The Challenges of Distinguishing Different Causes of TMA in a Pregnant Kidney Transplant Recipient.

Thrombotic microangiopathy (TMA) reflects a syndrome of endothelial injury characterised by microangiopathic haemolytic anaemia (nonimmune), thrombocytopenia, and often end-organ dysfunction. TMA disorders are well-recognised in kidney transplant recipients, often due to an underlying genetic predisposition related to complement dysregulation, or de novo due to infection, immunosuppression toxicity, or antibody-mediated rejection. In pregnancy, TMA disorders are most commonly due to severe pre-eclampsia or HELLP, but may also be due to thrombotic thrombocytopenic purpura (TTP) or complement-mediated (atypical) haemolytic uremic syndrome (aHUS). Complement dysregulation is being recognised as playing a role in the development of preeclampsia and HELLP syndrome in addition to aHUS. Due to overlapping clinical and laboratory features, diagnosis can be difficult and delays in treatment can be life-threatening for both mother and fetus. This report describes a 32 year-old female who had two successive wanted pregnancies. The first pregnancy was terminated at 22 weeks gestation due to presumed severe preeclampsia and fetal growth restriction in the context of known chronic kidney failure due to reflux nephropathy. A living-related kidney transplant was performed to improve the chances of pregnancy resulting in a live birth. A subsequent pregnancy was complicated by progressive kidney impairment and hypertension at 22 weeks gestation. Kidney biopsy showed TMA, but the etiology was unclear. This report highlights the diagnostic dilemma of TMA in a pregnant kidney transplant recipient and a role for the anti-C5 terminal complement blockade monoclonal antibody eculizumab, in pregnancy-associated TMA, especially at a peri-viable gestation.

Economic evaluation of tele-resuscitation intervention on emergency department pediatric visits in the Niagara Region, Canada a pilot study.

Introduction: The use of telemedicine in critical care is emerging, however, there is a paucity of information surrounding the costs relative to health gains in the pediatric population. This study aimed to estimate the cost-effectiveness of a pediatric tele-resuscitation (Peds-TECH) intervention compared to the usual care in five community hospital emergency departments (EDs). Using a decision tree analysis approach with secondary retrospective data from a 3-year time period, this cost-effectiveness analysis was completed. Methods: A mixed methods quasi-experimental design was embedded in the economic evaluation of Peds-TECH intervention. Patients aged <18 years triaged as Canadian Triage and Acuity Scale 1 or 2 at EDs were eligible to receive the intervention. Qualitative interviews were conducted with parents/caregivers to explore the out-of-pocket (OOP) expenses. Patient-level health resource utilization was extracted from Niagara Health databases. The Peds-TECH budget calculated one-time technology and operational costs per patient. Base-case analyses determined the incremental cost per year of life lost (YLL) averted, and additional sensitivity analysis confirmed the robustness of the results. Results: Odds ratio for mortality among cases was 0.498 (95% CI: 0.173, 1.43). The average cost of a patient receiving the Peds-TECH intervention was $2,032.73 compared to $317.45 in usual care. In total, 54 patients received the Peds-TECH intervention. Fewer children died in the intervention group resulting in 4.71 YLL. The probabilistic analysis revealed an incremental cost-effectiveness ratio of $64.61 per YLL averted. Conclusion: Peds-TECH appears to be a cost-effective intervention for resuscitating infants/children in hospital emergency departments.

Polypharmacy Predicts Onset and Transition of Frailty, Malnutrition, and Adverse Outcomes in Peritoneal Dialysis Patient.

BACKGROUND: Polypharmacy, frailty and malnutrition are known predictors of adverse outcomes in dialysis patients. Little has reported about their interaction and composite prognostic values. We aimed to describe the interaction between polypharmacy, frailty, nutrition, hospitalization, and survival in peritoneal dialysis patients. METHODS: In this prospective cohort study, we recruited 573 peritoneal dialysis patients. Drug burden was measured by medication number and daily pill load. Frailty and nutrition were assessed by the validated Frailty Score (FQ) and Subjective Global Assessment (SGA) respectively. All patients were followed for two years. Primary outcome was all-cause mortality. Secondary outcomes were fall and fracture episodes, hospitalization, change in FQ and SGA. RESULTS: At baseline, each patient took 7.5 ± 2.6 medications with 15.5 ± 8.5 tablets per day. Medication number, but not daily pill load predicted baseline FQ (p = 0.004) and SGA (p = 0.03). Over 2 years, there were 69 fall and 1,606 hospitalization episodes. In addition, 148 (25.8%) patients died, while FQ and SGA changed by 0.73 ± 4.23 and -0.07 ± 1.06 respectively in survivors. Medication number (hospitalization: p = 0.02, survival: p = 0.005), FQ (hospitalization: p < 0.001; survival: p = 0.01) predicted hospitalization and survival. Medication number also predicted fall episodes (p = 0.02) and frailty progression (p = 0.002). Daily pill load did not predict any of these outcomes. CONCLUSIONS: Drug burden is high in peritoneal dialysis patients, and it carries important prognostic implication. Medication number but not pill load significantly predicted onset and progression of frailty, malnutrition, fall, hospitalization, and mortality.

'Breast Cosmesis After Breast-Conserving Therapy' Who is the Judge, Patient or Surgeon?

INTRODUCTION: More than 80% of newly diagnosed breast cancers are managed with breast-conserving therapy (BCT). Preservation of cosmetically acceptable breasts is an inherent aim of all breast-conserving efforts-this can, however, be difficult to assess objectively. Compounding this is the difference in perception of breast cosmesis between patients and surgeons. This study compares the concordance of a new subscale-based cosmetic score (TCS) with the patient's perception. METHOD: Eastern Health Breast and Cancer Centre conducted this study on patients who had completed their BCT and radiotherapy. Participation was voluntary and involved permitting an assessor (breast surgery fellow or consultant) to grade cosmetic outcomes to generate a Total Cosmesis Score (TCS). The patients blinded to this assessment were then asked to complete the postoperative segment of the BCT module of the Breast-Q questionnaire. TCS from surgeon assessment was compared against patient assessment (questions BQ1i and BQ1k specifically). Cohen's kappa was calculated to define the strength of the inter-rater agreement. RESULTS: One hundred twelve patients with a mean age of 59 (range 27-89) participated in the study. TCS was low in 26% and high in 74% of participants. 76% and 69% of participants were satisfied when answering Breast-Q questions 'How your lumpectomy breast looks?' and 'How you look in the mirror unclothed?' respectively (Cohen's k = 0.464, 95% CI 0.337-0.591, p < 0.01). The agreement between the TCS and the patient assessment was poor (Cohen's k = 0.172, 95% CI - 0.020-2.093, p = 0.067). CONCLUSION: Cosmetic outcomes scored using TCS by surgeons do not match patient's own assessment of the cosmetic result.

Polygenic risk score as a determinant of risk of keratinocyte cancer in an Australian population-based cohort.

BACKGROUND: Keratinocyte cancer (KC) risk is determined by genetic and environmental factors. Genetic risk can be quantified by polygenic risk scores (PRS), which sum the combined effects of single nucleotide polymorphisms (SNPs). OBJECTIVES: Our objective here was to evaluate the contribution of the summed genetic score to predict the KC risk in the phenotypically well-characterized Nambour population. METHODS: We used PLINK v1.90 to calculate PRS for 432 cases, 566 controls, using 78 genome-wide independent SNPs that are associated with KC risk. We assessed the association between PRS and KC using logistic regression, stratifying the cohort into three risk groups (high 20%, intermediate 60%, low 20%). RESULTS: The fully adjusted model including traditional risk factors (phenotypic and sun exposure-related), showed a significant 50% increase in odds of KC per standard deviation of PRS (odds ratio (OR) = 1.51; 95% confidence interval (CI) = 1.30-1.76, P = 5.75 × 10-8 ). Those in the top 20% PRS had over three times the risk of KC of those in the lowest 20% (OR = 3.45; 95% CI = 2.18-5.50, P = 1.5 × 10-7 ) and higher absolute risk of KC per 100 person-years of 2.96 compared with 1.34. Area under the ROC curve increased from 0.72 to 0.74 on adding PRS to the fully adjusted model. CONCLUSIONS: These results show that PRS can enhance the prediction of KC above traditional risk factors.

Lesion Volume in Relapsing Multiple Sclerosis is Associated with Perivascular Space Enlargement at the Level of the Basal Ganglia.

BACKGROUND AND PURPOSE: Perivascular spaces surround the blood vessels of the brain and are involved in neuroimmune functions and clearance of metabolites via the glymphatic system of the brain. Enlarged perivascular spaces could be a marker of dysfunction in these processes and, therefore, are highly relevant to monitoring disease activity in MS. This study aimed to compare the number of enlarged perivascular spaces in people with relapsing MS with MR imaging markers of inflammation and brain atrophy. MATERIALS AND METHODS: Fifty-nine patients (18 with clinically isolated syndrome, 22 with early and 19 with late relapsing-remitting MS) were scanned longitudinally (mean follow-up duration = 19.6 [SD, 0.5] months) using T2-weighted, T1-weighted, and FLAIR MR imaging. Two expert raters identified and counted enlarged perivascular spaces on T2-weighted MR images from 3 ROIs (the centrum semiovale, basal ganglia, and midbrain). Baseline and change with time in the number of enlarged perivascular spaces were correlated with demographics and lesion and brain volumes. RESULTS: Late relapsing-remitting MS had a greater average number of enlarged perivascular spaces at baseline at the level of the basal ganglia (72.3) compared with early relapsing-remitting MS (60.5) and clinically isolated syndrome (54.7) (F = 3.4, P = .042), and this finding correlated with lesion volume (R = 0.44, P = .0004) but not brain atrophy (R = -0.16). Enlarged perivascular spaces increased in number with time in all regions, and the rate of increase did not differ among clinical groups. CONCLUSIONS: Enlarged perivascular spaces at the level of the basal ganglia are associated with greater neuroinflammatory burden, and the rate of enlargement appears constant in patients with relapsing-remitting disease phenotypes.

Characteristics of heterosexually-acquired compared to homosexually-acquired HIV and implications for clinical practice: results from the Australian HIV Observational Database.

Heterosexuals living with HIV report feeling additional HIV stigma compared to homosexual men, which may affect clinical outcomes. Yet, beyond routinely collected surveillance data, little is known about the characteristics of individuals who acquire HIV heterosexually and clinical outcomes by mode of sexual acquisition have not been directly compared. Using data from the Australian HIV Observational Database, we compared clinical characteristics of those with heterosexually-acquired (Het-HIV) to homosexually-acquired HIV (Hom-HIV) to investigate any differences and their implications for clinical management. 513 Het-HIV and 1467 Hom-HIV patients were included and contributed 3,127 and 9,457 person-years of follow-up, respectively. Compared with Hom-HIV, Het-HIV were more often born outside Australia (62.5% vs 39.9%, p<0.001), less likely to have Hepatitis C (4.8% vs 7.8%, p=0.029) and had lower median CD4 counts at diagnosis (292 vs 450 cells/µL, p<0.001) and cART initiation (270 vs 340 cells/µL, p<0.001). Despite these lower CD4 counts, there were no significant differences between groups for time to the major clinical endpoints of cART initiation, viral suppression, virological failure or all-cause mortality. Het-HIV had a lower risk of loss-to-follow-up than Hom-HIV (aHR 0.78; 95% CI 0.64-0.95). Further studies examining factors associated with, and interventions to inform retention in care are required.

Risk factors for melanoma by anatomical site: an evaluation of aetiological heterogeneity.

BACKGROUND: Melanoma aetiology has been proposed to have two pathways, which are determined by naevi and type of sun exposure and related to the anatomical site where melanoma develops. OBJECTIVES: We examined associations with melanoma by anatomical site for a comprehensive set of risk factors including pigmentary and naevus phenotypes, ultraviolet radiation exposure and polygenic risk. METHODS: We analysed harmonized data from 2617 people with incident first invasive melanoma and 975 healthy controls recruited through two population-based case-control studies in Australia and the UK. Questionnaire data were collected by interview using a single protocol, and pathway-specific polygenic risk scores were derived from DNA samples. We estimated adjusted odds ratios using unconditional logistic regression that compared melanoma cases at each anatomical site with all controls. RESULTS: When cases were compared with control participants, there were stronger associations for many naevi vs. no naevi for melanomas on the trunk, and upper and lower limbs than on the head and neck (P-heterogeneity < 0·001). Very fair skin (vs. olive/brown skin) was more weakly related to melanoma on the trunk than to melanomas at other sites (P-heterogeneity = 0·04). There was no significant difference by anatomical site for polygenic risk. Increased weekday sun exposure was positively associated with melanoma on the head and neck but not on other sites. CONCLUSIONS: We found evidence of aetiological heterogeneity for melanoma, supporting the dual pathway hypothesis. These findings enhance understanding of risk factors for melanoma and can guide prevention and skin examination education and practices.

Virological failure and HIV drug resistance among adults living with HIV on second-line antiretroviral therapy in the Asia-Pacific.

OBJECTIVES: To assess second-line antiretroviral therapy (ART) virological failure and HIV drug resistance-associated mutations (RAMs), in support of third-line regimen planning in Asia. METHODS: Adults > 18 years of age on second-line ART for ≥ 6 months were eligible. Cross-sectional data on HIV viral load (VL) and genotypic resistance testing were collected or testing was conducted between July 2015 and May 2017 at 12 Asia-Pacific sites. Virological failure (VF) was defined as VL > 1000 copies/mL with a second VL > 1000 copies/mL within 3-6 months. FASTA files were submitted to Stanford University HIV Drug Resistance Database and RAMs were compared against the IAS-USA 2019 mutations list. VF risk factors were analysed using logistic regression. RESULTS: Of 1378 patients, 74% were male and 70% acquired HIV through heterosexual exposure. At second-line switch, median [interquartile range (IQR)] age was 37 (32-42) years and median (IQR) CD4 count was 103 (43.5-229.5) cells/µL; 93% received regimens with boosted protease inhibitors (PIs). Median duration on second line was 3 years. Among 101 patients (7%) with VF, CD4 count > 200 cells/µL at switch [odds ratio (OR) = 0.36, 95% confidence interval (CI): 0.17-0.77 vs. CD4 ≤ 50) and HIV exposure through male-male sex (OR = 0.32, 95% CI: 0.17-0.64 vs. heterosexual) or injecting drug use (OR = 0.24, 95% CI: 0.12-0.49) were associated with reduced VF. Of 41 (41%) patients with resistance data, 80% had at least one RAM to nonnucleoside reverse transcriptase inhibitors (NNRTIs), 63% to NRTIs, and 35% to PIs. Of those with PI RAMs, 71% had two or more. CONCLUSIONS: There were low proportions with VF and significant RAMs in our cohort, reflecting the durability of current second-line regimens.

Advanced ADC Histogram, Perfusion, and Permeability Metrics Show an Association with Survival and Pseudoprogression in Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium.

BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a lethal childhood brain cancer with dismal prognosis and MR imaging is the primary methodology used for diagnosis and monitoring. Our aim was to determine whether advanced diffusion, perfusion, and permeability MR imaging metrics predict survival and pseudoprogression in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: A clinical trial using the poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor veliparib concurrently with radiation therapy, followed by maintenance therapy with veliparib + temozolomide, in children with diffuse intrinsic pontine glioma was conducted by the Pediatric Brain Tumor Consortium. Standard MR imaging, DWI, dynamic contrast-enhanced perfusion, and DSC perfusion were performed at baseline and approximately every 2 months throughout treatment. ADC histogram metrics of T2-weighted FLAIR and enhancing tumor volume, dynamic contrast-enhanced permeability metrics for enhancing tumors, and tumor relative CBV from DSC perfusion MR imaging were calculated. Baseline values, post-radiation therapy changes, and longitudinal trends for all metrics were evaluated for associations with survival and pseudoprogression. RESULTS: Fifty children were evaluable for survival analyses. Higher baseline relative CBV was associated with shorter progression-free survival (P = .02, Q = 0.089) and overall survival (P = .006, Q = 0.055). Associations of higher baseline mean transfer constant from the blood plasma into the extravascular extracellular space with shorter progression-free survival (P = .03, Q = 0.105) and overall survival (P = .03, Q = 0.102) trended toward significance. An increase in relative CBV with time was associated with shorter progression-free survival (P < .001, Q < 0.001) and overall survival (P = .004, Q = 0.043). Associations of longitudinal mean extravascular extracellular volume fraction with progression-free survival (P = .03, Q = 0.104) and overall survival (P = .03, Q = 0.105) and maximum transfer constant from the blood plasma into the extravascular extracellular space with progression-free survival (P = .03, Q = 0.102) trended toward significance. Greater increases with time were associated with worse outcomes. True radiologic progression showed greater post-radiation therapy decreases in mode_ADC_FLAIR compared with pseudoprogression (means, -268.15 versus -26.11, P = .01.) CONCLUSIONS: ADC histogram, perfusion, and permeability MR imaging metrics in diffuse intrinsic pontine glioma are useful in predicting survival and pseudoprogression.

Atherosclerotic cardiovascular disease screening and management protocols among adult HIV clinics in Asia.

OBJECTIVES: Integration of HIV and non-communicable disease services improves the quality and efficiency of care in low- and middle-income countries (LMICs). We aimed to describe current practices for the screening and management of atherosclerotic cardiovascular disease (ASCVD) among adult HIV clinics in Asia. METHODS: Sixteen LMIC sites included in the International Epidemiology Databases to Evaluate AIDS - Asia-Pacific network were surveyed. RESULTS: Sites were mostly (81%) based in urban public referral hospitals. Half had protocols to assess tobacco and alcohol use. Protocols for assessing physical inactivity and obesity were in place at 31% and 38% of sites, respectively. Most sites provided educational material on ASCVD risk factors (between 56% and 75% depending on risk factors). A total of 94% reported performing routine screening for hypertension, 100% for hyperlipidaemia and 88% for diabetes. Routine ASCVD risk assessment was reported by 94% of sites. Protocols for the management of hypertension, hyperlipidaemia, diabetes, high ASCVD risk and chronic ischaemic stroke were in place at 50%, 69%, 56%, 19% and 38% of sites, respectively. Blood pressure monitoring was free for patients at 69% of sites; however, most required patients to pay some or all the costs for other ASCVD-related procedures. Medications available in the clinic or within the same facility included angiotensin-converting enzyme inhibitors (81%), statins (94%) and sulphonylureas (94%). CONCLUSION: The consistent availability of clinical screening, diagnostic testing and procedures and the availability of ASCVD medications in the Asian LMIC clinics surveyed are strengths that should be leveraged to improve the implementation of cardiovascular care protocols.

A risk prediction model for the development of subsequent primary melanoma in a population-based cohort.

BACKGROUND: Guidelines for follow-up of patients with melanoma are based on limited evidence. OBJECTIVES: To guide skin surveillance, we developed a risk prediction model for subsequent primary melanomas, using demographic, phenotypical, histopathological, sun exposure and genomic risk factors. METHODS: Using Cox regression frailty models, we analysed data for 2613 primary melanomas from 1266 patients recruited to the population-based Genes, Environment and Melanoma study in New South Wales, Australia, with a median of 14 years' follow-up via the cancer registry. Discrimination and calibration were assessed. RESULTS: The median time to diagnosis of a subsequent primary melanoma decreased with each new primary melanoma. The final model included 12 risk factors. Harrell's C-statistic was 0·73 [95% confidence interval (CI) 0·68-0·77], 0·65 (95% CI 0·62-0·68) and 0·65 (95% CI 0·61-0·69) for predicting second, third and fourth primary melanomas, respectively. The risk of a subsequent primary melanoma was 4·75 times higher (95% CI 3·87-5·82) for the highest vs. the lowest quintile of the risk score. The mean absolute risk of a subsequent primary melanoma within 5 years was 8·0 ± SD 4.1% after the first primary melanoma, and 46·8 ± 15·0% after the second, but varied substantially by risk score. CONCLUSIONS: The risk of developing a subsequent primary melanoma varies considerably between individuals and is particularly high for those with two or more primary melanomas. The risk prediction model and its associated nomograms enable estimation of the absolute risk of subsequent primary melanoma, on the basis of on an individual's risk factors, and can be used to tailor surveillance intensity, communicate risk and provide patient education. What's already known about this topic? Current guidelines for the frequency and length of follow-up to detect new primary melanomas in patients with one or more previous primary melanomas are based on limited evidence. People with one or more primary melanomas have, on average, a higher risk of developing another primary invasive melanoma, compared with the general population, but an accurate way of estimating individual risk is needed. What does this study add? We provide a comprehensive risk prediction model for subsequent primary melanomas, using data from 1266 participants with melanoma (2613 primary melanomas), over a median 14 years' follow-up. The model includes 12 risk factors comprising demographic, phenotypical, histopathological and genomic factors, and sun exposure. It enables estimation of the absolute risk of subsequent primary melanomas, and can be used to tailor surveillance intensity, communicate individual risk and provide patient education.

Is there a causal relationship between vitamin D and melanoma risk? A Mendelian randomization study.

BACKGROUND: Several preclinical studies have identified the antiproliferative effects of 25-hydroxyvitamin D [25(OH)D; vitamin D]. Ultraviolet radiation (UVR) is essential for vitamin D synthesis yet increases the risk of melanoma. Observational studies on the association of vitamin D levels with melanoma risk have reported inconclusive results, and are difficult to interpret owing to the potential confounding from the dual role of UVR. OBJECTIVES: To determine whether there is a causal association between genetically predicted 25(OH)D concentrations and melanoma using a Mendelian randomization (MR) approach. METHODS: We performed MR using summary data from a large genome-wide association study (GWAS) meta-analysis of melanoma risk, consisting of 12 874 cases and 23 203 controls. Five single nucleotide polymorphisms associated with 25(OH)D concentration - rs12785878, rs10741657, rs2282679, rs6013897 and rs116970203 - were selected as instrumental variables. An inverse variance weighted method was used to access the evidence for causality. MR results from the melanoma meta-analysis were combined with results from an MR study based on a melanoma risk GWAS using UK Biobank data. RESULTS: A 20 nmol L-1 decrease in 25(OH)D was not associated with melanoma risk [odds ratio (OR) 1·06, 95% confidence interval (CI) 0·95-1·19]. Results from the UK Biobank were concordant with this, with meta-analysis of our and UK Biobank-derived MR causal estimates showing no association (OR 1·02, 95% CI 0·92-1·13 for a 20 nmol L-1 decrease). CONCLUSIONS: The results suggest that vitamin D levels may not be causally associated with the risk of melanoma. What's already known about this topic? Antitumour activity of vitamin D has been identified in preclinical studies. Observational studies link vitamin D deficiency with an increased risk of a range of cancers. There is a growing public interest for vitamin D supplementation. Observational studies of melanoma are fraught with difficulties because while higher ultraviolet radiation levels increase vitamin D levels, such exposure is also associated with increased melanoma risk. Results from observational studies are inconclusive regarding the effect of vitamin D on melanoma risk. What does this study add? Using Mendelian randomization, an approach to causal inference, which is analogous to a natural randomized controlled trial, we found no causal association between vitamin D levels and melanoma.

Early mortality after late initiation of antiretroviral therapy in the TREAT Asia HIV Observational Database (TAHOD) of the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Asia-Pacific.

OBJECTIVES: Early mortality among those still initiating antiretroviral therapy (ART) with advanced stages of HIV infection in resource-limited settings remains high despite recommendations for universal HIV treatment. We investigated risk factors associated with early mortality in people living with HIV (PLHIV) starting ART at low CD4 levels in the Asia-Pacific. METHODS: PLHIV enrolled in the Therapeutics, Research, Education and AIDS Training in Asia (TREAT Asia) HIV Observational Database (TAHOD) who initiated ART with a CD4 count < 100 cells/µL between 2003 and 2018 were included in the study. Early mortality was defined as death within 1 year of ART initiation. PLHIV in follow-up for > 1 year were censored at 12 months. Competing risk regression was used to analyse risk factors with loss to follow-up as a competing risk. RESULTS: A total of 1813 PLHIV were included in the study, of whom 74% were male. With 73 (4%) deaths, the overall first-year mortality rate was 4.27 per 100 person-years (PY). Thirty-eight deaths (52%) were AIDS-related, 10 (14%) were immune reconstituted inflammatory syndrome (IRIS)-related, 13 (18%) were non-AIDS-related and 12 (16%) had an unknown cause. Risk factors included having a body mass index (BMI) < 18.5 [sub-hazard ratio (SHR) 2.91; 95% confidence interval (CI) 1.60-5.32] compared to BMI 18.5-24.9, and alanine aminotransferase (ALT) ≥ 5 times its upper limit of normal (ULN) (SHR 6.14; 95% CI 1.62-23.20) compared to ALT < 5 times its ULN. A higher CD4 count (51-100 cells/µL: SHR 0.28; 95% CI 0.14-0.55; and > 100 cells/µL: SHR 0.12; 95% CI 0.05-0.26) was associated with reduced hazard for mortality compared to CD4 count ≤ 25 cells/µL. CONCLUSIONS: Fifty-two per cent of early deaths were AIDS-related. Efforts to initiate ART at CD4 counts > 50 cell/µL are associated with improved short-term survival rates, even in those with late stages of HIV disease.

Does polygenic risk influence associations between sun exposure and melanoma? A prospective cohort analysis.

BACKGROUND: Melanoma develops as the result of complex interactions between sun exposure and genetic factors. However, data on these interactions from prospective studies are scant. OBJECTIVES: To quantify the association between ambient and personal ultraviolet exposure and incident melanoma in a large population-based prospective study of men and women residing in a setting of high ambient ultraviolet radiation, and to examine potential gene-environment interactions. METHODS: Data were obtained from the QSkin Sun and Health Study, a prospective cohort study of men and women aged 40-69 years, randomly sampled from the Queensland population in 2011. Participants were genotyped and assessed for ultraviolet exposure. RESULTS: Among participants with genetic data (n = 15 373), 420 (2·7%) developed cutaneous melanoma (173 invasive, 247 in situ) during a median follow-up time of 4·4 years. Country of birth, age at migration, having > 50 sunburns in childhood or adolescence, and a history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk. CONCLUSIONS: An interaction with polygenic risk was suggested: among people at low polygenic risk, markers of cumulative sun exposure (as measured by actinic damage) were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early-life ambient exposure (as measured by place of birth) were associated with melanoma (hazard ratio for born in Australia vs. overseas 3·16, 95% confidence interval 1·39-7·22). These findings suggest interactions between genotype and environment that are consistent with divergent pathways for melanoma development. What's already known about this topic? The relationship between sun exposure and melanoma is complex, and exposure effects are highly modified by host factors and behaviours. The role of genotype on the relationship between ultraviolet radiation exposure and melanoma risk is poorly understood. What does this study add? We found that country of birth, age at migration, sunburns in childhood or adolescence, and history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk, while other measures of continuous or more intermittent patterns of sun exposure were not. We found evidence for gene-environment interactions that are consistent with divergent pathways for melanoma development. Linked Comment: Cust. Br J Dermatol 2020; 183:205-206. Plain language summary available online.

Diabetes, mortality and glucose monitoring rates in the TREAT Asia HIV Observational Database Low Intensity Transfer (TAHOD-LITE) study.

OBJECTIVES: Diabetes is a growing cause of morbidity and mortality in people living with HIV (PLHIV) receiving antiretroviral therapy (ART). We investigated the association between fasting plasma glucose (FPG) levels and mortality, and factors associated with FPG monitoring rates in Asia. METHODS: Patients from the Therapeutics Research, Education, and AIDS Training in Asia (TREAT Asia) HIV Observational Database Low Intensity Transfer (TAHOD-LITE) cohort were included in the present study if they had initiated ART. Competing risk and Poisson regression were used to analyse the association between FPG and mortality, and assess risk factors for FPG monitoring rates, respectively. FPG was categorized as diabetes (FPG ≥ 7.0 mmol/L), prediabetes (FPG 5.6-6.9 mmol/L) and normal FPG (FPG < 5.6 mmol/L). RESULTS: In total, 33 232 patients were included in the analysis. Throughout follow-up, 59% had no FPG test available. The incidence rate for diabetes was 13.7 per 1000 person-years in the 4649 patients with normal FPG at ART initiation. Prediabetes [sub-hazard ratio (sHR) 1.32; 95% confidence interval (CI) 1.07-1.64] and diabetes (sHR 1.90; 95% CI 1.52-2.38) were associated with mortality compared to those with normal FPG. FPG monitoring increased from 0.34 to 0.78 tests per person-year from 2012 to 2016 (P < 0.001). Male sex [incidence rate ratio (IRR) 1.08; 95% CI 1.03-1.12], age > 50 years (IRR 1.14; 95% CI 1.09-1.19) compared to ≤ 40 years, and CD4 count ≥ 500 cells/µL (IRR 1.04; 95% CI 1.00-1.09) compared to < 200 cells/µL were associated with increased FPG monitoring. CONCLUSIONS: Diabetes and prediabetes were associated with mortality. FPG monitoring increased over time; however, less than half of our cohort had been tested. Greater resources should be allocated to FPG monitoring for early diabetic treatment and intervention and to optimize survival.

Signal Hyperintensity on Unenhanced T1-Weighted Brain and Cervical Spinal Cord MR Images after Multiple Doses of Linear Gadolinium-Based Contrast Agent.

BACKGROUND AND PURPOSE: The clinical implications of gadolinium deposition in the CNS are not fully understood, and it is still not known whether gadolinium tends to be retained more in the brain compared with the spinal cord. In this study, we assessed the effects of linear gadolinium-based contrast agents on the T1 signal intensity of 3 cerebral areas (dentate nucleus, globus pallidus, and the less studied substantia nigra) and the cervical spinal cord in a population of patients with MS. MATERIALS AND METHODS: A single-center population of 100 patients with MS was analyzed. Patients underwent 2-16 contrast-enhanced MRIs. Fifty patients received ≤5 linear gadolinium injections, and 50 patients had ≥6 injections: Fifty-two patients had both Gd-DTPA and gadobenate dimeglumine injections, and 48 patients received only gadobenate dimeglumine. A quantitative analysis of signal intensity changes was independently performed by 2 readers on the first and last MR imaging scan. The globus pallidus-to-thalamus, substantia nigra-to-midbrain, dentate nucleus-to-middle cerebellar peduncle, and the cervical spinal cord-to-pons signal intensity ratios were calculated. RESULTS: An increase of globus pallidus-to-thalamus (mean, +0.0251 ± 0.0432; P < .001), dentate nucleus-to-middle cerebellar peduncle (mean, +0.0266 ± 0.0841; P = .002), and substantia nigra-to-midbrain (mean, +0.0262 ± 0.0673; P < .001) signal intensity ratios after multiple administrations of linear gadolinium-based contrast agents was observed. These changes were significantly higher in patients who received ≥6 injections (P < .001) and positively correlated with the number of injections and the accumulated dose of contrast. No significant changes were detected in the spinal cord (mean, +0.0008 ± 0.0089; P = .400). CONCLUSIONS: Patients with MS receiving ≥6 linear gadolinium-based contrast agent injections showed a significant increase in the signal intensity of the globus pallidus, dentate nucleus, and substantia nigra; no detectable changes were observed in the cervical spinal cord.