sequence. The genome of the haploid Clementine used to establish the citrus reference genome sequence appears to have been inherited primarily from the 'Mediterranean' mandarin. The high frequency of skewed allelic segregations in the male Clementine data underline the probable extent of deviation from Mendelian segregation for characters controlled by heterozygous loci in male parents.

Human health and climate change: leverage points for adaptation in urban environments.

The design of adaptation strategies that promote urban health and well-being in the face of climate change requires an understanding of the feedback interactions that take place between the dynamical state of a city, the health of its people, and the state of the planet. Complexity, contingency and uncertainty combine to impede the growth of such systemic understandings. In this paper we suggest that the collaborative development of conceptual models can help a group to identify potential leverage points for effective adaptation. We describe a three-step procedure that leads from the development of a high-level system template, through the selection of a problem space that contains one or more of the group's adaptive challenges, to a specific conceptual model of a sub-system of importance to the group. This procedure is illustrated by a case study of urban dwellers' maladaptive dependence on private motor vehicles. We conclude that a system dynamics approach, revolving around the collaborative construction of a set of conceptual models, can help communities to improve their adaptive capacity, and so better meet the challenge of maintaining, and even improving, urban health in the face of climate change.

Inspiring health advocacy in family medicine: a qualitative study.

CONTEXT: The Canadian Medical Education Directions for Specialists identifies health advocacy as an essential role for physicians. Health advocacy is also an integral part of the principles of family medicine. It relates to the physician's responsibility to identify and respond appropriately to the social determinants of health and the healthcare needs of vulnerable and marginalized populations. The competencies related to health advocacy are regarded by medical educators as difficult to integrate into residency training. OBJECTIVES: This qualitative study investigates what family medicine residents, educators and physicians perceive inspires them to engage in health advocacy, and explores how best to incorporate related competencies into medical training. METHODS: In-depth, semi-structured interviews conducted with a purposive sample of four family medicine residents, three physicians and two educators who self-identified or were identified by peers as health advocates. Interviews were recorded, transcribed and analyzed using framework analysis. Transcripts were made available to the participants to ensure transcript accuracy. FINDINGS: Early exposure to social injustice, parental influences, role modeling and internal motivators were seen as important inspirations for health advocacy. CONCLUSION: Creating an enabling and nurturing environment prior to and during residency training may be necessary to sustain the motivation to engage in health advocacy. Findings from this study suggest possibilities for a resident-guided participatory curriculum development process around health advocacy. Recommendations for promoting health advocacy in postgraduate training include effective integration of health advocacy in the curriculum by providing protected time and resources, providing experiential learning opportunities and fostering a community of practice for physician health advocates.

Access and utilization of a new low-vision rehabilitation service.

BACKGROUND: A new low-vision service linking a public hospital and a non-governmental organization was trialled in Melbourne, Australia. The factors associated with service use were investigated. METHODS: A survey was conducted with patients who used the service, those who accepted referrals but failed to attend and those who refused a referral. Hospital and non-governmental organization representatives were also interviewed. RESULTS: Ninety-eight eligible vision impaired people who were referred to the new service were recruited. Less than half (49%) followed through with their referral and attended the service. Proximity and convenience were listed as the main facilitators to service use while issues relating to transport, needing an accompanying person, lack of information about the service and poor health were the main barriers. More than a third of the non-compliant and referral refusers spoke a language other than English. Sixty-three per cent of all participants had not previously used low-vision services. Of the two main eye conditions, 81% of referred age-related macular degeneration participants (n = 26) attended the service, but only 32% of those with diabetic retinopathy (n = 31) did so. CONCLUSION: As more than 60% of participants in each of the three groups had no prior use of low-vision services, clearly current models of care are not reaching many who could benefit from such services. This suggests that higher rates of referral are warranted. However, given that substantially more were referred than attended, referral alone is obviously not the answer. Access and attitudinal barriers also need to be addressed.