A Lower Prevalence of Central Nervous System and Higher Prevalence of Cardiac Symptoms Characterises Indian Patients with Thyrotoxic Storm: A Retrospective Analysis.

Introduction: Thyroid storm is an uncommon but life-threatening presentation of thyrotoxicosis with a mortality rate of 10%. Our objective was to study the demographics, clinical and biochemical characteristics, and outcomes of inpatients diagnosed with thyroid storm in the Indian context. Methods: This retrospective study was conducted by analysing the institutional electronic medical records (EMR) of all patients admitted with thyroid storm from 2004 to 2020 with a Burch-Wartofsky score (BWS) of ≥45. Results: Thirty-five patients with a BWS ≥45 were included, of whom 71.4% were women, with a mean age of 44.9 ± 10.2 years. 43% did not have any prior history of thyrotoxicosis. Graves' disease was the most common underlying aetiology (71.4%), followed by toxic multinodular goitre (14.3%). Cardiovascular (94.3%) and gastrointestinal-hepatic dysfunction (88.6%) were the most common clinical manifestations. Features of Central nervous system (CNS) dysfunction were seen in only 42.3% of patients diagnosed with a thyroid storm. The Japanese Thyroid Association (JTA) criteria diagnosed only 26 patients (74.3%) with "definite" thyroid storm. The mortality rate was 8.6%, and all three patients expired within 48 hours of admission. Conclusion: Nearly one in every two patients with thyroid storm had previously undiagnosed thyrotoxicosis. Toxic multinodular goitre is a notable aetiology in Indians. Features of CNS dysfunction, considered relatively specific for thyroid storm, were less prominent in our series. The JTA criteria might alter the classification of some patients diagnosed with a thyroid storm, when compared to the BWS score due to fewer CNS features among Indian patients.

Prevalence of Neurovascular Microemboli After Transcatheter Aortic Valve Replacement.

Background: Neurolotic sequelae after transcatheter aortic valve replacement (TAVR) can cause significant morbidity and mortality. Transcranial Doppler (TCD) imaging can show real-time high intensity transient signals (HITS), which reflect active microembolization. Although it is well known that intraprocedural microembolism occurs, it is not known if this embolic phenomenon continues in the postprocedural period. We investigated whether microemboli occur post-TAVR and whether we could determine any clinical, procedural, or echocardiographic predictors. Methods: We evaluated HITS in 51 consecutive patients undergoing unprotected TAVR with low-, intermediate-, or high-risk Society of Thoracic Surgeons score. Patients were excluded if they did not have temporal windows for insonation of the middle cerebral artery or if they were not willing to participate. Primary outcomes of HITS 24 hours post-TAVR were observed using a Philips iU22 TCD. TCD was performed at 3 time points (pre-, peri-, and post-TAVR) for each patient, before, during, and 24 hours postprocedure. Results: While no HITS were detected in any of the patients preoperatively, all patients had HITS during the procedure. Interestingly, 56.8% had HITS 24 hours post-TAVR. One patient with HITS post-TAVR had a stroke 48 hours after TAVR. Conclusion: We observed a high prevalence of microemboli 24 hours post-TAVR. None of the predictors for intraprocedural microembolism seemed to play an important role for post-TAVR microemboli.

Macular Degeneration Drug Prescribing Patterns After Step Therapy Introduction in Medicare Advantage.

Importance: In Medicare Advantage (MA), step therapy for physician-administered drugs is an approach to lowering drug spending. The impact of step therapy in MA on prescribing behavior and the magnitude of any changes has not been analyzed. Objective: To evaluate the impact of step therapy on macular degeneration drug prescribing patterns for 3 large MA insurers. Design, Setting, and Participants: This was a retrospective encounter-based analysis using 20% nationally representative MA outpatient and carrier encounter records for 2017 to 2019. Participants were MA beneficiaries who were 65 years or older and had received a macular degeneration drug administration. Macular degeneration drug administrations for beneficiaries of MA Aetna, Humana, and UnitedHealthcare (UHC) insurers were assessed. Humana implemented macular degeneration step therapy in 2019, setting bevacizumab as the plan-preferred drug, and aflibercept and ranibizumab as the plan-nonpreferred drugs. Aetna and UHC, which did not implement macular degeneration step therapy, served as the control group. Data analyses were performed from May 2024 to December 2024. Exposures: A macular degeneration drug administration subject to a step therapy policy. Main Outcome and Measures: A binary indicator of whether the drug administered was bevacizumab. Linear probability models and a difference-in-differences framework were used to quantify changes in prescribing patterns before and after the introduction of step therapy for MA insurers that did and did not implement step therapy. To empirically measure the impact of step therapy, the first administration of a treatment episode was assessed, followed by switching patterns. Results: A total of 18 331 MA beneficiaries, 21 683 treatment episodes, and 171 985 drug administrations were included across the control and treatment groups. The difference-in-differences regressions found a 7.8% (95% CI, 4.9%-10.7%; P < .001) greater probability of being prescribed bevacizumab for the first administration due to step therapy. The predicted probabilities of preferred-drug administration in the treatment group increased from 0.61 to 0.70 between the periods before and after step therapy implementation for the first administration. Step therapy was not significantly associated with an increased rate of medication switching (hazard ratio, 0.86; 95% CI, 0.71-1.06; P = .15). Conclusions and Relevance: The findings of this retrospective encounter-based analysis indicate that step therapy is associated with a greater probability of prescribing the plan-preferred drug for the first administration. The analysis failed to find a statistically significant greater rate of medication switching within a treatment episode. Step therapy changed macular degeneration prescribing patterns, but step therapy alone did not transition all administrations to the plan-preferred drug.

Determination of metal ion transport rate of human ZIP4 using stable zinc isotopes.

The essential microelement zinc is absorbed in the small intestine mainly by the zinc transporter ZIP4, a representative member of the Zrt/Irt-like protein (ZIP) family. ZIP4 is reportedly upregulated in many cancers, making it a promising oncology drug target. To date, there have been no reports on the turnover number of ZIP4, which is a crucial missing piece of information needed to better understand the transport mechanism. In this work, we used a non-radioactive zinc isotope, 70Zn, and inductively coupled plasma mass spectrometry (ICP-MS) to study human ZIP4 (hZIP4) expressed in HEK293 cells. Our data showed that 70Zn can replace the radioactive 65Zn as a tracer in kinetic evaluation of hZIP4 activity. This approach, combined with the quantification of the cell surface expression of hZIP4 using biotinylation or surface-bound antibody, allowed us to estimate the apparent turnover number of hZIP4 to be in the range of 0.08-0.2 s-1. The turnover numbers of the truncated hZIP4 variants are significantly smaller than that of the full-length hZIP4, confirming a crucial role for the extracellular domain in zinc transport. Using 64Zn and 70Zn, we measured zinc efflux during the cell-based transport assay and found that it has little effect on the zinc import analysis under these conditions. Finally, we demonstrated that use of laser ablation (LA) ICP-TOF-MS on samples applied to a solid substrate significantly increased the throughput of the transport assay. We envision that the approach reported here can be applied to the studies of metal transporters beyond the ZIP family.

MI-181 Modulates Cilia Length and Restores Cilia Length in Cells with Defective Shortened Cilia.

Primary cilia are membrane-covered microtubule-based structures that protrude from the cell surface and are critical for cell signaling and homeostasis during human development and adulthood. Dysregulation of cilia formation, length, and function can lead to a spectrum of human diseases and syndromes known as ciliopathies. Although some genetic and chemical screens have been performed to define important factors that modulate cilia biogenesis and length control, there are currently no clinical treatments that restore cilia length in patients. We report that the microtubule-targeting agent MI-181(mitotic inhibitor-181) is a potent modulator of cilia length and biogenesis. Treatment of retinal pigment epithelial-1 cells with MI-181 induced an increase in the average size of cilia and in the percent ciliated cells under nonstarved conditions. Importantly, MI-181 was effective at rescuing cilia length and ciliation defects in cells that had been treated with the intraflagellar transport inhibitor Ciliobrevin D or the O-GlcNAc transferase inhibitor OSMI-1. Most importantly, MI-181 induced an increase in cilia length and restored ciliation in cells with compromised shortened cilia at low nanomolar concentrations and did not show an inhibitory response at high concentrations. Therefore, MI-181 represents a lead molecule for developing drugs targeting ciliopathies characterized by shortened cilia.

Pseudomyxoma Peritonei: An Incidental Diagnosis With Atypical Intraoperative Findings Discovered During a Laparoscopic Cholecystectomy.

Although pseudomyxoma peritonei (PMP) classically presents with profuse mucinous ascites within the peritoneal cavity, the physical manifestations of this disease exist on a spectrum, with the possibility of milder forms that lack typical findings. The authors report an indolent case of PMP diagnosed incidentally during workup and treatment for chronic cholecystitis in a 43-year-old male. This presentation of PMP was atypical due to a lack of discernible symptoms as well as uncharacteristic intraoperative findings consisting of numerous omental and pelvic adhesions with only sparse mucinous deposits. This case contributes to the growing understanding of PMP by exploring an uncharacteristic presentation of the disease with the hope that it may assist clinicians in diagnosing those cases of PMP that are more indolent and insidious in nature.

Femoral Neck Osteoporosis Is Associated with a Higher Odds of Coronary Artery Disease in Indian Postmenopausal Women: A Cross-sectional Study from a Teaching Hospital in Southern India.

Purpose: Epidemiological studies have shown an association between coronary artery disease (CAD) and osteoporosis. We studied the prevalence of CAD among postmenopausal women with osteoporosis. Factors that were significantly associated with CAD were also assessed. Methods: This was a cross-sectional study conducted over a period of 2 years. Consecutive postmenopausal women aged ≥50 years were recruited. The details of an underlying CAD were obtained. Bone biochemical parameters, bone mineral density and body composition were assessed. Results: A total of 370 postmenopausal women with mean (standard deviation [SD]) ages of 61.6 (6.2) and 60.1 (6.0) years and a body mass index of 25.3 (14.1) kg/m2 were recruited. Among them, 110 of 370 patients (29.7%) had an underlying CAD and 222 of 370 (60%) had osteoporosis at either the femoral neck or lumbar spine (LS). The odds of CAD among those with osteoporosis were 3.5 (95% confidence interval [CI]: 2.1-5.9). An LS T-score of ≤-2.2 had a sensitivity of 80% and a specificity of 45% in predicting CAD (area under the curve, AUC: 0.736; 95% CI: 0.677-0.795; p<0.001). A femoral neck T-score of ≤-1.9 had a sensitivity of 80% and a specificity of 60% in predicting CAD (AUC: 0.748; 95% CI: 0.696-0.800; p<0.001). On a logistic regression analysis after adjusting for various clinical parameters, femoral neck osteoporosis had the highest odds of CAD. Conclusion: The prevalence of CAD was higher among postmenopausal women with osteoporosis. Femoral neck osteoporosis conferred the highest odds of CAD after adjustment for other clinical factors.

Morphotype-specific calcium signaling in human microglia.

BACKGROUND: Key functions of Ca2+ signaling in rodent microglia include monitoring the brain state as well as the surrounding neuronal activity and sensing the danger or damage in their vicinity. Microglial Ca2+ dyshomeostasis is a disease hallmark in many mouse models of neurological disorders but the Ca2+ signal properties of human microglia remain unknown. METHODS: We developed a novel genetically-encoded ratiometric Ca2+ indicator, targeting microglial cells in the freshly resected human tissue, organotypically cultured tissue slices and analyzed in situ ongoing Ca2+ signaling of decades-old microglia dwelling in their native microenvironment. RESULTS: The data revealed marked compartmentalization of Ca2+ signals, with signal properties differing across the compartments and resident morphotypes. The basal Ca2+ levels were low in ramified and high in ameboid microglia. The fraction of cells with ongoing Ca2+ signaling, the fraction and the amplitude of process Ca2+ signals and the duration of somatic Ca2+ signals decreased when moving from ramified via hypertrophic to ameboid microglia. In contrast, the size of active compartments, the fraction and amplitude of somatic Ca2+ signals and the duration of process Ca2+ signals increased along this pathway.

Neuroendocrine challenges and clinical outcomes in men with chronic traumatic brain injury: a cross-sectional study.

BACKGROUND AND OBJECTIVES: Marked changes in the hypothalamic-pituitary axis have been documented in patients with traumatic brain injury (TBI). These enduring endocrine challenges could significantly influence the physical and psychological outcomes thereby impacting overall recovery. This study aimed to determine the prevalence and types of endocrine dysfunction in men with chronic TBI and to determine the association of endocrine dysfunction with clinical outcomes. METHODOLOGY: A cross-sectional study that included male participants of 25-45 years (N = 66) with moderate to severe TBI within 6-24 months of injury. Serum Cortisol, Free T4, TSH, Luteinizing hormone, Testosterone, ACTH, Prolactin and IGF-1 were assessed. Glasgow Outcome Scale Extended (GOS-E) and Modified Barthel Index (MBI) scores were also assessed in them. RESULTS: The study cohort comprised male patients with a mean ± age of 32.8 ± 5.7 years. Low IGF-1 levels were most commonly encountered, followed by hypogonadism. Hypopituitarism was present in 56.1%. The proportion of hypogonadism was significantly higher in the group with moderate-total dependence (13/26) as compared to the functionally independent (8/40) group (50% vs. 20%; P = 0.011). Univariate and multivariate logistic regression analysis was used to determine the factors associated with hypopituitarism, revealing that severity of injury (OR = 2.6;) and GOS-E (OR = 3.1) were significant (P < 0.10) on univariate analysis. CONCLUSIONS: This study emphasizes the need to screen TBI patients for neuroendocrine dysfunction during the chronic phases and to establish screening criteria.

Functional and perceptive differences between conventional and advanced ankle foot orthoses in community ambulators post-limb trauma: the injuries managed with advanced bracing of the lower extremity (IM ABLE) study.

Introduction: Many military service members and civilians suffer from lower extremity trauma. Despite recent advancements in lower limb bracing technology, it remains unclear whether these newer advanced braces offer improved comfort and functionality compared to conventional options. The IDEO (Intrepid Dynamic Exoskeletal Orthosis), a type of "advanced" orthosis was developed to assist in maintaining high functional performance in patients who have experienced high-energy lower extremity trauma and underwent limb salvage surgeries. Methods: A cross-sector multi-site initiative was completed to study the efficacy of advanced ankle foot orthoses (AFO) for lower limb trauma and injury compared to a conventional AFO. Following fitting, training, and accommodation, the subjects were assessed in each AFO system for mobility, self-reported function, safety and pain, and preference. Results: They preferred the advanced over the conventional AFO and the mobility and exertion perception improved with the advanced AFO with no difference in pain or overall health status scores. Discussion: Thus, an advanced AFO is an option for trauma affecting the lower limb. Long-term studies are required to better understand the accommodation and learning process of using an advanced AFO.

Pediatric Hematology and Oncology Patients on Extracorporeal Membrane Oxygenation: Outcomes in a Multicenter, Retrospective Cohort 2009-2021.

OBJECTIVE: To describe characteristics associated with survival for pediatric patients with an oncologic diagnosis or hematopoietic cell transplant (HCT) supported with extracorporeal membrane oxygenation (ECMO). DESIGN: Multicenter, retrospective study. SETTING: Sixteen PICUs in the United States and Israel. PATIENTS: We included patients aged younger than 19 years with an oncologic diagnosis or HCT who required ECMO support between 2009 and 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 149 patients were included in the study cohort. There were 118 patients with an oncologic diagnosis and 31 that received HCT. The indications for ECMO were respiratory failure (46%), combined respiratory and cardiac failure (28%), and cardiac failure (25%). Venovenous (V-V) ECMO was used in 45% of patients, with 53% of patients being placed on venoarterial (V-A) ECMO. For oncologic and HCT groups, survival to ECMO decannulation was 52% (62/118) and 64% (20/31), and survival to hospital discharge was 36% (43/118) and 42% (13/31), respectively. After adjusting for other factors, requiring cardiopulmonary resuscitation was associated with greater odds ratio of mortality (3.0 [95% CI, 1.2-7.7]). CONCLUSIONS: Survival to ECMO decannulation of pediatric oncologic and HCT patients in this study was 52-64%, depending upon diagnosis. However, survival to hospital discharge remains poor. Future research should prioritize understanding factors contributing to this survival gap within these patient populations.

Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes.

Research demonstrates the important role of genetic factors in attention-deficit/hyperactivity disorder (ADHD). DNA sequencing of families provides a powerful approach for identifying de novo (spontaneous) variants, leading to the discovery of hundreds of clinically informative risk genes for other childhood neurodevelopmental disorders. This approach has yet to be extensively leveraged in ADHD. We conduct whole-exome DNA sequencing in 152 families, comprising a child with ADHD and both biological parents, and demonstrate a significant enrichment of rare and ultra-rare de novo gene-damaging mutations in ADHD cases compared to unaffected controls. Combining these results with a large independent case-control DNA sequencing cohort (3206 ADHD cases and 5002 controls), we identify lysine demethylase 5B (KDM5B) as a high-confidence risk gene for ADHD and estimate that 1057 genes contribute to ADHD risk. Using our list of genes harboring ultra-rare de novo damaging variants, we show that these genes overlap with previously reported risk genes for other neuropsychiatric conditions and are enriched in several canonical biological pathways, suggesting early neurodevelopmental underpinnings of ADHD. This work provides insight into the biology of ADHD and demonstrates the discovery potential of DNA sequencing in larger parent-child trio cohorts.

Classification and Risk Factors for Surgical Site Infections in Radical Cystectomy: A 16-Year Analysis.

Introduction: Surgical site infection (SSI) is a substantial cause of peri-operative morbidity among patients undergoing radical cystectomy (RC). The purpose of this study was to identify the risk factors of SSI after RC and to classify and characterize treatment of SSIs. Methods: We retrospectively analyzed peri-operative characteristics and SSI, for patients undergoing RC from 2007 to 2022. Patients were stratified by SSI versus no SSI and differences were assessed. Uni-variable/multi-variable logistic regression analyses were performed to identify factors associated with SSI. SSIs were categorized by the Centers for Disease Control and Prevention (CDC) type: Superficial incisional, deep incisional, and organ/space confined. Results: Three hundred and ninety-eight patients had RC, 279 open, and 119 robotic; 78 (19.6%) developed SSI. Cohorts were similar demographically. Length of stay (LOS) was longer in the SSI cohort (8.8 d versus 12.4 d, p < 0.001), and body mass index (BMI) was greater in patients with SSI (24.34 vs. 25.39, p = 0.0003). On uni-variable analysis, age, gender, Charlson Comorbidity Index, diabetes mellitus, diversion, odds ratio (OR) time, blood loss, and open versus robotic technique were not substantial SSI predictors. BMI was an independent risk factor for SSI on both uni-variable (OR: 1.07, 95% confidence interval [CI]: 1.018-1.115, p = 0.0061) and multi-variable analysis (OR: 1.06, 95% CI: 1.009-1.109, p = 0.02) for 10 (12.8%) and 24 (30.8%) superficial and deep-incisional SSIs, respectively. Superficial wound SSI was treated conservatively with 60% receiving antibiotic agents and no procedural intervention. Deep SSIs received antibiotic agents and 50% required surgical intervention. There were 44 (56.4%) organ/space SSIs, and the most common treatment was antibiotic agents (100%) and IR drain placement (30, 68.2%). Conclusion: In patients undergoing RC, BMI was an independent risk factor for SSI. Type of the surgical procedure, robotic versus open, was not predictive of SSI. LOS was longer for patients with SSI. SSI was managed differently depending on CDC classification.

The genetics of trichotillomania and excoriation disorder: A systematic review.

BACKGROUND: Trichotillomania (TTM) and excoriation disorder (ED) are impairing obsessive-compulsive related disorders that are common in the general population and for which there are no clear first-line medications, highlighting the need to better understand the underlying biology of these disorders to inform treatments. Given the importance of genetics in obsessive-compulsive disorder (OCD), evaluating genetic factors underlying TTM and ED may advance knowledge about the pathophysiology of these body-focused repetitive behaviors. AIM: In this systematic review, we summarize the available evidence on the genetics of TTM and ED and highlight gaps in the field warranting further research. METHOD: We systematically searched Embase, PsycInfo, PubMed, Medline, Scopus, and Web of Science for original studies in genetic epidemiology (family or twin studies) and molecular genetics (candidate gene and genome-wide) published up to June 2023. RESULTS: Of the 3536 records identified, 109 studies were included in this review. These studies indicated that genetic factors play an important role in the development of TTM and ED, some of which may be shared across the OCD spectrum, but there are no known high-confidence specific genetic risk factors for either TTM or ED. CONCLUSIONS: Our review underscores the need for additional genome-wide research conducted on the genetics of TTM and ED, for instance, genome-wide association and whole-genome/whole-exome DNA sequencing studies. Recent advances in genomics have led to the discovery of risk genes in several psychiatric disorders, including related conditions such as OCD, but to date, TTM and ED have remained understudied.

In silico predicted compound targeting the IQGAP1-GRD domain selectively inhibits growth of human acute myeloid leukemia.

Acute myeloid leukemia (AML) is fatal in the majority of adults. Identification of new therapeutic targets and their pharmacologic modulators are needed to improve outcomes. Previous studies had shown that immunization of rabbits with normal peripheral WBCs that had been incubated with fluorodinitrobenzene elicited high titer antibodies that bound to a spectrum of human leukemias. We report that proteomic analyses of immunoaffinity-purified lysates of primary AML cells showed enrichment of scaffolding protein IQGAP1. Immunohistochemistry and gene-expression analyses confirmed IQGAP1 mRNA overexpression in various cytogenetic subtypes of primary human AML compared to normal hematopoietic cells. shRNA knockdown of IQGAP1 blocked proliferation and clonogenicity of human leukemia cell-lines. To develop small molecules targeting IQGAP1 we performed in-silico screening of 212,966 compounds, selected 4 hits targeting the IQGAP1-GRD domain, and conducted SAR of the 'fittest hit' to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apoptosis, resulted in G2/M arrest, and inhibited colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows response to IQGAP1 inhibition, and UR778Br, identified through in-silico studies, selectively targeted AML cells while sparing normal marrow.

Sex as a predictor of clinical phenotype and determinant of immune response in IgG4-related disease: a retrospective study of patients fulfilling the American College of Rheumatology-European League Against Rheumatism classification criteria.

BACKGROUND: IgG4-related disease is a multiorgan fibroinflammatory disease considered to have an autoimmune origin. Case series describing individual organ involvement have suggested differences in phenotypic expression between males and females. We aimed to characterise differences in IgG4-related disease manifestations between male and female patients in a large single-centre cohort. METHODS: In this retrospective, single-centre cohort study, patients were recruited from the Massachusetts General Hospital Rheumatology Clinic (Boston, MA, USA) and classified according to the American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) classification criteria. Only patients satisfying the ACR-EULAR classification criteria were included in the study. Data on age at diagnosis, organ involvement at baseline, treatment status, and pre-treatment laboratory values were collected. Circulating plasmablasts and B-cell subsets were quantitated by flow cytometry. Active disease was defined by an IgG4-related disease Responder Index score of more than 0. Laboratory values were analysed for patients who were untreated at baseline and had active IgG4-related disease. The main outcomes were assessed in all participants with available data. FINDINGS: Of the 564 participants enrolled in the Massachusetts General Hospital Rheumatology Clinic IgG4-related disease Registry, 328 fulfilled ACR-EULAR classification criteria and were included between January, 2008, and May, 2023. There was a strong male predominance (male:female ratio 2·2:1) with 226 (69%) males and 102 (31%) females, which contrasted markedly with our general rheumatology clinic population (0·4:1; p<0·001). The male predominance increased with each decade of life starting at age 40 years. On average, male patients were 5·5 years older at diagnosis than female patients (63·7 years vs 58·2 years; p=0·0031). We observed male patients to have higher ACR-EULAR classification criteria scores at baseline with a median score of 35·0 (IQR 28·0-46·0), compared with 29·5 (25·0-39·0) for females (p=0·0010). The proportion of male patients with pancreatic and renal involvement was almost double the proportion observed in female patients (50% of the male patients had pancreatic involvement, compared with about 26% of the female patients; p<0·0001). Male patients were more likely to have serological abnormalities at baseline. The distribution of IgG4 values differed significantly between male an female sexes, favouring higher values in males. We found that male patients with IgG4-related disease were more likely to have active B-cell responses in the blood as defined by plasmablast expansions. INTERPRETATION: IgG4-related disease is unusual among autoimmune diseases in that it is more likely to affect males than females and to present with a striking sex-dependent organ distribution and degree of B-cell response. These findings highlight important variation between IgG4-related disease and other conditions generally believed to have an autoimmune basis. Most autoimmune diseases, by contrast to IgG4-related disease, demonstrate pronounced predilections for affecting females more frequently than males. Hypotheses surrounding the cause and pathophysiology of this condition need to consider this unusual sex distribution among patients with IgG4-related disease. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Rheumatology Research Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Emotional Distress Symptoms, Coping Efficacy, and Social Support: A Network Analysis of Distress and Resources in Persons With Cancer.

BACKGROUND: The study's main aim was to analyze the structure and configuration of distress symptoms and resource factors. PURPOSE: Common methods of assessing distress symptoms in cancer patients (i) do not capture the configuration of individual distress symptoms and (ii) do not take into account resource factors (e.g., social support, coping, caring health professionals). Network analysis focuses on the configuration and relationships among symptoms that can result in tailored interventions for distress. Network analysis was used to derive a symptom-level view of distress and resource factors. METHODS: Nine hundred and ninety-two cancer patients (mixed diagnoses) completed an abridged Distress Screening Schedule that included 24 items describing symptoms related to distress (depression, anxiety) and resource factors (social support, coping, caring health professionals). RESULTS: In network analysis, the centrality strength index (CSI) is the degree to which an item is connected to all other items, thus constituting an important focal point in the network. A depression symptom had the highest CSI value: felt lonely/isolated (CSI = 1.30). In addition, resource factors related to coping efficacy (CSI = 1.20), actively seeking support (CSI = 1.10), perceiving one's doctor as caring (CSI = 1.10), and receiving social support (CSI = 1.10) also all had very high CSI scores. CONCLUSIONS AND IMPLICATIONS: These results emphasize the integral importance of the social symptoms of loneliness/isolation in distress. Thus, distress symptoms (loneliness) and resource factors (coping efficacy, seeking social support, and perceiving medical professionals as caring) should be integral aspects of distress management and incorporated into assessment tools and interventions to reduce distress.

Many persons with cancer experience emotional distress (i.e., depression and anxiety). Traditional methods of assessing distress do not capture the complex organization of individual symptoms of depression/anxiety or their relationship with specific personal resources such as seeking support and coping strategies. This study used network analysis to represent the structural configuration of individual distress symptoms and specific resources (agentic coping, seeking support, receiving support, satisfaction with medical care) and relationships between them. Participants were 992 persons with cancer who completed an inventory assessing distress and personal resources. The network configuration showed that loneliness and social isolation were most central to the network of distress symptoms, suggesting that these feelings are the most significant aspects of distress for persons with cancer. Importantly, agentic coping, seeking support, perceiving one's doctor as caring, and receiving social support were also highly central in the network. The results highlight the significance of the social symptoms of distress, namely loneliness and isolation, as well as the central importance of resource factors such as coping efficacy, seeking social support, and perceiving medical professionals as caring. These distress symptoms and resources can be incorporated into assessment tools and interventions to alleviate distress among persons with cancer.

Defining the phylogenetics and resistome of the major Clostridioides difficile ribotypes circulating in Australia.

Clostridioides difficile infection (CDI) remains a significant public health threat globally. New interventions to treat CDI rely on an understanding of the evolution and epidemiology of circulating strains. Here we provide longitudinal genomic data on strain diversity, transmission dynamics and antimicrobial resistance (AMR) of C. difficile ribotypes (RTs) 014/020 (n=169), 002 (n=77) and 056 (n=36), the three most prominent C. difficile strains causing CDI in Australia. Genome scrutiny showed that AMR was uncommon in these lineages, with resistance-conferring alleles present in only 15/169 RT014/020 strains (8.9 %), 1/36 RT056 strains (2.78 %) and none of 77 RT002 strains. Notably, ~90 % of strains were resistant to MLSB agents in vitro, but only ~5.9 % harboured known resistance alleles, highlighting an incongruence between AMR genotype and phenotype. Core genome analyses revealed all three RTs contained genetically heterogeneous strain populations with limited evidence of clonal transmission between CDI cases. The average number of pairwise core genome SNP (cgSNP) differences within each RT group ranged from 23.3 (RT056, ST34, n=36) to 115.6 (RT002, ST8, n=77) and 315.9 (RT014/020, STs 2, 13, 14, 49, n=169). Just 19 clonal groups (encompassing 40 isolates), defined as isolates differing by ≤2 cgSNPs, were identified across all three RTs (RT014/020, n=14; RT002, n=3; RT056, n=2). Of these clonal groups, 63 % (12/19) comprised isolates from the same Australian State and 37 % (7/19) comprised isolates from different States. The low number of plausible transmission events found for these major RTs (and previously documented populations in animal and environmental sources/reservoirs) points to widespread and persistent community sources of diverse C. difficile strains as opposed to ongoing nationwide healthcare outbreaks dominated by a single clone. Together, these data provide new insights into the evolution of major lineages causing CDI in Australia and highlight the urgent need for enhanced surveillance, and for public health interventions to move beyond the healthcare setting and into a One Health paradigm to effectively combat this complex pathogen.