Clinical Associations Research Articles

Species distribution and antimicrobial susceptibility of Burkholderia cepacia complex isolates in clinical infections: Experience from a tertiary care hospital, Southern India

PurposeBurkholderia cepacia complex (Bcc) is a diverse group of environmental bacteria associated with opportunistic infections. The identification of Bcc using conventional methods poses challenges. Bcc infections are difficult to treat due to intrinsic antibiotic resistance. The study aimed to investigate the species distribution and antimicrobial susceptibility of clinical Bcc isolates. MethodsA total of 153 Bcc isolates obtained from clinical samples were analysed. Species identification was carried out using automated methods, including MALDI-TOF MS and VITEK2. Antimicrobial susceptibility testing was performed using the disc diffusion method. ResultsBurkholderia cenocepacia (70.5%) emerged as the most prevalent species, followed by Burkholderia contaminans (9.8%) and Burkholderia cepacia (7.2%). Ventilator-associated pneumonia (38.6%) was the most common infection, followed by sepsis (28.1%). Co-existence of Bcc with other pathogens in many cases suggested potential co-infection scenarios. Antimicrobial susceptibility revealed that ceftazidime, co-trimoxazole and meropenem were the most effective drugs, while levofloxacin proved to be the least effective. Moderate susceptibility was noted to minocycline, with 4.6% of isolates exhibiting multi-drug resistance. ConclusionThis study provides valuable insights into the prevalence, clinical associations, and antibiotic susceptibility of Bcc in India. It highlights the importance of Bcc as a nosocomial pathogen, especially in vulnerable patient populations. The findings contribute to understanding Bcc infections, their distribution, and emphasize the necessity for accurate identification methods in clinical settings.

Clinical, genetic, and cognitive correlates of seizure occurrences in Phelan-McDermid syndrome

BackgroundPhelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome.MethodsWe report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features.ResultsSeizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype–phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers.ConclusionsThese results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype–phenotype relationships when deletion size is taken into account.

The role of clinical associates in South Africa as a health workforce: A scoping review

Background: South Africa’s health care system grapples with persistent challenges, including health care provider shortages and disparities in distribution. In response, the government introduced clinical associates (Clin-As) as a novel category of health care providers.Aim: This study mapped Clin-As’ history and practice in South Africa, assessing their roles in the health workforce and offering recommendations.Methods: Following the framework outlined by Arksey and O’Malley, we conducted a comprehensive literature search from January 2001 to November 2021, utilising PubMed, Scopus and EBSCOhost databases. One thousand six hundred and seventy-two articles were identified and then refined to 36 through title, abstract and full-text screening.Results: Strengths of the Clin-A cadre included addressing rural workforce shortages and offering cost-effective health care in rural areas. Challenges to the success of the cadre included stakeholder resistance, rapid implementation, scope of practice ambiguity, inadequate supervision, unclear roles, limited Department of Health (NDoH) support, funding deficits, Clin-As’ perceived underpayment and overwork, degree recognition issues, inadequate medical student training on Clin-A roles, vague career paths and uneven provincial participation.Conclusion: As a health care provider cadre, Clin-As have been welcomed by multiple stakeholders and could potentially be a valuable resource for South Africa’s health care system, but they face substantial challenges. Realising their full potential necessitates enhanced engagement, improved implementation strategies and precise scope definition.Contribution: This study acknowledges Clin-As in SA as a promising solution to health care workforce shortages but highlights challenges such as stakeholder resistance, insufficient NDoH support and unclear policies, emphasising the need for comprehensive efforts to maximise their potential.

Pitfalls in Valganciclovir Prophylaxis Dose Adjustment Based on Renal Function in Kidney Transplant Recipients

Valganciclovir (VGC) is administered as prophylaxis to kidney transplant recipients (KTR) CMV donor (D)+/recipient (R)− and CMV R+ after thymoglobulin-induction (R+/TG). Although VGC dose adjustments based on renal function are recommended, there is paucity of real-life data on VGC dosing and associations with clinical outcomes. This is a retrospective Swiss Transplant Cohort Study-embedded observational study, including all adult D+/R− and R+/TG KTR between 2010 and 2020, who received prophylaxis with VGC. The primary objective was to describe the proportion of inappropriately (under- or over-) dosed VGC week-entries. Secondary objectives included breakthrough clinically significant CMV infection (csCMVi) and potential associations between breakthrough-csCMVi and cytopenias with VGC dosing. Among 178 KTR, 131 (73.6%) patients had ≥2 week-entries for the longitudinal data of interest and were included in the outcome analysis, with 1,032 VGC dose week-entries. Overall, 460/1,032 (44.6%) were appropriately dosed, while 234/1,032 (22.7%) and 338/1,032 (32.8%) were under- and over-dosed, respectively. Nineteen (14.5%) patients had a breakthrough-csCMVi, without any associations identified with VCG dosing (p = 0.44). Unlike other cytopenias, a significant association between VGC overdosing and lymphopenia (OR 5.27, 95% CI 1.71–16.22, p = 0.004) was shown. VGC prophylaxis in KTR is frequently inappropriately dosed, albeit without meaningful clinical associations, neither in terms of efficacy nor safety.

Increased Erythrocyte Sedimentation Rate in Dogs: Frequency in Routine Clinical Practice and Association with Hematological Changes

(1) Background: the erythrocyte sedimentation rate (ESR) has been reported to increase in some infectious or inflammatory diseases in dogs, but no information on the frequency of increases in a routine clinical setting exists. The aim of this study was to assess the frequency of an increased ESR in dogs and to investigate its possible association with hematologic changes; (2) Methods: A total of 295 EDTA blood samples were randomly selected from the routine caseload of the Veterinary Teaching Hospital. Samples were grouped in controls and in pathologic groups based on the clinical presentation. A routine hemogram was performed, then the ESR was measured using the instrument MINI-PET; (3) Results: compared with controls, the ESR was significantly higher in all the pathologic groups, except for the hematological disorders group. The highest ESR was found in samples from dogs with chronic kidney disease or inflammation, followed by those from dogs with mild chronic disorders, severe/acute diseases, tumors and urinary disorders. The ESR negatively correlated with hematocrit and positively with neutrophil counts. (4) Conclusions: The ESR increases more frequently in dogs with clinically evident inflammation or CKD, but also in several other conditions, likely as a consequence of anemia and acute phase response.

RETHINKING ETHICAL LEADERSHIP IN THE C‐SUITE

AbstractThe author is a clinical associate professor at NYU Stern School of Business, and the executive director at Ethical Systems. She writes that “behavioral ethicists agree that while leading by example is important, it’s crucial to focus on building employee capacity for ethical decision‐making.” She further contends that “Companies… they must also manage the full spectrum of ethical commitments in practical ways. This poses particular challenges when you’re dealing with an increasingly vocal yet divided workforce.” She also discusses the nuances of sustainability and ESG {Environmental, Social, and Governance} within organizational ethics. Quotes are presented from such experts as Hui Chen, “a former prosecutor who became the first in‐house compliance counsel expert in the US Department of Justice”; Klaus Moosmayer, chief ethics, risk, and compliance officer at Novartis; and Nell Minow, described as “one of the leading corporate governance specialists in the United States.” For instance, according to Chen, “I’ve been baffled by the complete lack of interaction between the ethics and compliance community and the ESG community, because to me they’re really the same thing.” The author concludes: “Organizations don’t just need tone at the top; they need to solicit and support awareness, accountability, and voice at all levels.”

High prevalence of dermatophytosis of the feet in acral melanoma of the foot.

The clinical characteristics and pathogenesis of acral melanoma of the foot (AMF) have not been sufficiently elucidated. Clinical or subclinical persistent inflammation of the feet is caused by dermatophytosis of the feet (DPF). Persistent inflammation is potentially associated with oncogenesis. Moreover, diabetes has been reported to be associated with the development of dermatophytosis and cancer. The present study aimed to elucidate the clinical association between DPF and AMF, with consideration of diabetes. The medical records of 114 Japanese patients were retrospectively examined and divided into an AMF group (n = 30) and a control group consisting of patients with foot diseases other than melanoma (n = 84). Microscopic DPF screening was performed on all patients who reported symptoms in the foot, with or without AMF. Patients underwent a microscopic test to detect the presence of dermatophytes, and the diagnosis of DPF was made based on a positive result. In the AMF group, 18 (60.0%) and eight (26.7%) patients had DPF and diabetes, respectively. Four patients (13.3%) had both DPF and diabetes. In the control group, 25 (29.8%) and 11 (13.1%) patients had DPF and diabetes, respectively. Five patients (6.0%) had both DPF and diabetes. Univariate analyses showed a significantly higher prevalence of DPF in the AMF group than in the control group (odds ratio, 3.540; p = 0.003, Pearson χ2 test). Furthermore, multivariate analyses of sex, body mass index, DPF, and diabetes revealed DPF as a significant factor associated with AMF (odds ratio, 4.285; p = 0.002, logistic regression analysis). The hyperkeratotic type of DPF was more frequently observed in patients with AMF than in control patients (odds ratio, 11.083; p < 0.001, Pearson χ2 test). In conclusion, the present study found a significantly higher prevalence of DPF, especially its hyperkeratotic type, in patients with AMF. DPF may be associated with AMF pathogenesis.

Autoantibodies against complement proteins in patients with antiphospholipid syndrome: Prevalence and clinical associations.

Seventy-seven patients with antiphospholipid syndrome were tested for autoantibodies against C1q, C3, FB, FH, and C4bp. Fifty-seven patients had at least one anti-complement antibody. IgM anti-FH positivity was associated with thrombosis when anti-C3 and anti-FB were, negatively or positively, associated with various noncriteria manifestations of antiphospholipid syndrome.

The Clinical Association Between the Inflammation-Nutritional Condition and Prognosis of Locally Advanced Intrahepatic Cholangiocarcinoma After R0 Resection: Evidence from Competing Risk and Propensity Matching Analysis.

Intrahepatic cholangiocarcinoma (ICC) correlates with poor outcomes, necessitating the identification of prognostic factors from an inflammation-nutritional perspective in locally advanced ICC patients after R0 resection. We retrospectively reviewed the medical records of 159 locally advanced ICC patients from Sun Yat-sen University Cancer Center. Univariate and multivariate Cox regression analysis, as well as competing risk analysis, were conducted to explore prognostic variables for locally advanced ICC following surgery. To validate the robustness of our findings, we performed propensity score matching (PSM) analyses to evaluate survival differences based on inflammation-nutritional indexes. Considering non-cancer-specific death as competing risk factors, both systemic immune-inflammation index (SII, HR: 1.934) and prognostic nutrition index (PNI, HR: 0.604) emerged as significant prognostic variables for locally advanced ICC after R0 resection (P < 0.05). After PSM, the survival benefit between the low and high PNI sets remained clear (median survival time: 15.7 months vs 35.1 months, P = 0.002). Although the 5-year overall survival (OS) rate of the low SII group was higher than that of the high SII group, the difference was not statistically significant (17.5% VS 27.4%, P = 0.112). Other influencing factors included tumor number, tumor diameter, preoperative carcinoembryonic antigen (CEA)and carbohydrate antigen 19-9 (CA19-9) levels, and postoperative adjuvant therapy. Individual inflammatory and nutritional status significantly impact the prognosis of locally advanced ICC undergoing R0 hapectomy. Oncologists should consider incorporating inflammation-nutritional conditions into the decision-making process for this subset of advanced ICC.

NAFLD PATHOGENESIS AND CLINICAL ASSOCIATIONS WITH CARDIOVASCULAR DISEASES

NAFLD PATHOGENESIS AND CLINICAL ASSOCIATIONS WITH CARDIOVASCULAR DISEASES

Isolated retinal neovascularization in retinopathy of prematurity: clinical associations and prognostic implications

Isolated retinal neovascularization (IRNV) is a common finding in patients with stage 2 and 3 retinopathy of prematurity (ROP). This study aims to further classify the clinical course and significance of these lesions (previously described as "popcorn" based on clinical appearance) in patients with ROP as visualized with ultra-widefield optical coherence tomography (UWF-OCT). Single center, retrospective case series. Images were collected from 136 babies in the Oregon Health and Science University neonatal intensive care unit. A prototype UWF-OCT device captured en face scans (>140°), which were reviewed for the presence of IRNV along with standard zone, stage, and plus classification. In a cross-sectional analysis we compared demographics and the clinical course of eyes with and without IRNV. Longitudinally, we compared ROP severity using a clinician-assigned vascular severity score (VSS) and compared the risk of progression among eyes with and without IRNV using multivariable logistic regression (MLR). Differences in clinical demographics and disease progression between patients with and without IRNV. Of the 136 patients, 60 developed stage 2 or worse ROP during their disease course, 22 of whom had IRNV visualized on UWF-OCT (37%). On average, patients with IRNV had lower birth weights (BW) (660.1g vs 916.8g, p = 0.001), gestational age (GA) (24.9 vs 26.1 weeks, p = 0.01), and were more likely to present with ROP in zone I (63.4% vs 15.8%, p < 0.001). They were also more likely to progress to stage 3 (68.2% vs 13.2%, p < 0.001) and receive treatment (54.5% vs 15.8%, p = 0.002). Eyes with IRNV had a higher peak VSS (5.61 vs 3.73, p < 0.001) and averaged a higher VSS throughout their disease course. On MLR, IRNV was independently associated with progression to stage 3 (p = 0.02) and requiring treatment (p = 0.03), controlling for GA, BW, and initial zone 1 disease. In this single center study, we found that IRNV occurs in higher risk babies and was an independent risk factor for ROP progression and treatment. These findings may have implications for OCT-based ROP classifications in the future.

Consumer-driven evaluation of assistive technology usage and perceived value in people with myositis in Australia.

Idiopathic inflammatory myopathies (known as 'myositis') are a group of rare sporadic inflammatory muscle disorders that significantly impact function and quality of life. There are no standardised approaches in the use of assistive technologies in myositis. This study was initiated to investigate current use and perceived value of assistive technology (AT) by people with myositis. A cross-sectional online questionnaire (Qualtrics) was designed to capture information regarding AT use and perceived value and demographic information from people with myositis across Australia. The questionnaire was distributed via the Myositis Association of Australia and specialist myositis clinics. Participants were asked to identify which AT items they owned and how frequently the item was used and to rate the 'usefulness' of those items. Information was also collected on participants' engagement with health professionals regarding assistive technologies. Consumer involvement via the Myositis Research Consumer Panel identified a knowledge gap regarding AT. The questionnaire was designed with consumer input and review. One hundred two people (102) with myositis completed the questionnaire. One hundred (100) participants owned at least one AT device, with a median of 12.5 items and a maximum of 65 items. The most used devices were associated with toileting, personal care and mobility. Participants rated AT devices relating to environmental support, sleeping, seating and body support as most useful. There was a positive correlation between disease duration and number of devices used (r2= 0.248, p= 0.012). Majority of participants (75.5%) were interested in talking to health professionals about AT; however, only 50% had done so. AT device usage is high among people with myositis, with most items deemed to be useful. Greater occupational therapy input into recommendations and potential funding options may improve knowledge and access to AT.

Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes

Mutations in UBA1, which are disease-defining for VEXAS syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet PCR profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established WHO disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n=2,027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n=12) and unknown significance (n=15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO2016 as MDS-MLD/SLD. Patients had a median of one additional myeloid gene mutation, often in TET2 (n=12), DNMT3A (n=10), ASXL1 (n=3), or SF3B1 (n=3). Retrospective clinical review where possible showed that 83% (28/34) UBA1-mutant cases had VEXAS-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1-mutations in MDS patients argues for systematic screening for UBA1 in the management of MDS.

Liver steatosis in patients with transfusion-dependent thalassaemia.

We evaluated the prevalence and the clinical associations of liver steatosis (LS) in patients with transfusion-dependent thalassaemia (TDT). We considered 301 TDT patients (177 females, median age = 40.61 years) enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 25 healthy subjects. Magnetic resonance imaging was used to quantify iron overload and hepatic fat fraction (FF) by T2* technique and cardiac function by cine images. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Hepatic FF was significantly higher in TDT patients than in healthy subjects (median value: 1.48% vs. 0.55%; p = 0.013). In TDT, hepatic FF was not associated with age, gender, serum ferritin levels or liver function parameters, but showed a weak inverse correlation with high-density lipoprotein cholesterol. The 36.4% of TDT patients showed LS (FF >3.7%). Active hepatitis C virus (HCV) infection, increased body mass index and hepatic iron were independent determinants of LS. A hepatic FF >3.53% predicted the presence of an abnormal OGTT. Hepatic FF was not correlated with cardiac iron, biventricular volumes or ejection fractions, but was correlated with left ventricular mass index. In TDT, LS is a frequent finding, associated with iron overload, increased weight and HCV, and conveying an increased risk for the alterations of glucose metabolism.

Asymmetric proptosis in thyroid eye disease

PurposePatients with thyroid eye disease (TED) can present with asymmetric disease. The purpose of this study was to evaluate the prevalence of asymmetric TED in an Australian cohort and investigate clinical, biochemical, and radiological associations of asymmetric TED.MethodsThis was a retrospective study of patients with TED who underwent Hertel exophthalmometry and orbital computed tomography (CT) scans. Asymmetry was defined as a difference in the globe protrusion of ≥ 3 mm using Hertel exophthalmometry. Data was collected on patient demographics, clinical disease presentation, thyroid function tests and antibody levels. Muscles volumes were determined by manually segmenting the extraocular muscles on CT scans using a commercially available software.Results172 orbits from 86 patients were included in the study. 28 (33%) patients had asymmetric TED. No significant differences were observed in age, gender, thyroid hormone status, anti-thyroid peroxidase levels, thyroid stimulating hormone receptor antibodies, disease activity status, or dysthyroid optic neuropathy between the asymmetric and non-asymmetric groups. The extraocular muscle volumes were significantly higher in the asymmetric orbit compared to its contralateral orbit.ConclusionAsymmetric TED is a reasonably common occurrence in the course of TED. It is associated with higher extraocular muscle volumes, suggesting muscle enlargement as one of the underlying contributors to asymmetric proptosis. Thyroid eye disease should be considered in the differential of asymmetric orbital inflammatory disease.

Fibroblast diversity and clinical associations in systemic sclerosis

Fibroblast diversity and clinical associations in systemic sclerosis

[HLA alleles heterogeneity in a sample of colombian patients with a diagnosis of psoriatic arthritis].

The objective is to describe the HLA allelic frequency in PsA and correlate it with demographic and clinical variables. Retrospective study of adult patients with a diagnosis of PsA (n=23) and healthy controls (n=46), all with a request for HLA-A, B, C, DR. Typing was performed using HLA-PCR/SSO LifeCodes and analyzed on the LUMINEX IS100/200 xMAP® system. (Ethics/Code HMC2022-014). One hundred thirty-eight alleles were included from 69 individuals, 43,5% women, aged 44,5±16,5 years in patients with PsA, with a mean age of disease onset of 33.4±14 years. Only 9.5% had a high Body Mass Index and dyslipidemia was the most frequent comorbidity (34.8%), followed by high blood pressure (26,1%). 82% debuted with skin manifestation and once the joint disease was established, the predominance was peripheral (74%) due to arthritis/arthralgia in 74%, enthesitis in 30% and dactylitis in 13%. The allele frequencies were for HLA*A 2402 (13%), 3201 (13%) and 2427 (8,7%), for HLA*B 1402 (17,4%), 4002 (17,4%), 3801 (13%) and HLA*DR 0404 (17,4%), 0407 (13%). No HLA*B27 was identified and HLA*C0602 was only 2,2%. HLA A*0201 and DR*1301 were less frequent in controls versus PsA (p=0.024 and 0,029, respectively), while HLA*B1302 was frequent in PsA (p=0,035). Curiously, there were no positive results for HLAB*27, which may be related to the population mix. HLA Cw6 is traditionally associated with psoriasis. However, its absence has been linked to nail disorders and PsA; consequently, in our study, it had a low frequency (2,2%). On the other hand, HLA*B1302 has been related to the disease and its early onset; in the healthy Colombian population, it has been described in 0,92%; in our group, it is found to be significant in patients without establishing a clinical association. Few previous studies report HLA results in PsA in Colombia.

Cardiorespiratory Fitness Is Impaired in Type 1 and Type 2 Diabetes: A Systematic Review, Meta-Analysis, and Meta-Regression.

Low cardiorespiratory fitness (CRF) increases the risk of cardiovascular disease by up to 8-fold, and is one of the strongest predictors of mortality. Some studies demonstrate impaired CRF in people living with type 1 and type 2 diabetes compared to those without diabetes, while others demonstrate no diabetes-associated impairment in CRF. We aimed to determine whether diabetes can influence CRF, and if so, identify clinical associations underlying diabetes-associated exercise impairments. 68 studies were included in the quantitative analysis. Standardized mean difference (SMD) was calculated and meta-analyses and meta-regressions were performed by using a random-effects model. Diabetes is associated with a large negative effect on CRF (SMD = -0.80; p < 0.001)- an effect that is partially mitigated, but still significant, in those with high physical activity levels (SMD = -0.50; p = 0.007). A sedentary lifestyle (SMD = -0.83; p = 0.007), and the presence of clinical complications related to diabetes (SMD = -1.66; p < 0.001) predict a greater magnitude of CRF reduction in people with diabetes compared to controls without diabetes. Both type 1 and type 2 diabetes are independently associated with impaired CRF compared to controls without diabetes; however, the effect is significantly greater in those type 2 diabetes (SMD = -0.97; p < 0.001). Meta-regression analysis demonstrates the effects of diabetes on CRF are primarily associated with HbA1c levels for type 1 diabetes (B = -0.07; p < 0.001) and body mass index for type 2 diabetes (B = -0.17; p = 0.005). These data demonstrate a negative influence of diabetes on the key risk factor of low CRF and provide critical insight into specific clinical markers of low CRF associated with diabetes.

Clinical associations with a polygenic predisposition to benign lower white blood cell counts

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30−0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69−0.88], p = 4.0 × 10−5) or immunosuppressant (n = 354, HR = 0.61 [0.38–0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44−0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

Epidemiologic association and shared genetic architecture between cataract and hearing difficulties among middle-aged and older adults

Age-related cataract and hearing difficulties are major sensory disorders that often co-exist in the global-wide elderly and have a tangible influence on the quality of life. However, the epidemiologic association between cataract and hearing difficulties remains unexplored, while little is known about whether the two share their genetic etiology. We first investigated the clinical association between cataract and hearing difficulties using the UK Biobank covering 502,543 individuals. Both unmatched analysis (adjusted for confounders) and a matched analysis (one control matched for each patient with cataract according to confounding factors) were undertaken and confirmed that cataract was associated with hearing difficulties (OR, 2.12; 95% CI, 1.98–2.27; OR, 2.03; 95% CI, 1.86–2.23, respectively). Furthermore, we explored and quantified the shared genetic architecture of these two complex sensory disorders at the common variant level using the bivariate causal mixture model (MiXeR) and conditional/conjunctional false discovery rate method based on the largest available genome-wide association studies of cataract (N = 585,243) and hearing difficulties (N = 323,978). Despite detecting only a negligible genetic correlation, we observe polygenic overlap between cataract and hearing difficulties and identify 6 shared loci with mixed directions of effects. Follow-up analysis of the shared loci implicates candidate genes QKI, STK17A, TYR, NSF, and TCF4 likely contribute to the pathophysiology of cataracts and hearing difficulties. In conclusion, this study demonstrates the presence of epidemiologic association between cataract and hearing difficulties and provides new insights into the shared genetic architecture of these two disorders at the common variant level.