Survey of pretreatment HIV drug resistance and the genetic transmission networks among HIV-positive individuals in southwestern China, 2014–2020

Background Pretreatment drug resistance (PDR) can limit the effectiveness of HIV antiretroviral therapy (ART). The aim of this study was to assess the prevalence of PDR among HIV-positive individuals that initiated antiretroviral therapy in 2014–2020 in southwestern China. Methods Consecutive cross-sectional surveys were conducted in Qinzhou, Guangxi. We obtained blood samples from individuals who were newly diagnosed with HIV in 2014–2020. PDR and genetic networks analyses were performed by HIV-1 pol sequences using the Stanford HIV-database algorithm and HIV-TRACE, respectively. Univariate and multivariate logistic regression models were used to explore the potential factors associated with PDR. Results In total, 3236 eligible HIV-positive individuals were included. The overall prevalence of PDR was 6.0% (194/3236). The PDR frequency to NNRTI (3.3%) was much higher than that of NRTI (1.7%, p < 0.001) and PI (1.2%, p < 0.001). A multivariate logistic regression analysis revealed that PDR was significantly higher among individuals aged 18–29 (adjusted odds ratio (aOR): 1.79, 95% CI 1.28–2.50) or 30–49 (aOR: 2.82, 95% CI 1.73–4.82), and harboring CRF08_BC (aOR: 3.23, 95% CI 1.58–6.59). A total of 1429 (43.8%) sequences were linked forming transmission clusters ranging in size from 2 to 119 individuals. Twenty-two individuals in 10 clusters had the same drug resistant mutations (DRMs), mostly to NNRTIs (50%, 5/10). Conclusions The overall prevalence of PDR was medium, numerous cases of the same DRMs among genetically linked individuals in networks further illustrated the importance of surveillance studies for mitigating PDR.

Paracetamol (Acetaminophen) and the Developing Brain

Paracetamol is commonly used to treat fever and pain in pregnant women, but there are growing concerns that this may cause attention deficit hyperactivity disorder and autism spectrum disorder in the offspring. A growing number of epidemiological studies suggests that relative risks for these disorders increase by an average of about 25% following intrauterine paracetamol exposure. The data analyzed point to a dose–effect relationship but cannot fully account for unmeasured confounders, notably indication and genetic transmission. Only few experimental investigations have addressed this issue. Altered behavior has been demonstrated in offspring of paracetamol-gavaged pregnant rats, and paracetamol given at or prior to day 10 of life to newborn mice resulted in altered locomotor activity in response to a novel home environment in adulthood and blunted the analgesic effect of paracetamol given to adult animals. The molecular mechanisms that might mediate these effects are unknown. Paracetamol has diverse pharmacologic actions. It reduces prostaglandin formation via competitive inhibition of the peroxidase moiety of prostaglandin H2 synthase, while its metabolite N-arachidonoyl-phenolamine activates transient vanilloid-subtype 1 receptors and interferes with cannabinoid receptor signaling. The metabolite N-acetyl-p-benzo-quinone-imine, which is pivotal for liver damage after overdosing, exerts oxidative stress and depletes glutathione in the brain already at dosages below the hepatic toxicity threshold. Given the widespread use of paracetamol during pregnancy and the lack of safe alternatives, its impact on the developing brain deserves further investigation.

Prevalence and Molecular Epidemiology of Transmitted Drug Resistance and Genetic Transmission Networks Among Newly Diagnosed People Living With HIV/AIDS in a Minority Area, China

Introduction: Transmitted drug resistance (TDR) can compromise antiretroviral therapy (ART) efficacy. We aimed to understand the molecular epidemiology of TDR and its genetic transmission networks among newly diagnosed people living with HIV/AIDS (PLWH).Methods: A total of 1,318 newly diagnosed PLWH, identified in all population-based HIV screening in an HIV-affected county of a minority area of China (i.e., Butuo county), were enrolled between January 1, 2018, and November 31, 2018. HIV-1 pol gene sequences were used for phylogenetic and genotypic drug resistance analyses. The genetic transmission networks were identified.Results: The prevalence of TDR among newly diagnosed PLWH was 8.12% (107/1,318). Patients in the stage of AIDS (adjusted odds ratio, OR: 2.32) and who had a history of sharing a needle ≥5 times (adjusted OR: 3.89) were more likely to have an increased risk of TDR. The prevalence of TDR for non-nucleoside reverse transcriptase inhibitors (NNRTIs) is higher than that of other inhibitors, with a relatively high prevalence of three mutations [V179D/E/DE (4.93%), K103N/KN (3.11%), and E138A/G (1.52%)]. A total of 577 (43.78%) pol sequences were involved in the genetic transmission network, with 171 clusters ranging in size from 2 to 91 pol sequences; 37.38% (40/107) of individuals carrying TDR were involved in the network, and individuals with the same TDR-associated mutations were usually cross-linked.Conclusions: Our data suggest a relatively high level of TDR and many transmission clusters among the newly diagnosed PLWH. Targeted intervention, early identification, and monitoring of resistance are warranted to reduce the TDR and prevent HIV-1 transmission in areas with a high rate of HIV-1.

Alpers- and MNGIE-like disease with disturbed CSF folate transport and an unusual mode of genetic transmission of POLG mutations: a case report

We report about a family with three of five siblings affected by a variable remitting-relapsing disease with epileptic seizures, coma and abdominal crises, and lethal outcome in all. In the youngest son and in one of his deceased brothers we identified two disease causing compound heterozygous POLG mutations. One of these was inherited from the mother, but the other was absent in the father`s blood, saliva, buccal swab and hair bulbs although his paternity was proven genetically. Thus, we assume germline mosaicism for this mutation in the father. Very low 5-methyltetrahydrofolate (5-MTHF) and absence of folate receptor-alpha was repeatedly found in the CSF of the youngest brother indicating a secondary cerebral folate transport deficiency. Folinic acid supplementation over 18 months resulted in some improvement of the neurological condition; however, it did not prevent progression of the systemic disease.

Biallelic CAV1 null variants induce Congenital Generalized Lipodystrophy with achalasia

Objective : CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signalling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic and cellular characteristics of CGL3. Design/Methods: In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3. Results: Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n=9) were asymptomatic, without any metabolic abnormality. Patients’ fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients’ fibroblasts also displayed insulin resistance, increased oxidative stress and premature senescence. Conclusions: The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.

The experience of being a mother with end stage renal disease: A qualitative study of women receiving treatment at an ambulatory dialysis unit

Background End-stage kidney disease (ESKD) has considerable effects on the quality of life, impairing daily activities and leading to lifestyle changes. The purpose of this study was therefore to explore the experience of motherhood and taking care of children in women with ESKD. Methods A qualitative exploratory study was conducted based on an interpretive framework. Participants were recruited using non-probabilistic purposeful sampling. In total, 14 women with ESKD were included, who were treated at the dialysis unit of a Spanish hospital. In-depth interviews (unstructured and semi-structured interviews) and researchers’ field notes were used to collect the data. A systematic text condensation analysis was performed. The techniques performed and application procedures used to control trustworthiness were credibility, transferability, dependability, and confirmability. Results Three themes emerged from the data. “Coping with being a mother” described how women are faced with the decision to become mothers and assess the risks of pregnancy. The second theme, called “Children and the experience of illness”, highlighted the women’s struggle to prevent the disease from affecting their children emotionally or disrupting their lives. The third theme, “Fear of genetic transmission”, was based on the women’s fear of passing the disease on to their children. Conclusions Deciding to become a mother and taking care of children represents a challenge for women with ESKD, coupled with the losses in their lives caused by the disease. These findings are only relevant to women on dialysis.

Ocular dermoids in 13 cats: a multicentre retrospective study

Objectives The aim of this multicentre retrospective study was to review the clinical data, outcomes and histopathological features of cats that had been treated for ocular surface dermoids. Methods Thirteen cats from various private practices in France with a clinical diagnosis of ocular surface dermoid were included in the study. Results The mean age of the study population at the time of diagnosis was 5 months. There were nine males and four females. Three different breeds were, including: domestic shorthair (n = 7), Birman (n = 4) and Havana Brown (n = 2). Two of the four Birmans were related (same sire). The two Havana Browns were also related (same sire). All of the dermoids were unilateral. Five of the dermoids were strictly conjunctival. Four affected both the conjunctiva and the cornea. Three affected both the conjunctiva and the eyelid, and one was strictly corneal. They were located in various positions: temporal (n = 9), inferonasal (n = 1), dorsonasal (n = 1) and dorsotemporal (n = 1). The last dermoid was heterogeneous and involved the nasal, dorsal and temporal quadrants. Concurrent eye diseases were observed in five patients: four cats exhibited associated eyelid agenesis and one cat exhibited persistent iris-to-iris pupillary membranes. Ten dermoids were surgically excised with no recurrences. Surgery was not performed for three cats: one cat died a few days after diagnosis and two cats were lost to follow-up after initial presentation. Conclusions and relevance Ocular surface dermoids are a rare condition in cats that can be treated successfully by surgical excision. Although our study reports only a small number of cases, the observation of ocular surface dermoids in two related cats in two different breeds indicates that genetic transmission is likely.

Transmitted drug resistance and transmission clusters among HIV-1 treatment-naïve patients in Guangdong, China: a cross-sectional study

Background Transmitted drug resistance (TDR) that affects the effectiveness of the first-line antiretroviral therapy (ART) regimen is becoming prevalent worldwide. However, its prevalence and transmission among HIV-1 treatment-naïve patients in Guangdong, China are rarely reported. We aimed to comprehensively analyze the prevalence of TDR and the transmission clusters of HIV-1 infected persons before ART in Guangdong. Methods The HIV-1 treatment-naïve patients were recruited between January 2018 and December 2018. The HIV-1 pol region was amplified by reverse transcriptional PCR and sequenced by sanger sequencing. Genotypes, surveillance drug resistance mutations (SDRMs) and TDR were analyzed. Genetic transmission clusters among patients were identified by pairwise Tamura-Nei 93 genetic distance, with a threshold of 0.015. Results A total of 2368 (97.17%) HIV-1 pol sequences were successfully amplified and sequenced from the enrolled 2437 patients. CRF07_BC (35.90%, 850/2368), CRF01_AE (35.56%, 842/2368) and CRF55_01B (10.30%, 244/2368) were the main HIV-1 genotypes circulating in Guangdong. Twenty-one SDRMs were identified among fifty-two drug-resistant sequences. The overall prevalence of TDR was 2.20% (52/2368). Among the 2368 patients who underwent sequencing, 8 (0.34%) had TDR to protease inhibitors (PIs), 22 (0.93%) to nucleoside reverse transcriptase inhibitors (NRTIs), and 23 (0.97%) to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Two (0.08%) sequences showed dual-class resistance to both NRTIs and NNRTIs, and no sequences showed triple-class resistance. A total of 1066 (45.02%) sequences were segregated into 194 clusters, ranging from 2 to 414 sequences. In total, 15 (28.85%) of patients with TDR were included in 9 clusters; one cluster contained two TDR sequences with the K103N mutation was observed. Conclusions There is high HIV-1 genetic heterogeneity among patients in Guangdong. Although the overall prevalence of TDR is low, it is still necessary to remain vigilant regarding some important SDRMs.

Non-Syndromic Cleft Palate and Transverse Limb Deficiency Segregating in a Family of Dogs

Oro-facial clefts are one of the most common birth defects in humans, most are non-syndromic, and few have established molecular diagnoses. Here we report the morphology and genetic transmission of isolated cleft palate in a naturally occurring dog model. Palate morphology was evaluated grossly, by microcomputed tomography, and by histologic examination of serial coronal sections. In repeated matings of a clinically normal sire/dam pair, 18% (12/68) of live-born pups had full-length cleft of the secondary palate with no other abnormalities. At the gestational stage of normal palate fusion, palate shelves of affected fetuses were above the tongue but did not meet at midline. Mandibles were normal, and oral epithelium and periderm were intact. Genetic transmission was determined in experimental backcross matings of surgically repaired affected dogs with a normal parent, which produced 20 cleft, 11 male and 9 female, and 24 normal-palate pups. Furthermore, all offspring of matings between affected dogs had cleft palate. These data were as expected under the hypothesis of autosomal recessive transmission of the cleft palate trait ([1 df, N = 44] Χ2 = 0.36, p = 0.55). About half of cleft offspring produced in backcross matings of which the dam had cleft palate, also exhibited various transverse limb deficiencies. No limb deficiencies occurred in backcross offspring of a dam with normal palate, suggesting a possible maternal effect. This dog family constitutes a large animal model of non-syndromic isolated cleft palate coincident with developmental limb deficiency.