Genomic Evidence for the Nonpathogenic State in HIV-1-Infected Northern Pig-Tailed Macaques.

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.

A Novel Vpu Adaptive Mutation of HIV-1 Degrades Tetherin in Northern Pig-Tailed Macaques (Macaca leonina) Mainly via the Ubiquitin-Proteasome Pathway and Increases Viral Release.

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.

The impact of hepatitis B vaccination in the United States, 1999-2018.

BACKGROUND AND AIMS: Hepatitis B vaccine has been included in the infant immunization schedule since 1991 in the United States. We aimed to assess its effectiveness against HBV infection and its impact on mortality. APPROACH AND RESULTS: The study population was participants aged 6+ years with an HBV vaccination history and an HBV serologic test from the National Health and Nutrition Examination Survey, 1999-2018. Participants aged 18+ years with linked mortality records from 1999-2014 were followed for mortality analysis. Multivariable logistic regression was used to compute vaccine effectiveness (VE) overall, by year of birth, and by age. Cox regression was used to estimate HRs for all-cause, cancer-related, and cardiovascular disease-related mortality. A total of 64,107 participants were included in the main analysis, with 29,600 (40.7%) having completed HBV vaccination (three or more doses, vaccinated). The highest vaccination uptake was found among those born after 1991, at 86.5%. Vaccinated participants had higher prevalence of vaccine-induced immunity than the unvaccinated (47.2% vs. 7.4%). Among those born after 1991, VE was found at 58% (95% CI, 18%-79%) overall and 85% for those aged ≥20 years (mean age, 22), whereas no effect was found among those born prior to 1990. HBV vaccination was associated with reduced risk of all-cause mortality (HR, 0.78; 95% CI, 0.68-0.90) and cancer-related mortality (HR, 0.76; 95% CI, 0.58-1.00) but not for cardiovascular disease-related mortality. CONCLUSIONS: In the universal infant vaccination era, the HBV vaccine has shown substantial effectiveness against HBV infection and maintained strong protection for 20 years. It was also associated with reduced risk of all-cause and cancer-related mortality.

Examination of validity of identifying congenital heart disease from hospital discharge data without a gold standard: Using a data linkage approach.

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.

Effectiveness of quadrivalent HPV vaccination in reducing vaccine-type and nonvaccine-type high risk HPV infection.

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.

Associations between severe and notifiable respiratory infections during the first trimester of pregnancy and congenital anomalies at birth: a register-based cohort study.

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.

Self-reported symptoms in patients with acromegaly: a 6-month follow-up in a single neurosurgical center.

Acromegaly is characterized by hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), accompanied by a compromise in the perception of wellness. The Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) is relevant to assessing signs and symptoms but is mainly used to evaluate the efficacy of a pharmacological intervention. To explore the perioperative variation in symptom severity, the divergence between subgroups stratified according to clinical outcomes or treatment modalities, and the interaction between symptom scores and clinical indices, we prospectively recruited 106 patients with acromegaly from 2016 to 2018. Oral glucose tolerance and GH tests were performed, and PASQ was administered before treatment and 6 months postoperatively. Patients were divided into active (n = 49) and remission (n = 57) groups according to postoperative GH and IGF-1 levels. PASQ scores and GH and IGF-1 levels decreased significantly postoperatively in both groups. A significantly higher preoperative headache score and greater extent of decrease in arthralgia were seen in the active and remission groups, respectively. No significant variation in PASQ scores was found between patients receiving surgery alone and those receiving preoperative somatostatin analogs. Preoperative fasting GH (GH0) levels were positively correlated with preoperative excessive perspiration. Further regression analyses validated the variation in GH0 as a noteworthy determinant of the extent of change in soft-tissue swelling, excessive perspiration, fatigue, and total PASQ scores. Patient-reported symptoms were substantially alleviated after surgery, independent of endocrine remission or use of preoperative somatostatin. A GH level decrease was a notable coefficient for PASQ scores.

Comparison of primary liver cancer mortality estimates from World Health Organization, global burden disease and global cancer observatory.

AIMS: This study aims to compare estimates of primary liver cancer mortality from World Health Organization (WHO), Global Burden Disease (GBD) and Global Cancer Observatory (GCO). METHODS: Liver cancer mortality was extracted from WHO, GBD and GCO for 92 countries for the most recent year. Age-standardized rate (ASR) was computed and used for current comparisons across the three data sources. Temporal trend for 75 countries was analysed and compared between WHO and GBD from 1990 to 2019 using joinpoint regression. Average annual percentage change for the most recent 10 years was used as indicator for change. RESULTS: The estimates of ASR were quite consistent across the three data sources, but most similar estimates were found between WHO and GCO in both region and country levels. The differences in ASR were negatively correlated with completeness of cause-of-death registration, human development index and proportion of liver cancer because of alcohol consumption. Consistent trends of ASR were found from 35 countries between WHO and GBD in the most recent 10 years. However, opposite trends were found from 10 countries with five from Southern America, four from Europe and one from Asia. Of the 18 countries for projection, opposite trends between WHO and GBD were found from seven countries. CONCLUSION: While the ASR of primary liver cancer mortality was comparable across the three data sources, most similar estimates were found between WHO and GCO. The opposite trends found from 10 countries between WHO and GBD raised concerns of true patterns in these countries.

Characteristics Associated with Monitoring and Treatment of Chronic Hepatitis B in a Large Cohort of Australian Adults.

BACKGROUND: Regular monitoring and treatment of chronic hepatitis B (CHB) are known to reduce the risk of hepatocellular carcinoma. We sought to describe patterns of monitoring and treatment among adults diagnosed with CHB in Australia. METHODS: Population-based prospective cohort study of Australian adults aged 45 + years followed by record-linkage to hepatitis B notifications, monitoring and treatment. Proportions of those with CHB who: had viral load test; were dispensed antiviral treatment; and had ultrasound surveillance were estimated. The characteristics associated with viral load test and ultrasound surveillance were examined using logistic regression. RESULTS: A total of 576 adults with CHB were identified. From 2008 to 2015, 14.8% (85/576) had at least one viral load test recorded every 2 years and 19.1% (110/576) had at least one antiviral treatment recorded, 19.9% (58/292) had at least one ultrasound recorded every year among those eligible for ultrasound surveillance. A record of having at least one viral load test every 2 years was more likely among adults born in Asia compared to Australian-born (21.4% vs 8.6%), those notified in more recent years compared to earlier years, and those on antiviral treatment compared to not on treatment. Increasing proportions of cases had records of at least one viral load test over time (2008: 10.5%, 2015: 27.2%) and at least one antiviral treatment (2008: 3.0%, 2015: 18.5%). CONCLUSIONS: In Australian adults, estimates of care interventions for CHB management have increased over time but still fall short of targets recommended in the National Hepatitis B Strategy.

Combined pre-retrochiasmatic resection of third ventricle craniopharyngioma by endoscopic endonasal approach.

BACKGROUNDS: Third ventricle craniopharyngioma (TVC) refers to the tumor originating from the tuberoinfundibular, and completely located in the third ventricle; unlike most TVCs, the retrochiasmatic-infundibulum corridor is too narrow to expose the tumor with anterior extension via an endoscopic endonasal approach. METHODS: Retrospective analysis of two TVCs via an endoscopic endonasal combined pre-retrochiasmatic approach. CONCLUSIONS: The tumor inside the third ventricle can be satisfactorily exposed through a combined pre-retrochiasmatic approach and be completely removed with the lowest injury of the hypothalamus and optic nerve.

Recent global burden of cervical cancer incidence and mortality, predictors, and temporal trends.

BACKGROUNDS: This study investigated the global incidence and mortality of cervical cancer, its predictors, the temporal trend by country and age. METHODS: Data from Global Cancer Observatory 2020 for 185 countries was used to estimate current cervical cancer incidence and mortality and their associations with predictors by linear regression analysis. Estimated age-standardized rates (ASR) and average annual percentage changes (AAPC) from cancer registries for up to 53 countries through 2018 were used for trend analysis by joinpoint regression. RESULTS: Wide variations in cervical cancer were observed globally with the highest rates of incidence and mortality in East Africa (ASR, 40.1 and 28.6). The incidence and mortality of cervical cancer were positively associated with human papillomavirus, human immunodeficiency virus infection and negatively associated with cervical cancer screening coverage. In the most recent 5 years, reduction of incidence and mortality was found from 22 (AAPC, -11.2 to -0.5) and 27 countries (-21.5 to -0.3). Increase of incidence and mortality was found from 13 (1.7 to 6.5) and 5 (0.3 to 1.8) countries. Comparing to women aged above 50 years, increasing incidence were additionally found among women under age 50 years from 9 countries (ranging from 0.2 in Denmark to 3.8 in Sweden). CONCLUSIONS: While most countries with cancer registry have shown reduction in cervical cancer incidence and mortality, the increasing incidence among younger women from some developed countries warrants further implementation of effective cancer screening.

The impact of universal hepatitis B vaccine on the trend of liver cancer from the Global Burden of Disease Study 2017.

AIMS: This study aims to assess the trend of hepatitis B virus (HBV)-attributable liver cancer as well as the impact of HBV vaccine on it. METHODS: We retrieved data from Global Burden Disease study to estimate trends of HBV-attributable liver cancer by region and age from 1990 to 2017 and HBV vaccine data from World Health Organization to assess its impact on these trends for children (0-14 years), adolescents and young adults (15-29 years). Change of cancer cases, age-standardized incidence rate (ASR) and estimated annual percentage change (EAPC) were used to quantify the trends of HBV-attributable liver cancer. RESULTS: In this study, reduction in HBV-attributable cancer incident cases was found among children (from 2080 to 1430), adolescents and young adults (from 10 890 to 9090). In terms of ASR, overall reduction was observed globally by an average of -0.45% (95% CI: -0.62 to -0.29) per year in the same period. The highest reduction in ASR was found in adolescents and young adults with EAPC of -3.02 (95% CI: -3.57 to -2.46). Although the ASR has decreased from all the five regions with universal HBV immunization programme, it has increased in the region without universal vaccination and the highest increase was found among children with EAPC of 1.97 (95% CI: 1.71-2.23). CONCLUSION: Significant reduction in HBV-attributable liver cancer among children was mainly because of the universal HBV vaccination. However, the increasing trend of HBV-attributable liver cancer in region without universal HBV vaccination suggested the necessity of introducing universal immunization.

High risk groups for severe COVID-19 in a whole of population cohort in Australia.

BACKGROUND: Increasing age is the strongest known risk factor for severe COVID-19 disease but information on other factors is more limited. METHODS: All cases of COVID-19 diagnosed from January-October 2020 in New South Wales Australia were followed for COVID-19-related hospitalisations, intensive care unit (ICU) admissions and deaths through record linkage. Adjusted hazard ratios (aHR) for severe COVID-19 disease, measured by hospitalisation or death, or very severe COVID-19, measured by ICU admission or death according to age, sex, socioeconomic status and co-morbidities were estimated. RESULTS: Of 4054 confirmed cases, 468 (11.5%) were classified as having severe COVID-19 and 190 (4.7%) as having very severe disease. After adjusting for sex, socioeconomic status and comorbidities, increasing age led to the greatest risk of very severe disease. Compared to those 30-39 years, the aHR for ICU or death from COVID-19 was 4.45 in those 70-79 years; 8.43 in those 80-89 years; 16.19 in those 90+ years. After age, relative risks for very severe disease associated with other factors were more moderate: males vs females aHR 1.40 (95%CI 1.04-1.88); immunosuppressive conditions vs none aHR 2.20 (1.35-3.57); diabetes vs none aHR 1.88 (1.33-2.67); chronic lung disease vs none aHR 1.68 (1.18-2.38); obesity vs not obese aHR 1.52 (1.05-2.21). More comorbidities was associated with significantly greater risk; comparing those with 3+ comorbidities to those with none, aHR 5.34 (3.15-9.04). CONCLUSIONS: In a setting with high COVID-19 case ascertainment and almost complete case follow-up, we found the risk of very severe disease varies by age, sex and presence of comorbidities. This variation should be considered in targeting prevention strategies.

Machine learning in predicting early remission in patients after surgical treatment of acromegaly: a multicenter study.

PURPOSE: Accurate prediction of postoperative remission is beneficial for effective patient-physician communication in acromegalic patients. This study aims to train and validate machine learning prediction models for early endocrine remission of acromegalic patients. METHODS: The training cohort included 833 patients with growth hormone (GH) secreting pituitary adenoma from 2010 to 2018. We trained a partial model (only using pre-operative variables) and a full model (using all variables) to predict off-medication endocrine remission at six-month follow-up after surgery using multiple algorithms. The models were validated in 99 prospectively collected patients from a second campus and 52 patients from a third institution. RESULTS: C-statistic and the accuracy of the best partial model was 0.803 (95% CI 0.757-0.849) and 72.5% (95% CI 67.6-77.5%), respectively. C-statistic and the accuracy of the best full model was 0.888 (95% CI 0.861-0.914) and 80.3% (95% CI 77.5-83.1%), respectively. The c-statistics (and accuracy) of using only Knosp grade, total resection, or postoperative day 1 GH level as the single predictor were lower than our partial model or full model (p < 0.001). C-statistics remained similar in the prospective cohort (partial model 0.798, and full model 0.903) and in the external cohort (partial model 0.771, and full model 0.871). A web-based application integrated with the trained models was published at  https://deepvep.shinyapps.io/Acropred/ . CONCLUSION: We developed and validated interpretable and applicable machine learning models to predict early endocrine remission after surgical resection of a GH-secreting pituitary adenoma. Predication accuracy of the trained models were better than those using single variables.

Effectiveness of Acellular Pertussis Vaccine in Older Adults: Nested Matched Case-control Study.

BACKGROUND: Despite recommendations that older adults receive acellular pertussis vaccines, data on direct effectiveness in adults aged over 50 years are sparse. METHODS: A case-control study nested within an adult cohort. Cases were identified from linked pertussis notifications and each matched to 3 controls on age, sex, and cohort recruitment date. Cases and controls were invited to complete a questionnaire, with verification of vaccination status by their primary care provider. Vaccine effectiveness (VE) was estimated by conditional logistic regression, with adjustment for reported contact with children and area of residence. RESULTS: Of 1112 notified cases in the cohort, we had complete data for 333 cases and 506 controls. Among 172 PCR-diagnosed cases (mean age, 61 years), 11.2% versus 19.5% of controls had provider-verified pertussis vaccination, on average, 3.2 years earlier. Adjusted VE against PCR-diagnosed pertussis was 52% (95% CI, 15-73%), nonsignificantly higher if vaccinated within 2 years (63%; -5-87%). Adjusted VE was similar in adults born before 1950, presumed primed by natural infection (51%; -8-77%) versus those born 1950 or later who may have received whole-cell pertussis vaccine (53%; -11-80%) (P-heterogeneity = 0.9). Among 156 cases identified by single-point serology, adjusted VE was -55% (-177-13%). CONCLUSIONS: We found modest protection against PCR-confirmed pertussis among older adults (mean age, 61 years; range, 46-81 years) within 5 years after acellular vaccine. The most likely explanation for the markedly divergent VE estimate from cases identified by single-titer serology is misclassification arising from limited diagnostic specificity in our setting.

Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas.

Pituitary adenoma (PA) is one of the most common intracranial neoplasms. Several genetic predisposing factors for PA have been identified, but they account for a small portion of cases. In this study, we sought to identify the PA genetic risk factors by focusing on causative mutations for PAs. Among the 4 affected and 17 asymptomatic members from one family with familial PA, whole-exome sequencing identified cosegregation of the PA phenotype with the heterozygous missense mutation c.4136G>T (p.Arg1379Leu) in cadherin-related 23 (CDH23). This mutation causes an amino acid substitution in the calcium-binding motif of the extracellular cadherin (EC) domains of CDH23 and is predicted to impair cell-cell adhesion. Genomic screening in a total of 12 families with familial PA (20 individuals), 125 individuals with sporadic PA, and 260 control individuals showed that 33% of the families with familial PA (4/12) and 12% of individuals with sporadic PA (15/125) harbored functional CDH23 variants. In contrast, 0.8% of the healthy control individuals (2/260) carried functional CDH23 variants. Gene-based analysis also revealed a significant association between CDH23 genotype and PA (p = 5.54 × 10-7). Moreover, PA individuals who did not harbor functional CDH23 variants displayed tumors that were larger in size (p = 0.005) and more invasive (p < 0.001). Therefore, mutations in CDH23 are linked with familial and sporadic PA and could play important roles in the pathogenesis of PA.

Trends in chronic hepatitis B prevalence in Australian women by country of birth, 2000 to 2016.

Routine antenatal screening for chronic hepatitis B (HBV) in countries with high migrant populations provides an opportunity to monitor trends in HBV prevalence and can inform estimates locally and in countries with limited seroprevalence data. We linked perinatal birth register records with HBV notifications in the largest Australian state, over the period 2000-2016. Among women aged 15-44 years, we estimated age-standardized chronic HBV prevalence overall and by country of birth and also estimated trends in age-standardized HBV prevalence over time using regression modelling. Among 903 831 women, 8001 linked to a chronic HBV infection record (overall age-standardized prevalence 0.76%, 95% CI: 0.74-0.78). Prevalence varied by country of birth with the highest estimates among women born in Sierra Leone (11.13%, 95% CI: 8.29-13.96), Taiwan (8.08%, 95% CI: 6.74%-9.43%), Cambodia (7.47%, 95% CI: 6.50%-8.45%) and Vietnam (7.36%, 95% CI: 6.97%-7.75%); more moderate estimates among women from North Korea (2.76%, 95% CI: 1.99-3.53) and Samoa (2.64%, 95% CI: 1.99%-3.29%); prevalence was 0.18% (95% CI: 0.17-0.19) in Australian-born women. Over 17 years, there were significant reductions in HBV prevalence among all women (from 0.88% in 2000 to 0.57% in 2016; P < .0001). Among women from high prevalence countries, the greatest absolute reductions were observed among those from Taiwan (10.1%, P < .001) followed by Tonga (5.4%, P < .001), whereas no reductions were observed for women born in Vietnam (P = .08), South Korea (P = .41) and Sudan (P = .06). In conclusion, routine antenatal HBV testing can be used to inform HBV prevalence estimates and vaccine programme impact in countries with limited surveillance and high migration to Australia.

Surgical outcomes and multidisciplinary management strategy of Cushing's disease: a single-center experience in China.

OBJECTIVE: The primary aim of this study was to investigate the value of multidisciplinary team (MDT) management in treating patients with Cushing's disease (CD). The secondary aim was to assess the concordance of bilateral inferior petrosal sinus sampling (BIPSS) lateralization with intraoperative observations. METHODS: The authors recruited 124 consecutive patients (128 procedures) who had undergone endoscopic endonasal resection of adrenocorticotropic hormone-secreting pituitary adenomas from May 2014 to April 2018 and assessed their clinical characteristics, surgical outcomes, and adjuvant therapies. The criteria for surgical remission were normalized serum and urinary cortisol levels, which could be suppressed by a low-dose dexamethasone suppression test at 3-months' follow-up without adjuvant treatment. RESULTS: The remission rates of the 113 patients with long-term follow-up (20.3 ± 12.2 months) were 83.2% after surgery alone and 91.2% after adjuvant therapy. The surgical remission rates of macroadenomas, MRI-visible microadenomas, and MRI-negative tumors were 66.7% (12/18), 89.3% (67/75), and 75% (15/20), respectively (p = 0.039). The surgical remission rates had a trend of improvement during the study period (87.5% in 2017-2018 vs 76.5% in 2014, p = 0.517). Multivariate regression analysis showed that a history of previous pituitary surgery (OR 0.300, 95% CI 0.100-0.903; p = 0.032) and MRI-visible microadenoma (OR 3.048, 95% CI 1.030-9.019; p = 0.044) were independent factors influencing surgical remission. The recurrence rate was 3.2% after a mean of 18 months after surgery. The remission rate of postoperative MDT management in patients with persistent disease was higher than non-MDT management (66.7% vs 0%, p = 0.033). In cases with preoperative BIPSS lateralization, 84.6% (44/52) were concordant with intraoperative findings. CONCLUSIONS: MRI-visible microadenoma and primary surgery were independent predictors of surgical remission in CD. The MDT management strategy helps to achieve a better overall outcome. BIPSS may help to lateralize the tumor in MRI-negative/equivocal microadenomas.

Structurally conserved erythrocyte-binding domain in Plasmodium provides a versatile scaffold for alternate receptor engagement.

Understanding how malaria parasites gain entry into human red blood cells is essential for developing strategies to stop blood stage infection. Plasmodium vivax preferentially invades reticulocytes, which are immature red blood cells. The organism has two erythrocyte-binding protein families: namely, the Duffy-binding protein (PvDBP) and the reticulocyte-binding protein (PvRBP) families. Several members of the PvRBP family bind reticulocytes, specifically suggesting a role in mediating host cell selectivity of P. vivax. Here, we present, to our knowledge, the first high-resolution crystal structure of an erythrocyte-binding domain from PvRBP2a, solved at 2.12 Å resolution. The monomeric molecule consists of 10 α-helices and one short ß-hairpin, and, although the structural fold is similar to that of PfRh5--the essential invasion ligand in Plasmodium falciparum--its surface properties are distinct and provide a possible mechanism for recognition of alternate receptors. Sequence alignments of the crystallized fragment of PvRBP2a with other PvRBPs highlight the conserved placement of disulfide bonds. PvRBP2a binds mature red blood cells through recognition of an erythrocyte receptor that is neuraminidase- and chymotrypsin-resistant but trypsin-sensitive. By examining the patterns of sequence diversity within field isolates, we have identified and mapped polymorphic residues to the PvRBP2a structure. Using mutagenesis, we have also defined the critical residues required for erythrocyte binding. Characterization of the structural features that govern functional erythrocyte binding for the PvRBP family provides a framework for generating new tools that block P. vivax blood stage infection.