Novel genetic markers for chronic kidney disease in a geographically isolated population of Indigenous Australians: Individual and multiple phenotype genome-wide association study.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent among Indigenous Australians, especially those in remote regions. The Tiwi population has been isolated from mainland Australia for millennia and exhibits unique genetic characteristics that distinguish them from other Indigenous and non-Indigenous populations. Notably, the rate of end-stage renal disease is up to 20 times greater in this population compared to non-Indigenous populations. Despite the identification of numerous genetic loci associated with kidney disease through GWAS, the Indigenous population such as Tiwi remains severely underrepresented and the increased prevalence of CKD in this population may be due to unique disease-causing alleles/genes. METHODS: We used albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) to estimate the prevalence of kidney disease in the Tiwi population (N = 492) in comparison to the UK Biobank (UKBB) (N = 134,724) database. We then performed an exploratory factor analysis to identify correlations among 10 CKD-related phenotypes and identify new multi-phenotype factors. We subsequently conducted a genome-wide association study (GWAS) on all single and multiple phenotype factors using mixed linear regression models, adjusted for age, sex, population stratification, and genetic relatedness between individuals. RESULTS: Based on ACR, 20.3% of the population was at severely increased risk of CKD progression and showed elevated levels of ACR compared to the UKBB population independent of HbA1c. A GWAS of ACR revealed novel association loci in the genes MEG3 (chr14:100812018:T:A), RAB36 (rs11704318), and TIAM2 (rs9689640). Additionally, multiple phenotypes GWAS of ACR, eGFR, urine albumin, and serum creatinine identified a novel variant that mapped to the gene MEIS2 (chr15:37218869:A:G). Most of the identified variants were found to be either absent or rare in the UKBB population. CONCLUSIONS: Our study highlights the Tiwi population's predisposition towards elevated ACR, and the collection of novel genetic variants associated with kidney function. These associations may prove valuable in the early diagnosis and treatment of renal disease in this underrepresented population. Additionally, further research is needed to comprehensively validate the functions of the identified variants/genes.

Variance of age-specific log incidence decomposition (VALID): a unifying model of measured and unmeasured genetic and non-genetic risks.

BACKGROUND: The extent to which known and unknown factors explain how much people of the same age differ in disease risk is fundamental to epidemiology. Risk factors can be correlated in relatives, so familial aspects of risk (genetic and non-genetic) must be considered. DEVELOPMENT: We present a unifying model (VALID) for variance in risk, with risk defined as log(incidence) or logit(cumulative incidence). Consider a normally distributed risk score with incidence increasing exponentially as the risk increases. VALID's building block is variance in risk, Δ2, where Δ = log(OPERA) is the difference in mean between cases and controls and OPERA is the odds ratio per standard deviation. A risk score correlated r between a pair of relatives generates a familial odds ratio of exp(rΔ2). Familial risk ratios, therefore, can be converted into variance components of risk, extending Fisher's classic decomposition of familial variation to binary traits. Under VALID, there is a natural upper limit to variance in risk caused by genetic factors, determined by the familial odds ratio for genetically identical twin pairs, but not to variation caused by non-genetic factors. APPLICATION: For female breast cancer, VALID quantified how much variance in risk is explained-at different ages-by known and unknown major genes and polygenes, non-genomic risk factors correlated in relatives, and known individual-specific factors. CONCLUSION: VALID has shown that, while substantial genetic risk factors have been discovered, much is unknown about genetic and familial aspects of breast cancer risk especially for young women, and little is known about individual-specific variance in risk.

Computed tomography scan radiation and brain cancer incidence.

BACKGROUND: Computed tomography (CT) scans make substantial contributions to low-dose ionizing radiation exposures, raising concerns about excess cancers caused by diagnostic radiation. METHODS: Deidentified medicare records for all Australians aged 0-19 years between 1985-2005 were linked to national death and cancer registrations to 2012. The National Cancer Institute CT program was used to estimate radiation doses to the brain from CT exposures in 1985-2005, Poisson regression was used to model the dependence of brain cancer incidence on brain radiation dose, which lagged by 2 years to minimize reverse causation bias. RESULTS: Of 10 524 842 young Australians, 611 544 were CT-exposed before the age of 20 years, with a mean cumulative brain dose of 44 milligrays (mGy) at an average follow-up of 13.5 years after the 2-year lag period. 4472 were diagnosed with brain cancer, of whom only 237 had been CT-exposed. Brain cancer incidence increased with radiation dose to the brain, with an excess relative risk of 0.8 (95% CI 0.57-1.06) per 100 mGy. Approximately 6391 (95% CI 5255, 8155) persons would need to be exposed to cause 1 extra brain cancer. CONCLUSIONS: For brain tumors that follow CT exposures in childhood by more than 2 years, we estimate that 40% (95% CI 29%-50%) are attributable to CT Radiation and not due to reverse causation. However, because of relatively low rates of CT exposure in Australia, only 3.7% (95% CI 2.3%-5.4%) of all brain cancers are attributable to CT scans. The population-attributable fraction will be greater in countries with higher rates of pediatric scanning.

Emphysematous cholecystitis in a patient with porcelain gallbladder.

Our case uniquely presents a patient with two rare gallbladder disease entities occurring simultaneously. The patient presented to hospital with abdominal pain and was subsequently diagnosed with emphysematous cholecystitis and porcelain gallbladder. After initial conservative management failed, cholecystectomy was performed, and the patient recovered well post-operatively and was discharged home.

Cohort profile: The Australian Paediatric Exposure to Radiation Cohort (Aust-PERC).

Although the carcinogenic effects of high-dose radiation are well-established, the risks at low doses, such as from diagnostic X-rays, are less well understood. Children are susceptible to radiation induced cancers, and in the last decade, several cohort studies have reported increased cancer risks following computed tomography (CT) scans in childhood. However, cohort studies can be limited by insufficient follow-up, indication bias, reverse causation, or by lack of organ doses from CT scans or other exposures. Aust-PERC is a retrospective cohort designed to study the effects of low-dose medical radiation exposure, primarily from CT scans, in young Australians. The cohort was ascertained using deidentified billing records from patients who were aged 0-19 years while enrolled in Medicare (Australia's universal healthcare system) between 1985 and 2005. All procedures billed to Medicare in this age/time window that involved low-dose radiation were identified, and persons without such procedures were flagged as unexposed. The Aust-PERC cohort has been linked, using confidential personal identifiers, to the Australian Cancer Database and the National Death Index, on two occasions (to Dec. 2007 and Dec. 2012) by the responsible government agency (Australian Institute of Health and Welfare). Deidentified Medicare service records of all radiological procedures including CT scans, nuclear medicine (NM) scans and fluoroscopy and plain X-ray procedures have been available to derive estimated radiation doses in the cohort. Records of other medical and surgical procedures, together with demographic and socioeconomic variables are being used in analyses to assess biases arising from reverse causation and confounding. After excluding patients with errant records, 11 802 846 persons remained in the baseline cohort, with an average follow-up time of 22.3 years to December 2012. There were 275 489 patients exposed to diagnostic nuclear medicine scans and 688 363 patients exposed to CT scans before age 20 and before cancer diagnosis. Between 1 January 1985 and 31 December 2012, there were 105 124 deaths and 103 505 incident cancers. Dose-response analyses based on the relevant organ doses are underway for individual cancers, and we plan to extend the follow-up for another 8 years to Dec 2020. Analyses using this very large Aust-PERC cohort, with extended follow-up, will help to resolve international uncertainties about the causal role of diagnostic medical radiation as a cause of cancer.

A prospective phase II clinical trial identifying the optimal regimen for carboplatin plus standard backbone of anthracycline and taxane-based chemotherapy in triple negative breast cancer.

Addition of platinums to combination chemotherapy for triple negative breast cancer (TNBC) has shown efficacy and is increasingly accepted in the clinic, yet optimal delivery is unknown. A prospective clinical trial with TNBC patients was conducted to determine the optimal chemotherapy regimen to deliver carboplatin with standard dose dense ACT. Tissue microarray was conducted to isolate markers indicative of response to treatment. 90 TNBC patients were enrolled onto our trial. The most successful version placed the carboplatin on the second and final paclitaxel treatment with liberal hematological parameters. Our final regimen had the lowest grade 3 or 4 toxicities, no delays, no dose reductions of carboplatin, and 32% reduction in paclitaxel doses. Stage I (AJCC7) patients did well with carboplatin-based chemotherapy with zero relapse rate. Reduction in protein levels of androgen receptor and PD-L1 were found to be potential indicators of patient relapse. We have optimized a protocol for the addition of carboplatin to standard of care chemotherapy in TNBC patients. Early data indicates reduced protein levels of androgen receptor and PD-L1 as indicators of response to treatment.Trial registration This trial was registered at Canadian Cancer Trials. http://www.canadiancancertrials.ca/.

Diverticulitis complicated by colovenous fistula formation and pylephlebitis.

Acute diverticulitis is associated with a range of complications including fistula formation. Colovenous fistula formation, where there is a fistula between the inferior mesenteric vein and colon, is an extremely rare and serious complication of diverticulitis. Pylephlebitis, which is defined as infective suppurative thrombosis of the portal vein, is another uncommon complication of any intra-abdominal source of infection, including diverticulitis. Both complications are independently associated with significant morbidity and mortality. We report a case of a patient with acute diverticulitis who subsequently developed both colo-venous fistula and pylephlebitis and was successfully managed conservatively.

A case of mesenteric panniculitis in a patient with Tangier disease.

Mesenteric panniculitis is a rare disease caused by idiopathic inflammation of adipose tissue, most commonly affecting the mesentery of the small bowel. We present a unique case of mesenteric panniculitis in a patient with Tangier disease; a rare genetic disorder caused by mutations in the ABCA1 gene, leading to deficiency of high-density lipoprotein in the blood and accumulation of cholesterol esters within various tissues. The accumulation of cholesterol esters in body tissues in patients with Tangier disease may contribute to the pathogenesis of mesenteric panniculitis; although there is limited evidence to support this hypothesis due to the rarity of concurrent disease.

Contiguous Meningioma and B-Cell Lymphoma: A Scoping Review and Case Illustration.

BACKGROUND: The diagnosis of a contiguous, synchronous meningioma and central nervous system B-cell lymphoma is rare and associated with paradoxical treatment paradigms. We performed a scoping review of contiguous meningioma and B-cell lymphoma and included an additional illustrative case. METHODS: The OVID Medline and PubMed databases were systematically searched using the Preferred Reporting Items of Systematic Reviews and Meta-Analysis guidelines. Only human clinical reports of contiguous, synchronous meningioma and B-cell lymphoma were included. We concurrently detailed a representative case from our institution. RESULTS: Nine case reports met our criteria, including the present case. The average age at diagnosis was 67.4 years. Patients showed a female-to-male predominance of 7:2. The diagnosis of synchronous intracranial tumors was not suspected or discovered until after surgical resection in 100% of cases. All meningiomas were grade I on histopathologic diagnosis, while lymphomas were distributed between diffuse large B-cell lymphoma (56%), metastatic lymphoma (22%), Burkitt lymphoma (11%), and follicular lymphoma (11%). All patients underwent surgical resection. Patients (n = 5) treated with adjuvant chemotherapy had evidence of longer progression-free survival (median 12 months; range, 3-18 months) than patients without adjuvant chemotherapy (n = 2; median 2 months; range, 1-3 months). CONCLUSIONS: Contiguous, synchronous meningioma/B-cell lymphoma is a rare diagnosis that may appear as an inconspicuous solitary intracranial neoplasm on imaging. Based on the limited cases and current treatment of lymphoma, progression-free survival may be contingent on the prompt initiation of chemotherapy targeting the lymphoma rather than surgical resection of the meningeal mass. Providers should prioritize prompt medical management.

Seronegative granulomatosis with polyangiitis presenting as an acute skull base osteomyelitis with multiple cranial neuropathies.

Granulomatosis with polyangiitis (GPA, formerly Wegener's) is a rare form of vasculitis, commonly affecting the upper and lower respiratory tract with simultaneous glomerulonephritis. Ear, nose and throat (ENT) manifestations account for the majority of presentations. The presence of antineutrophil cytoplasmic antibody is a recognized hallmark of GPA, but clinicians should remain cautious of false negative results. We describe a rare case of GPA presenting with concurrent middle ear disease and multiple lower cranial nerve palsies. Clinical judgment was affected by repeated negative autoimmune screens, and a definitive diagnosis was only achieved following renal biopsy. Reported cases of GPA presenting with mastoiditis or cranial nerve involvement are typically seropositive, with seronegative GPA following a less aggressive process. This case highlights the importance of clinical suspicion in the face of treatment resistant ENT pathology, and the need for early histopathological analysis. Early diagnosis and treatment are crucial in limiting disease progression.

Deletions in VANGL1 are a risk factor for antibody-mediated kidney disease.

We identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.1,2 We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1+/- mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.

Ct Dosimetry for The Australian Cohort Data Linkage Study.

Children undergoing computed tomography (CT) scans have an increased risk of cancer in subsequent years, but it is unclear how much of the excess risk is due to reverse causation bias or confounding, rather than to causal effects of ionising radiation. An examination of the relationship between excess cancer risk and organ dose can help to resolve these uncertainties. Accordingly, we have estimated doses to 33 different organs arising from over 900 000 CT scans between 1985 and 2005 in our previously described cohort of almost 12 million Australians aged 0-19 years. We used a multi-tiered approach, starting with Medicare billing details for government-funded scans. We reconstructed technical parameters from national surveys, clinical protocols, regulator databases and peer-reviewed literature to estimate almost 28 000 000 individual organ doses. Doses were age-dependent and tended to decrease over time due to technological improvements and optimisation.

Top ten research priorities for problematic knee arthroplasty.

AIMS: The James Lind Alliance aims to bring patients, carers, and clinicians together to identify uncertainties regarding care. A Priority Setting Partnership was established by the British Association for Surgery of the Knee in conjunction with the James Lind Alliance to identify research priorities related to the assessment, management, and rehabilitation of patients with persistent symptoms after knee arthroplasty. METHODS: The project was conducted using the James Lind Alliance protocol. A steering group was convened including patients, surgeons, anaesthetists, nurses, physiotherapists, and researchers. Partner organizations were recruited. A survey was conducted on a national scale through which patients, carers, and healthcare professionals submitted key unanswered questions relating to problematic knee arthroplasties. These were analyzed, aggregated, and synthesized into summary questions and the relevant evidence was checked. After confirming that these were not answered in the current literature, 32 questions were taken forward to an interim prioritization survey. Data from this survey informed a shortlist taken to a final consensus meeting. RESULTS: A total of 769 questions were received during the initial survey with national reach across the UK. These were refined into 32 unique questions by an independent information specialist. The interim prioritization survey was completed by 201 respondents and 25 questions were taken to a final consensus group meeting between patients, carers, and healthcare professionals. Consensus was reached for ranking the top ten questions for publication and dissemination. CONCLUSIONS: The top ten research priorities focused on pain, infection, stiffness, health service configuration, surgical and non-surgical management strategies, and outcome measures. This list will guide funders and help focus research efforts within the knee arthroplasty community. Cite this article: Bone Joint J 2020;102-B(9):1176-1182.

CT scans in childhood predict subsequent brain cancer: Finite mixture modelling can help separate reverse causation scans from those that may be causal.

BACKGROUND: Excess brain cancers observed after computed tomography (CT) scans could be caused by ionizing radiation. However, as scans are often used to investigate symptoms of brain cancer, excess cancers could also be due to reverse causation bias. We used finite mixture models (FMM) to differentiate CT exposures that are plausibly causal from those due to reverse causation. METHODS: Persons with at least one CT scan exposure and a subsequent diagnosis of brain cancer were selected from a cohort of 11 million young Australians. We fitted FMMs and used the posterior probability to inform the choice of exclusion periods. We validated our findings using a separate clinical dataset describing the time between first symptoms and brain cancer diagnosis (pre-diagnostic symptomatic interval; PSI). RESULTS: The cohort included 1028 persons with a diagnosed brain tumor and exposed to a total of 1,450 CT scans. The best-fitting model was a generalized linear mixture model using the exponential distribution with three latent classes and two covariates (age at exposure and year of exposure). The 99th percentile classifier cutoff was 18.9 months. The sample-size weighted mean of the 99th percentile of the PSI, derived from clinical data, was 15.6 months. CONCLUSIONS: To minimize reverse causation bias in studies of CT scan and brain cancer, the optimal exclusion period is one to two years (depending on the choice of classifier). This information will inform the interpretation of current and future studies.

Analysis of the F2LR3 (PAR4) Single Nucleotide Polymorphism (rs773902) in an Indigenous Australian Population.

The F2RL3 gene encoding protease activated receptor 4 (PAR4) contains a single nucleotide variant, rs773902, that is functional. The resulting PAR4 variants, Thr120, and Ala120, are known to differently affect platelet reactivity to thrombin. Significant population differences in the frequency of the allele indicate it may be an important determinant in the ethnic differences that exist in thrombosis and hemostasis, and for patient outcomes to PAR antagonist anti-platelet therapies. Here we determined the frequency of rs773902 in an Indigenous Australian group comprising 467 individuals from the Tiwi Islands. These people experience high rates of renal disease that may be related to platelet and PAR4 function and are potential recipients of PAR-antagonist treatments. The rs773902 minor allele frequency (Thr120) in the Tiwi Islanders was 0.32, which is similar to European and Asian groups and substantially lower than Melanesians and some African groups. Logistic regression and allele distortion testing revealed no significant associations between the variant and several markers of renal function, as well as blood glucose and blood pressure. These findings suggest that rs773902 is not an important determinant for renal disease in this Indigenous Australian group. However, the relationships between rs773902 genotype and platelet and drug responsiveness in the Tiwi, and the allele frequency in other Indigenous Australian groups should be evaluated.

Bilateral occlusive retinal vasculitis associated with primary sclerosing cholangitis.

We present the case of a 46-year-old man who presented with bilateral panuveitis and occlusive retinal vasculitis 6 months after being acutely admitted with abnormal liver function and diagnosed with primary sclerosing cholangitis (PSC). Initial investigations by the medical and ophthalmic departments including all autoimmune investigations were within normal parameters. Of particular interest was the high likelihood of inadvertent androgenic-anabolic steroid self-suppression of disease. As a lifelong bodybuilder, the patient had been taking oral and intramuscular steroids for years. He became symptomatic upon cessation of these recreational medications. There remains a significant paucity of information describing the relationship between uveitis and PSC. Given the poorly understood aetiology of this rare cholestatic disease, we review the current literature and highlight the diagnostic and therapeutic challenges for such a patient. PSC may predispose patients to an occlusive panuveitis with androgenic-anabolic steroids suppressing ocular autoimmune disease.

Cervical Subcutaneous Emphysema following Total Laryngectomy: An Unusual Complication of Nasogastric Intubation.

The nasogastric tube remains an important route of enteral feeding in the early postoperative period following total laryngectomy. Its insertion, however, is not without any risks of complications. In this article, we report an unusual case of inadvertent nasopharyngeal perforation secondary to intraoperative nasogastric tube insertion presenting as unilateral cervical subcutaneous emphysema in a patient who underwent total laryngectomy.

New Genetic Loci Associated With Chronic Kidney Disease in an Indigenous Australian Population.

The common occurrence of renal disease in Australian Aboriginal populations such as Tiwi Islanders may be determined by environmental and genetic factors. To explore genetic contributions, we performed a genome-wide association study (GWAS) of urinary albumin creatinine ratio (ACR) in a sample of 249 Tiwi individuals with genotype data from a 370K Affymetrix single nucleotide polymorphism (SNP) array. A principal component analysis (PCA) of the 249 individual Tiwi cohort and samples from 11 populations included in phase III of the HapMap Project indicated that Tiwi Islanders are a relatively distinct and unique population with no close genetic relationships to the other ethnic groups. After adjusting for age and sex, the proportion of ACR variance explained by the 370K SNPs was estimated to be 37% (using the software GCTA.31; likelihood ratio = 8.06, p-value = 0.002). The GWAS identified eight SNPs that were nominally significantly associated with ACR (p < 0.0005). A replication study of these SNPs was performed in an independent cohort of 497 individuals on the eight SNPs. Four of these SNPs were significantly associated with ACR in the replication sample (p < 0.05), rs4016189 located near the CRIM1 gene (p = 0.000751), rs443816 located in the gene encoding UGT2B11 (p = 0.022), rs6461901 located near the NFE2L3 gene, and rs1535656 located in the RAB14 gene. The SNP rs4016189 was still significant after adjusting for multiple testing. A structural equation model (SEM) demonstrated that the rs4016189 SNP was not associated with other phenotypes such as estimated glomerular filtration rate (eGFR), diabetes, and blood pressure.