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This study aims to assess the prevalence of Autism Spectrum Disorder (ASD) and its treatment. The study population was children aged 3-17 years with information on current ASD from National Survey of Children's Health, 2016-2022. Analysis of treatment was also conducted within the population of children with a current ASD diagnosis. A multivariate log-binomial regression model was used to assess the change of current ASD prevalence and ASD treatment by two study period (prior to COVID-19 pandemic: 2016-2019; during COVID-19 pandemic: 2020-22) and sociodemographic information. Compared to the current ASD at 2.5% in 2016, it increased to 3.6% in 2022. The treatment has decreased from 70.5% in 2016 to 61.6% in 2022 for any treatment and from 27.2% in 2016 to 20.4% in 2022 for medication treatment. Compared to children from 2016-2019, children from the following group were more likely to have ASD diagnosis during the pandemic (2020-2022), including those aged 3-5 years (aPR = 1.66, 95%CI 1.29-2.13), non-Hispanic white children, children from family with above national family income, and those with private insurance. However, medication treatment almost halved during the pandemic for non-Hispanic black children (aPR = 0.49, 95%CI 0.26-0.93) and children born overseas. In conclusion, higher prevalence of ASD might indicate a better awareness of ASD. The reduction in treatment correlates to the health service disruption caused by the pandemic, highlighting the needs of policy efforts to improve treatment for ASD.

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BACKGROUND AND OBJECTIVES: Silent corticotroph adenoma (SCA) is a high-risk pituitary neuroendocrine tumor (PitNET) which exhibits more aggressive behavior than other nonfunctioning PitNETs. Some SCAs are observed to recur after total resection (TR). We aim to discuss the long-term outcomes after endoscopic endonasal surgery for SCAs and explore optimal treatment after operation. METHODS: Clinical data and intraoperative videos from 367 SCAs who underwent endoscopic endonasal surgery were retrospectively collected. Patients were categorized into TR and subtotal resection (STR) groups according to 3-month postoperative MRIs. Based on close-up intraoperative observation of the relationship between tumor and pituitary gland, diaphragm, and medial wall cavernous sinus, patients in the TR group were further subdivided into gross total resection (GTR) and near total resection (NTR) groups. Patients in the STR group were subdivided as STR followed by observation (STR + ob) and STR followed by adjuvant stereotactic radiosurgery (SRS) (STR + SRS). Kaplan-Meier analysis was used to compare the event-free survival among these subgroups. RESULTS: Headache (27.5%) and vision loss (55.3%) were the most common presenting symptoms. Cavernous sinus (CS) invasion was confirmed intraoperatively in 167 (45.5%) patients. After operation, 175 (47.7%), 83 (22.6%), 32 (8.7%), and 77 (21%) patients were divided into GTR, NTR, STR + ob, and STR + SRS groups, respectively. The mean follow-up time was 40.9 ± 25.8 months. There were 0, 17 (20.5%), 9 (28.1%), and 4 (5.2%) patients noted to have PitNET recurrence or progression in GTR, NTR, STR + ob, and STR + SRS groups, respectively. Event-free survival distribution in the NTR group was similar to that in the STR + ob group (P = .696), which was significantly lower than that in the STR + SRS group (P = .008). Adrenocorticotropic hormone (ACTH)-negative SCAs have lower preoperative ACTH levels and were more likely to invade CS than ACTH-positive SCAs. CONCLUSION: CS invasion was commonly seen in SCAs, often precluding GTR. Radical surgery and close follow-up were proposed. Early postoperative adjuvant SRS for remnant tumor should be considered.

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BACKGROUND AND OBJECTIVES: The cavernous internal carotid artery (cICA) and its branches can make it challenging to approach the lateral portion of the retrocarotid area of the cavernous sinus (RcACS) and surrounding areas during the endoscopic endonasal approach (EEA). This can sometimes require more invasive transcranial approaches, causing a higher risk of complications. We sought to explore the feasibility of adding a contralateral transmaxillary (CTM) corridor to improve access to the RcACS during EEA. METHODS: We performed EEA and CTM extensions on 6 cadavers (12 sides) using image guidance. The depth of the surgical corridor, the surgical exposure, the angle of attack, and the trajectory to the anterior genu of the cICA were measured. Two illustrative clinical cases are presented. RESULTS: Compared with the contralateral transnasal approach, the CTM corridor provided a 10.76 (5.32)-mm shorter distance ( P < .001), 36.23% (20.70%) larger surgical exposure ( P < .001), and a 24.6° (3.4°) more parallel trajectory to the anterior genu of the cICA ( P < .001). The mean angle of the lateral nasal wall line and the middle eye line was equal to the mean angle of the contralateral transnasal ( P = .075) and CTM ( P = .262) approaches, respectively. The CTM corridor allowed us to achieve near-total resection of the RcACS and beyond in 2 invasive adenomas with significant lateral extension. CONCLUSION: The CTM corridor is a feasible addition to standard EEA to access the RcACS and beyond, providing a more medial-to-lateral trajectory and improved access. The middle eye line can be used as a reference to help select patients for this approach.

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BACKGROUND: Childhood infection might be associated with adverse child development and neurocognitive outcomes, but the results have been inconsistent. METHODS: Two population-based record-linkage cohorts of all singleton children born at term in New South Wales, Australia, from 2001 to 2014, were set up and followed up to 2019 for developmental outcome (N=276 454) and school performance (N=644 291). The primary outcome was developmentally high risk (DHR) at age 4-6 years and numeracy and reading below the national minimum standard at age 7-9 years. Cox regression was used to assess the association of childhood infection ascertained from hospital records with each outcome adjusting for maternal, birth and child characteristics, and sensitivity analyses were conducted assessing E-values and sibling analysis for discordant exposure. RESULTS: A higher proportion of children with an infection-related hospitalisation were DHR (10.9% vs 8.7%) and had numeracy (3.7% vs 2.7%) and reading results (4.3% vs 3.1%) below the national minimum standard, compared with those without infection-related hospitalisation. In the multivariable analysis, children with infection-related hospitalisation were more likely to be DHR (adjusted HR 1.12, 95% CI 1.08 to 1.15) and have numeracy (adjusted HR 1.22, 95% CI 1.18 to 1.26) and reading results (adjusted HR 1.16, 95% CI 1.12 to 1.20) below the national minimum standard. However, these results may be impacted by unmeasured confounding, based on E-values of 1.48-1.74, and minimal association with education outcome was found in the sibling analysis. CONCLUSIONS: Infection-related hospitalisation was modestly associated with adverse child development and school performance, but the association may be explained by shared familial factors, particularly in those with most socioeconomic disadvantages.

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Prostate cancer (PCa) ranks as the second most prevalent malignancy among males worldwide at present, and its prevalence keeps rising. Focal therapy not only results in tumor necrosis but also encourages the release of autoantigens originating from the tumor into the bloodstream and activates the host immune system to effectively fight the tumor. However, focal therapy alone may not achieve the total ablation of cancer cells and may cause locoregional recurrence. Immunotherapy, by boosting the body's immune response, destroys tumor cells and prevents immune escape. Recent studies show that focal therapy combined with immunotherapy can produce a better clinical efficacy by enhancing the initial immune response, especially for low- to intermediate-risk confined PCa. This article offers some fresh perspectives on the management of PCa by reviewing the etiology and progression of the malignancy, focal therapeutic options, and advantages and vista of focal therapy combined with immunotherapy.

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OBJECTIVES: There is conflicting data regarding the response of older people with HIV (PWH) to antiretroviral therapy (ART). The objective of this study was to evaluate the long-term immunological and virological responses, changes in regimen, and adverse drug reactions (ADRs) in older participants (50+ years) compared with younger (18-34 years) and middle-aged (35-49 years) PWH. METHODS: A retrospective review of medical records was conducted on 1622 participants who received ART in Yunnan Province, China, from 2010 to 2019. The study compared CD4+ T-cell counts, CD4+/CD8+ ratio, and relative numbers between different groups using the Kruskal-Wallis test. Cox proportional hazards regression models were used to identify variables associated with the occurrence of immune reconstitution insufficiency. The rates of immune reconstitution, incidence of ADRs, and rates of treatment change were analyzed using the chi-squared test or Fisher's exact test. RESULTS: Over 95% achieved viral load 200 copies/ml or less, with no age-related difference. However, older participants exhibited significantly lower CD4+ T-cell counts and CD4+/CD8+ recovery post-ART (P < 0.001), with only 32.21% achieving immune reconstitution (compared with young: 52.16%, middle-aged: 39.29%, P < 0.001) at the end of follow-up. Middle-aged and elderly participants changed ART regimens more because of ADRs, especially bone marrow suppression and renal dysfunction. CONCLUSION: Although the virological response was consistent across age groups, older individuals showed poorer immune responses and higher susceptibility to side effects. This underscores the need for tailored interventions and comprehensive management for older patients with HIV.

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BACKGROUND: While the 23-valent pneumococcal polysaccharide vaccine (PPV23) has demonstrated its role in preventing severe pneumococcal disease, its impact on more non-specific conditions like acute respiratory tract infection (ARI) and lower respiratory tract infections (LRTI) remains unclear. We aimed to investigate the role of PPV23 in prevention of presentations for ARI and LRTI and related antibiotic prescriptions among older adults in primary care. METHODS: Using a nationwide general practice dataset, we followed a cohort of regularly attending patients aged ≥65 years from 1 January 2014 until 31 December 2018 for presentations for ARI, LRTI, and related antibiotic prescriptions. Associations between PPV23 receipt and each outcome were assessed using a multiple failures survival model to estimate hazard ratios (HR) adjusted for age, sex, socioeconomic status, and various health measures. RESULTS: A cohort of 75,264 patients aged ≥65 years (mean 75.4, 56% female) in 2014 was followed. The incidence of presentations for ARI, ARI-related antibiotic prescription, LRTI, and LRTI-related antibiotic prescription was 157.6, 76.0, 49.6, and 24.3 per 1000 person-years, respectively. Recent PPV23 vaccine receipt was associated with a small reduction in ARI presentations (adjusted HR vaccinated vs. unvaccinated 0.96; 95%CI 0.94-0.98; p = 0.002); however, there was no reduction in ARI-related antibiotic prescription, LRTI presentation, nor LRTI-related antibiotic prescription (adjusted HR were 0.99[95%CI 0.96-1.03], 1.04[95%CI 0.99-1.09], 1.07[95%CI 1.00-1.14]). CONCLUSION: PPV23 vaccination in older adults may result in a small reduction in the incidence of total ARI presentations in primary care. However, the effect is small and residual confounding cannot be excluded.

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OBJECTIVE: To review experience regarding the treatment of prolactinomas by endoscopic endonasal surgery focusing on the association between presurgical dopamine agonist (DA) treatment and perioperative outcomes, surgical morbidities, endocrine outcomes, and pathological characteristics. METHODS: A single-center series of 290 cases was analyzed retrospectively and clinical data were collected. Intratumoral collagen content was assessed by Masson trichrome staining. RESULTS: Tenacious tumor consistency (27.8% vs 9.8%, P < .001) was more common in DA-pretreated patients compared with patients who underwent initial surgery. Moreover, DA-pretreated macroadenomas presented more intraoperative blood loss (200 [100-400] mL vs 175 [100-300] mL; P = .014), longer surgical duration (177 ± 95 minutes vs 154 ± 57 minutes; P = .043), and more surgical morbidities (19.4% vs 8.9%; P = .034). Additionally, DA-pretreated macroadenomas presented a higher collagen volume fraction than that of the initial surgery group (23.6 ± 2.2% vs 13.2 ± 2.1%; P = .001). Correlation analysis revealed a close correlation between collagen volume fraction and the cumulative dose of bromocriptine (BRC) in macroadenomas (r = 0.438, P < .001). Regarding endocrine outcomes, DA-pretreated microadenomas showed a lower proportion of initial remission compared with patients who underwent initial surgery (86.7% vs 100%, P = .047). CONCLUSION: This study described increased surgical difficulty and inferior endocrine outcomes associated with tumor fibrosis secondary to presurgical BRC treatment in prolactinomas. Neurosurgeons should note that presurgical BRC treatment may render subsequent surgery more challenging.

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BACKGROUND: Respiratory infections including influenza and pertussis are associated with significant morbidity and mortality in mothers and newborns. Vaccination during pregnancy against influenza and pertussis is recommended for all women but data on uptake in Australia is limited. METHODS: We conducted a retrospective population-based cohort study in Australia's largest state, New South Wales (NSW), using a Perinatal Data Collection (PDC). Data included demographic, pregnancy, and birth details including pertussis and influenza vaccination during pregnancy for all women giving birth between 01 January 2016 and 31 December 2020. We used descriptive statistics to assess uptake of influenza and pertussis vaccination during pregnancy and Poisson loglinear regression to estimate associations between maternal characteristics and vaccine receipt. RESULTS: During 2016-2020, there were 477,776 births (mean maternal age 32.25 years). In 176,255 (36.9%) births the mother received both vaccines; 202,922 (42.5%) influenza and 315,620 (66.1%) pertussis vaccine. From 2016 to 2020, reported coverage increased from 26.7% to 58.7% for influenza and 43.1% to 78.8% for pertussis, respectively. After adjustment, characteristics associated with lower likelihood of receiving influenza and pertussis vaccination included: younger age (<30 years), being born in Australia/New Zealand, from lower socio-economic strata, having previous pregnancies, being later to first antenatal care, utilising the public hospital care model, smoking, having chronic hypertension and BMI > 25 kg/m2. CONCLUSIONS: While reported coverage of both influenza and pertussis vaccine in birthing women in NSW has increased over time, disparities in coverage exist and they highlight areas where evidence-based interventions to improve maternal vaccination could be targeted.

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Background: Ferroptosis is a distinct form of cell death that has the potential to supersede the drug resistance that is commonly observed with current chemotherapeutic agents. As a result, ferroptosis presents a new and innovative therapeutic pathway for cancer treatment. The current understanding regarding the expression of genes associated with ferroptosis in bladder cancer (BLCA) and their prognostic implications remains unclear. Consequently, this study aimed to examine the potential prognostic value of ferroptosis-associated long non-coding RNAs (lncRNAs) in BLCA. Methods: The Cancer Genome Atlas (TCGA) was accessed to download RNA sequencing data and clinicopathological features of BLCA while accessing the FerrDb database to download ferroptosis-associated genes. The study calculated risk scores for ferroptosis-associated lncRNAs, and subsequently divided patients with BLCA into two groups, namely high- and low-risk, on the basis of the median risk score. Moreover, Kaplan-Meier (K-M) curves, Cox regression analysis, and column plots were utilized for evaluating the risk score prognostic value. Subsequently, the involvement of ferroptosis-associated mRNA, N6-methyladenosine (m6A) mRNA status, and immune responses was investigated for BLCA prognosis. Results: Thirty-six lncRNAs were identified to be differently expressed and linked to the prognosis of BLCA. The findings from the K-M curve analysis indicated a significant association between a high-risk lncRNA profile and poor BLCA prognosis. The area under curve (AUC) value of the receiver operating characteristic (ROC) curve was 0.810. The risk assessment model exhibited superior performance in predicting prognosis for BLCA compared to conventional clinicopathological features. Conclusions: Thirty-six lncRNAs were found to be linked to ferroptosis for the prognosis of patients with BLCA, and these results may provide new insights for treating BLCA.

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OBJECTIVE: The objective of this review is to examine the association between proton pump inhibitors (PPIs) and neurological and/or psychiatric disorders in adults. INTRODUCTION: The association between PPIs and neurological and/or psychiatric disorders remains unclear, despite the widespread use of the medications. A systematic review is required to investigate the risk of developing neurological and/or psychiatric disorders following the use of PPIs. INCLUSION CRITERIA: Studies including participants aged ≥18 years and using any PPIs, including participants with comorbid conditions or using other medications, will be considered for inclusion. Randomized controlled trials, quasi-experimental studies, and observational studies examining the association of neurological and/or psychiatric disorders with the use of PPIs among adults will be included. METHODS: MEDLINE, Embase, PsycINFO, CINAHL, and Cochrane CENTRAL databases will be searched from inception until the present. Two authors will independently screen and review the titles, abstracts, and full texts. The methodological quality of included studies will be assessed using the JBI critical appraisal checklists. Study characteristics, populations, type and duration of PPI usage, status of existing neurological and/or psychiatric disorders, comorbidity conditions, use of other medications, identification of neurological and/or psychiatric disorders (International Classification of Diseases codes vs others), and estimation of the associated neurological and/or psychiatric disorders will be extracted. Studies will be pooled using statistical meta-analysis where available; otherwise, the findings will be presented in narrative format. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for grading the certainty of evidence will be followed. REVIEW REGISTRATION: PROSPERO CRD42022355543.

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The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs, this necessitates the development of broad-spectrum antiviral drugs. In the previous study, we designed a recombinant protein, heptad repeat (HR) 121, as a variant-proof vaccine. Here, we found it can act as a fusion inhibitor and demonstrated broadly neutralizing activities against SARS-CoV-2 and its main variants. Structure analysis suggested that HR121 targets the HR2 domain in SARS-CoV-2 spike (S) 2 subunit to block virus-cell fusion. Functional experiments demonstrated that HR121 can bind HR2 at serological-pH and endosomal-pH, highlighting its inhibition capacity when SARS-CoV-2 enters via either cellular membrane fusion or endosomal route. Importantly, HR121 can effectively inhibit SARS-CoV-2 and Omicron variant pseudoviruses entering the cells, as well as block authentic SARS-CoV-2 and Omicron BA.2 replications in human pulmonary alveolar epithelial cells. After intranasal administration to Syrian golden hamsters, it can protect hamsters from SARS-CoV-2 and Omicron BA.2 infection. Together, our results suggest that HR121 is a potent drug candidate with broadly neutralizing activities against SARS-CoV-2 and its variants.

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Although species can arise through hybridization, compelling evidence for hybrid speciation has been reported only rarely in animals. Here, we present phylogenomic analyses on genomes from 12 macaque species and show that the fascicularis group originated from an ancient hybridization between the sinica and silenus groups ~3.45 to 3.56 million years ago. The X chromosomes and low-recombination regions exhibited equal contributions from each parental lineage, suggesting that they were less affected by subsequent backcrossing and hence could have played an important role in maintaining hybrid integrity. We identified many reproduction-associated genes that could have contributed to the development of the mixed sexual phenotypes characteristic of the fascicularis group. The phylogeny within the silenus group was also resolved, and functional experimentation confirmed that all extant Western silenus species are susceptible to HIV-1 infection. Our study provides novel insights into macaque evolution and reveals a hybrid speciation event that has occurred only very rarely in primates.

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HIV-1 is a highly host-specific retrovirus that infects humans but not most nonhuman primates. Thus, the lack of a suitable primate model that can be directly infected with HIV-1 hinders HIV-1/AIDS research. In the previous study, we have found that the northern pig-tailed macaques (NPMs) are susceptible to HIV-1 infection but show a nonpathogenic state. In this study, to understand this macaque-HIV-1 interaction, we assembled a de novo genome and longitudinal transcriptome for this species during the course of HIV-1 infection. Using comparative genomic analysis, a positively selected gene, Toll-like receptor 8, was identified with a weak ability to induce an inflammatory response in this macaque. In addition, an interferon-stimulated gene, interferon alpha inducible protein 27, was upregulated in acute HIV-1 infection and acquired an enhanced ability to inhibit HIV-1 replication compared with its human ortholog. These findings coincide with the observation of persistently downregulated immune activation and low viral replication and can partially explain the AIDS-free state in this macaque following HIV-1 infection. This study identified a number of unexplored host genes that may hamper HIV-1 replication and pathogenicity in NPMs and provided new insights into the host defense mechanisms in cross-species infection of HIV-1. This work will facilitate the adoption of NPM as a feasible animal model for HIV-1/AIDS research.

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PURPOSE: To describe and predict the risk of venous thromboembolism (VTE) after surgical resection of major sellar region tumors. METHOD: Patients with sellar region tumors were identified from a database. The outcome was VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) within 60 days after surgery. We trained regression and machine learning models to predict the outcome using baseline characteristics, surgical findings and postoperative laboratory tests. RESULTS: Among 3818 patients included, 124 patients developed VTE after surgery. The total 60-day VTE incidence was 3.2 %, with incidence peak within ten days after the surgery. The risk increased in patients >65 years old (OR 2.96, p < 0.001), in patients with chordoma (OR 3.40, p = 0.006) or craniopharyngioma (OR 1.86, p = 0.036), in patients underwent craniotomy approach (OR 2.78, p = 0.017), in patients with high volume CSF leakage (OR 4.24, p < 0.001), and in patients with longer surgical duration (OR 1.78, p = 0.029). The linear discriminant analysis algorithm had the highest AUC (0.869, 95%CI, 0.840-0.898) in predicting the outcome. The specificity, accuracy, and sensitivity of the best model were 61.8 %, 93.6 %, and 92.8 %, respectively. Risk stratification using our best model suggested that 1.3 % and 24.5 % of the patient developed VTE in the low-risk group and in the high-risk group, respectively. We developed an online decision-support tool available on https://deepvep.shinyapps.io/VTEpred/. CONCLUSION: The overall incidence of VTE after surgical resection of major sellar region tumors was clinically significant, especially in older patients with chordoma or craniopharyngioma.

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Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging bunyavirus, causes severe fever with thrombocytopenia syndrome (SFTS), with a high fatality rate of 20%-30%. At present, however, the pathogenesis of SFTSV remains largely unclear and no specific therapeutics or vaccines against its infection are currently available. Therefore, animal models that can faithfully recapitulate human disease are important to help understand and treat SFTSV infection. Here, we infected seven Chinese rhesus macaques (Macaca mulatta) with SFTSV. Virological and immunological changes were monitored over 28 days post-infection. Results showed that mild symptoms appeared in the macaques, including slight fever, thrombocytopenia, leukocytopenia, increased aspartate aminotransferase (AST) and creatine kinase (CK) in the blood. Viral replication was persistently detectable in lymphoid tissues and bone marrow even after viremia disappeared. Immunocyte detection showed that the number of T cells (mainly CD8+ T cells), B cells, natural killer (NK) cells, and monocytes decreased during infection. In detail, effector memory CD8+ T cells declined but showed increased activation, while both the number and activation of effector memory CD4+ T cells increased significantly. Furthermore, activated memory B cells decreased, while CD80+/CD86+ B cells and resting memory B cells (CD27+CD21+) increased significantly. Intermediate monocytes (CD14+CD16+) increased, while myeloid dendritic cells (mDCs) rather than plasmacytoid dendritic cells (pDCs) markedly declined during early infection. Cytokines, including interleukin-6 (IL-6), interferon-inducible protein-10 (IP-10), and macrophage inflammatory protein 1 (MCP-1), were substantially elevated in blood and were correlated with activated CD4+ T cells, B cells, CD16+CD56+ NK cells, CD14+CD16+ monocytes during infection. Thus, this study demonstrates that Chinese rhesus macaques infected with SFTSV resemble mild clinical symptoms of human SFTS and provides detailed virological and immunological parameters in macaques for understanding the pathogenesis of SFTSV infection.

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BACKGROUND: Administrative health data has been used extensively to examine congenital heart disease (CHD). However, the accuracy and completeness of these data must be assessed. OBJECTIVES: To use data linkage of multiple administrative data sources to examine the validity of identifying CHD cases recorded in hospital discharge data. METHODS: We identified all liveborn infants born 2013-2017 in New South Wales, Australia with a CHD diagnosis up to age one, recorded in hospital discharge data. Using record linkage to multiple data sources, the diagnosis of CHD was compared with five reference standards: (i) multiple hospital admissions containing CHD diagnosis; (ii) receiving a cardiac procedure; (iii) CHD diagnosis in the Register of Congenital Conditions; (iv) cardiac-related outpatient health service recorded; and/or (v) cardiac-related cause of death. Positive predictive values (PPV) comparing CHD diagnosis with the reference standards were estimated by CHD severity and for specific phenotypes. RESULTS: Of 485,239 liveborn infants, there were 4043 infants with a CHD diagnosis identified in hospital discharge data (8.3 per 1000 live births). The PPV for any CHD identified in any of the five methods was 62.8% (95% confidence interval [CI] 60.9, 64.8), with PPV higher for severe CHD at 94.1% (95% CI 88.2, 100). Infant characteristics associated with higher PPVs included lower birthweight, presence of a syndrome or non-cardiac congenital anomaly, born to mothers aged <20 years and residing in disadvantaged areas. CONCLUSION: Using data linkage of multiple datasets is a novel and cost-effective method to examine the validity of CHD diagnoses recorded in one dataset. These results can be incorporated into bias analyses in future studies of CHD.

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Tetherin prevents viral cross-species transmission by inhibiting the release of multiple enveloped viruses from infected cells. With the evolution of simian immunodeficiency virus of chimpanzees (SIVcpz), a pandemic human immunodeficiency virus type 1 (HIV-1) precursor, its Vpu protein can antagonize human tetherin (hTetherin). Macaca leonina (northern pig-tailed macaque [NPM]) is susceptible to HIV-1, but host-specific restriction factors limit virus replication in vivo. In this study, we isolated the virus from NPMs infected with strain stHIV-1sv (with a macaque-adapted HIV-1 env gene from simian-human immunodeficiency virus SHIV-KB9, a vif gene replaced by SIVmac239, and other genes originating from HIV-1NL4.3) and found that a single acidic amino acid substitution (G53D) in Vpu could increase its ability to degrade the tetherin of macaques (mTetherin) mainly through the proteasome pathway, resulting in an enhanced release and resistance to interferon inhibition of the mutant stHIV-1sv strain, with no influence on the other functions of Vpu. IMPORTANCE HIV-1 has obvious host specificity, which has greatly hindered the construction of animal models and severely restricted the development of HIV-1 vaccines and drugs. To overcome this barrier, we attempted to isolate the virus from NPMs infected with stHIV-1sv, search for a strain with an adaptive mutation in NPMs, and develop a more appropriate nonhuman primate model of HIV-1. This is the first report identifying HIV-1 adaptations in NPMs. It suggests that while tetherin may limit HIV-1 cross-species transmission, the Vpu protein in HIV-1 can overcome this species barrier through adaptive mutation, increasing viral replication in the new host. This finding will be beneficial to building an appropriate animal model for HIV-1 infection and promoting the development of HIV-1 vaccines and drugs.

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BACKGROUND: Evidence regarding the association between acute respiratory infections during pregnancy and congenital anomalies in babies, is limited and conflicting. The aim of this study was to examine the association between acute respiratory infections during the first trimester of pregnancy and congenital anomalies in babies using record linkage. METHODS: We linked a perinatal register to hospitalisation and disease notifications in the Australian state of New South Wales (NSW) between 2001 to 2016. We quantified the risk of congenital anomalies, identified from the babies' linked hospital record in relation to notifiable respiratory and other infections during pregnancy using generalized Estimating Equations (GEE) adjusted for maternal sociodemographic and other characteristics. RESULTS: Of 1,453,037 birth records identified from the perinatal register between 2001 and 2016, 11,710 (0.81%) mothers were hospitalised for acute respiratory infection, 2850 (0.20%) had influenza and 1011 (0.07%) had high risk infections (a record of cytomegalovirus, rubella, herpes simplex, herpes zoster, toxoplasmosis, syphilis, chickenpox (varicella) and zika) during the pregnancy. During the first trimester, acute respiratory infection, influenza and high-risk infections were reported by 1547 (0.11%), 399 (0.03%) and 129 (0.01%) mothers. There were 15,644 (1.08%) babies reported with major congenital anomalies, 2242 (0.15%) with cleft lip/ plate, 7770 (0.53%) with all major cardiovascular anomalies and 1746 (0.12%) with selected major cardiovascular anomalies. The rate of selected major cardiovascular anomalies was significantly higher if the mother had an acute respiratory infection during the first trimester of pregnancy (AOR 3.64, 95% CI 1.73 to 7.66). The rates of all major congenital anomalies and all major cardiovascular anomalies were also higher if the mother had an acute respiratory infection during the first trimester of pregnancy, however the difference was no statistically significant. Influenza during the first trimester was not associated with major congenital anomalies, selected major cardiovascular anomalies or all major cardiovascular anomalies in this study. CONCLUSION: This large population-based study found severe acute respiratory infection in first trimester of pregnancy was associated with a higher risk of selected major cardiovascular anomalies in babies. These findings support measures to prevent acute respiratory infections in pregnant women including through vaccination.

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This study aimed to assess human papillomavirus (HPV) vaccine effectiveness (VE) against both vaccine-type and nonvaccine-type high-risk HPV (hrHPV) infection, and duration of protection in United States. The study population was female participants aged 18-35 years with an HPV vaccination history and genital testing for HPV from the National Health and Nutrition Examination Survey, 2007-2016. Participants vaccinated before sexual debut were assessed against 13 nonvaccine-type hrHPV infection including 31/33/35/39/45/51/52/56/58/59/68/73/82. Multivariable logistic regression was used to estimate VE overall, by age at diagnosis, time since vaccination and lifetime sexual partners. A total of 3866 women were included in the analysis, with 23.3% (95% CI 21.3%-25.4%) having been vaccinated (≥1 dose). VE against vaccine-type HPV18/16/11/6 infection was 58% overall, which was mainly driven by those aged 18-22 years (VE = 64%) and 23-27 years (65%). Among participants aged 18-22 years vaccinated before sexual debut, the VE was 47% (23%-64%) against 13 nonvaccine-type hrHPV and 61% (95% CI 36%-77%) against 5 selected nonvaccine-type hrHPV35/39/52/58/59. Both direct effectiveness and cross-protection maintained effective for 5-10 years post vaccination. We also found the prevalence of ever diagnosed cervical cancer among vaccinated was significantly lower (0.46%, 4/874) than that among unvaccinated participants (1.27%, 38/2992). These findings highlight the potential of significant reduction of cervical cancer following the universal HPV vaccination programme.

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