Outcomes of possible and probable rheumatic fever: A cohort study using northern Australian register data, 2013-2019.

In Australia, there is a high burden of acute rheumatic fever (ARF) among Aboriginal and Torres Strait Islander peoples. Clinical diagnostic criteria can result in a diagnosis of 'definite', 'probable' or 'possible' ARF and outcomes range from recovery to severe rheumatic heart disease (RHD). We compared outcomes by ARF diagnosis, where the main outcome was defined as disease progression from: possible to probable ARF, definite ARF or RHD; probable to definite ARF or RHD; or definite ARF to definite ARF recurrence or RHD. Data were extracted from the Northern Territory RHD register for Indigenous Australians with an initial diagnosis of ARF during the 5.5-year study period (01/01/2013-30/06/2019). Descriptive statistics were used to describe cohort characteristics, probability of survival, and cumulative incidence risk of disease progression. Cox proportional hazards regression was used to determine whether time to disease progression differed according to ARF diagnosis. Sub-analyses on RHD outcome, clinical manifestations, and antibiotic adherence were also performed. In total there were 913 cases with an initial ARF diagnosis. Of these, 92 (13%) experienced disease progression. The probability of disease progression significantly differed between ARF diagnoses (p = 0.0043; log rank test). Cumulative incidence risk of disease progression at 5.5 years was 33.6% (95% CI 23.6-46.2) for definite, 13.5% (95% CI 8.8-20.6) for probable and 11.4% (95% CI 6.0-21.3) for possible ARF. Disease progression was 2.19 times more likely in those with definite ARF than those with possible ARF (p = 0.026). Progression to RHD was reported in 52/732 (7%) of ARF cases with normal baseline echocardiography. There was a significantly higher risk of progression from no RHD to RHD if the initial diagnosis was definite compared to possible ARF (p<0.001). These data provide a useful way to stratify risk and guide prognosis for people diagnosed with ARF and can help inform practice.

External validation of the Health Care Homes hospital admission risk stratification tool in the Aboriginal Australian population of the Northern Territory.

Objective This study aimed to externally validate the Commonwealth's Health Care Homes (HCH) algorithm for Aboriginal Australians living in the Northern Territory (NT). Methods A retrospective cohort study design using linked primary health care (PHC) and hospital data was used to analyse the performance of the HCH algorithm in predicting the risk of hospitalisation for the NT study population. The study population consisted of Aboriginal Australians residing in the NT who have visited a PHC clinic at one of the 54 NT Government clinics at least once between 1 January 2013 and 31 December 2017. Predictors of hospitalisation included demographics, patient observations, medications, diagnoses, pathology results and previous hospitalisation. Results There were a total of 3256 (28.5%) emergency attendances or preventable hospitalisations during the study period. The HCH algorithm had an area under the receiver operating characteristic curve (AUC) of 0.58 for the NT remote Aboriginal population, compared with 0.66 in the Victorian cohort. A refitted model including 'previous hospitalisation' had an AUC of 0.72, demonstrating better discrimination than the HCH algorithm. Calibration was also improved in the refitted model, with an intercept of 0.00 and a slope of 1.00, compared with an intercept of 1.29 and a slope of 0.55 in the HCH algorithm. Conclusion The HCH algorithm performed poorly on the NT cohort compared with the Victorian cohort, due to differences in population demographics and burden of disease. A population-specific hospitalisation risk algorithm is required for the NT.

Update of penetrance estimates in Birt-Hogg-Dubé syndrome.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the FLCN gene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series. METHODS: A comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in FLCN. Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of FLCN pathogenic variants. RESULTS: Our final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of the FLCN variant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers. CONCLUSIONS: These updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.

Genomic Evidence of In-Flight SARS-CoV-2 Transmission, India to Australia, April 2021.

Epidemiologic and genomic investigation of SARS-CoV-2 infections associated with 2 repatriation flights from India to Australia in April 2021 indicated that 4 passengers transmitted SARS-CoV-2 to >11 other passengers. Results suggest transmission despite mandatory mask use and predeparture testing. For subsequent flights, predeparture quarantine and expanded predeparture testing were implemented.

Dengue virus type 3 vaccine candidates generated by introduction of deletions in the 3' untranslated region (3'-UTR) or by exchange of the DENV-3 3'-UTR with that of DENV-4.

The dengue virus type 3 (DENV-3) vaccine candidate, rDEN3Delta30, was previously found to be under-attenuated in both SCID-HuH-7 mice and rhesus monkeys. Herein, two strategies have been employed to generate attenuated rDEN3 vaccine candidates which retain the full complement of structural and nonstructural proteins of DENV-3 and thus are able to induce humoral or cellular immunity to each of the DENV-3 proteins. First, using the predicted secondary structure of the 3' untranslated region (3'-UTR) of DENV-3 to design novel deletions, nine deletion mutant viruses were engineered and found to be viable. Four of nine deletion mutants replicated efficiently in Vero cells and were genetically stable. Second, chimeric rDENV-3 viruses were generated by replacement of the 3'-UTR of the rDENV-3 cDNA clone with that of rDENV-4 or rDEN4Delta30 yielding the rDEN3-3'D4 and rDEN3-3'D4Delta30 viruses, respectively. Immunization of rhesus monkeys with either of two deletion mutant viruses, rDEN3Delta30/31 and rDEN3Delta86, or with rDEN3-3'D4Delta30 resulted in infection without detectable viremia, with each virus inducing a strong neutralizing antibody response capable of conferring protection from DENV-3 challenge. The rDEN3Delta30/31 virus showed a strong host range restriction phenotype with complete loss of replication in C6/36 mosquito cells despite robust replication in Vero cells. In addition, rDEN3Delta30/31 had reduced replication in Toxorynchites mosquitoes following intrathoracic inoculation. The results are discussed in the context of vaccine development and the physical structure of the DENV 3'-UTR.

Infectivity of West Nile/dengue chimeric viruses for West Nile and dengue mosquito vectors.

West Nile virus (WN), an agent of significant human and veterinary disease, is endemic in the Old World and rapidly spreading throughout the Americas. Vaccines are needed to halt the geographic expansion of this virus and prevent disease where it is established. However, to preclude introduction of a vaccine virus into the environment, a live attenuated WN vaccine should have low potential for transmission by mosquitoes. A chimeric WN vaccine candidate was previously generated by replacing the membrane and envelope structural protein genes of recombinant dengue type 4 virus (rDEN4) with those of WN; a derivative of this virus, WN/DEN4-3'delta30, contains a 30-nucleotide deletion in the 3' untranslated region. To assess the potential for transmission by mosquitoes of these vaccine candidates, the ability of each chimeric virus to infect the mosquito midgut, disseminate to the head, and pass into the saliva was compared to that of their wild-type parental WN and DEN4 viruses in three vector species. The WN/DEN4 chimeric viruses were significantly attenuated in both Culex tarsalis, a vector able to transmit WN but not dengue, and in Ae. aegypti, a vector able to transmit dengue but not WN. However, the chimeric viruses were as infectious as either wild-type virus for Ae. albopictus, a vector able to transmit both dengue and WN. These results indicate that chimerization caused a contraction in vector host range rather than universal attenuation for mosquitoes per se. This restriction in potential vectors renders it less likely that WN/DEN4 and WN/DEN4-3'delta30 would be transmitted from vaccinees to mosquitoes.

Blinded laboratory comparison of the in situ enzyme immunoassay, the VecTest wicking assay, and a reverse transcription-polymerase chain reaction assay to detect mosquitoes infected with West Nile and St. Louis encephalitis viruses.

A blinded laboratory evaluation compared the accuracy, sensitivity, and specificity of an in situ enzyme immunoassay (EIA), VecTest wicking assay, and reverse transcription-polymerase chain reaction (RT-PCR) to detect and distinguish West Nile (WN) and St. Louis encephalitis (SLE) viruses in pools of 50 mosquitoes. Adult female Culex tarsalis Coquillett were inoculated with either WN or SLE viruses, held for 0-11 d at 28 degrees C, killed by freezing, and then were added to 49 or 48 uninfected mosquitoes to make up 14 pools positive for WN virus, 14 positive for SLE virus, 14 positive for both WN and SLE viruses, and 14 negative for virus. Pools were number coded and tested blindly. Virus was not detected in known negative pools. VecTest and RT-PCR assays were comparably sensitive and accurate, detecting virus in pools containing females held for 3 d postinoculation; only RT-PCR detected SLE virus in pools on days 0-1. The VecTest and RT-PCR produced a single false-positive result for WN and SLE, respectively. RT-PCR detected RNA in samples positive by the VecTest, indicating that the detergent in the wicking buffer did not prevent RT-PCR from confirming VecTest results. Detector antibodies used in the in situ EIA cross-reacted between SLE and WN viruses, reducing accuracy. Both the VecTest and RT-PCR provided rapid and specific results, but they detected only those viruses known to be present. Plaque assay on Vero cells was comparably sensitive and had the added benefit of detecting newly emerging viruses, but this method required virus culture followed by identification, thereby delaying reporting.

Vertical transmission of West Nile Virus by three California Culex (Diptera: Culicidae) species.

Three California Culex species previously identified as efficient laboratory vectors of West Nile (WN) virus were tested for their capability to vertically transmit WN virus. Wild-caught Culex pipiens pipiens L., Culex pipiens quinquefasciatus Say, and two populations of Culex tarsalis Coquillett females were inoculated intrathoracically with 10(2.7 +/- 0.1) plaque-forming units of WN virus. F1 progeny were reared at 18 degrees C and subsequently tested as adults for infectious virus on Vero cell culture. Virus was not detected in 197 pools comprising 4,884 Cx. p. pipiens. The minimum filial infection rate (MFIR) for Cx. p. quinquefasciatus was approximately 3.0/1,000 for 665 progeny tested in 28 pools. There was no virus detected in 102 pools of 2,453 progeny from Cx. tarsalis collected in Riverside County. The MFIR for Cx. tarsalis collected in Yolo County was approximately 6.9/1,000 for 2,165 progeny tested in 86 pools. Mosquito progeny infected vertically during the fall could potentially serve as a mechanism for WN virus to overwinter and initiate horizontal transmission the following spring.

Vector competence of California mosquitoes for West Nile virus.

To identify the mosquito species competent for West Nile virus (WNV) transmission, we evaluated 10 California species that are known vectors of other arboviruses or major pests: Culex tarsalis, Cx. pipiens pipiens, Cx. p. quinquefasciatus, Cx. stigmatosoma, Cx. erythrothorax, Ochlerotatus dorsalis, Oc. melanimon, Oc. sierrensis, Aedes vexans, and Culiseta inornata. All 10 became infected and were able to transmit WNV at some level. Ochlerotatus, Culiseta, and Aedes were low to moderately efficient vectors. They feed primarily on mammals and could play a secondary role in transmission. Oc. sierrensis, a major pest species, and Cx. p. quinquefasciatus from southern California were the least efficient laboratory vectors. Cx. tarsalis, Cx. stigmatosoma, Cx. erythrothorax, and other populations of Cx. pipiens complex were the most efficient laboratory vectors. Culex species are likely to play the primary role in the enzootic maintenance and transmission of WNV in California.