Citations

ABSTRACT Introduction Hepatocellular carcinoma (HCC) development in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) is a growing health concern, but the underlying mechanisms are not fully understood. Epigenetic aging biomarkers, reflecting cellular and tissue aging, have been linked to various age‐related pathologies, but their association with MASLD‐HCC is unknown. We investigated associations between five epigenetic aging biomarkers and MASLD‐HCC risk. Methods We performed whole blood DNA methylation assay (Infinium 850k array) and calculated principal components‐based (PC) versions of HorvathAge, HannumAge, PhenoAge and GrimAge and the DunedinPACE aging rate. We further calculated relative age accelerations for PCHorvathAge, PCHannumAge, PCPhenoAge and PCGrimAge. The aging biomarkers were modelled as continuous variables and categorised into tertiles based on distributions among controls. Associations between each aging biomarker and MASLD‐HCC were examined using logistic regression, calculating odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for covariates. Results Data on 272 MASLD‐HCC cases and 316 cancer‐free MASLD controls recruited from six sites and matched on chronological age, sex and study site were analysed. Higher relative age accelerations of PCPhenoAge (OR T3 vs. T1 = 2.25, 95% CI: 1.45–3.50; OR continuous = 1.04, 95% CI: 1.02–1.07, p = 0.009), PCGrimAge (OR T3 vs. T1 = 3.97, 95% CI: 2.41–6.64; OR continuous = 1.16, 95% CI: 1.10–1.24, p = 8.76 × 10 −07 ) and DunedinPACE (OR T3 vs. T1 = 3.45, 95% CI: 2.17–5.55; OR continuous = 1.72, 95% CI: 1.43–2.10, p = 2.58 × 10 −08 ) were associated with MASLD‐HCC, but not PCHorvathAge or PCHannumAge. Conclusion Higher relative age accelerations of PCPhenoAge, PCGrimAge and DunedinPACE aging rate are associated with risk of MASLD‐HCC. These aging biomarkers could improve HCC risk assessment and facilitate risk stratification in patients with MASLD.

ABSTRACT Background Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis highly associated with systemic comorbidities. Accurate diagnosis and treatment remain challenging due to its rarity and clinical mimickers. Objectives To evaluate demographic, clinical features and treatment outcomes in patients referred with suspected PG at a tertiary wound care centre. Methods A prospective observational study was conducted of patients referred for suspected PG between April 2021 and June 2023. Demographic, clinical and laboratory data, including biopsies and tissue cultures, were collected. Patients were categorised as having PG vs alternative diagnoses based on diagnostic criteria from Su, Maverakis and the PARACELSUS score. Results Of 60 patients (female, 51.7%; mean [SD] age 52.9 [14.0] years), 44 (73.3%) met at least one published diagnostic criterion for PG. The most common comorbidity was IBD (63.6%), followed by inflammatory arthritis (25.0%) and monoclonal gammopathy of undetermined significance (MGUS) (4.5%). Systemic corticosteroids were used by 40.9% of patients before referral, but steroid‐sparing agents and biologics were the primary treatments after consultation. Biologics and steroid‐sparing agents were associated with significant improvement in disease activity using the PGA score (average score decreased from 2.3 to 1.5, p < 0.005), with 40.9% achieving complete remission. Elevated serum inflammatory markers and faecal calprotectin were observed in PG patients but absent in non‐PG cases. Conclusions These prospective data support previously published rates of association between PG and systemic comorbidities. Steroid‐sparing anti‐neutrophilic and targeted therapies are effective steroid‐sparing strategies in managing PG. Small sample size and referral bias may limit generalisability.

Matrix metalloproteinases (MMPs) are secreted and cell membrane‐associated enzymes that remodel the extracellular matrix (ECM) and cleave extracellular proteins to promote tumor invasion, angiogenesis, immune evasion, and many other aspects of cancer progression. Among this family, the gelatinases MMP‐2 and MMP‐9, specialized for cleaving collagen IV, are tightly linked to metastatic progression in breast cancer and adverse clinical outcomes. Here, we summarize gelatinase biochemistry and regulation, including zymogen activation, TIMP control, cell‐surface trafficking and tethering, and receptor‐mediated clearance, and explain how crosstalk between ECM and proteases amplifies invasion and metastatic seeding. We then review therapeutic strategies in two parts: direct inhibition and indirect pathway modulation. Direct approaches emphasize selective small molecules (thiirane mechanism‐based inhibitors, allosteric blockers of pro‐MMP‐9 activation) and protein biologics (monoclonal antibodies, nanobodies, engineered TIMPs). Indirect strategies target upstream signals that drive MMP‐2/‐9, including MAPK/AP‐1, PI3K/Akt/mTOR, NF‐κB, EGFR/JAK/STAT, and nuclear receptor and Nrf2/HO‐1 programs, with agents that curb invasion, angiogenesis, and metastasis in breast cancer models. Together, these advances define a maturing toolkit for precise gelatinase control and support prospective evaluation in rational combinations to restrain metastatic progression in high‐risk breast cancer.

Introduction: Psychosocial assessments by behavioral health (BH) professionals before metabolic and bariatric surgery (MBS) are recommended by national guidelines. Accordingly, insurance companies often require patients to undergo psychosocial assessments before MBS. This paper reviews the historical evolution of the MBS psychosocial assessment, clarifies the role of BH professionals within the team before and after MBS, and describes strategies to effectively utilize psychosocial assessments to optimize patient outcomes. Methods: Authors conducted a manual search of the available literature and completed a narrative review. Results: The original intent of the psychosocial assessment for MBS was to correlate psychiatric profiles to weight loss outcomes or identify which patients were predicted to succeed or “fail” after MBS. Historically, these evaluations were gatekeeping mechanisms, which invalidates the myriad ways that psychosocial assessments can identify and support patients. Controversy exists about the necessity of these evaluations, leading some MBS team members and patients to see it as an unavoidable “checkbox” with little clinical utility outcomes. Conclusion: Viewing the psychosocial assessment as a checkbox minimizes the potential benefits to patients and MBS team members. Additionally, it diminishes the expertise of BH professionals who are uniquely trained to support this patient population toward an optimal surgical outcome.

Parkinson's disease (PD) is a progressive neurodegenerative disease with multiple manifestations including both motor and non-motor symptoms. One manifestation of PD that is often overlooked is the sexual dysfunction (SD) that patients may experience. Individuals with PD can experience impairment in sexual desire, arousal or lubrication, orgasm, ejaculation, pain and the physical aspect of intimacy. This article aims to provide an overview of the current practices in the evaluation and treatment of sexual dysfunction in men in the context PD. Note that this article focuses on the male population as it reviews the available American Urology Association practice guidelines many practitioners follow, which focus on the male population. Sexual dysfunction guidelines for the female population are much more limited, and future work should review the existing literature and gaps to provide a more robust understanding of sexual dysfunction in PD. PD represents a particularly vulnerable population for development of sexual dysfunction given the multifactorial nature of its manifestations. Given its profound impact on not only the patient, but their partner, it is important to be aware of the various manifestations of SD when evaluating individuals with PD. Through thorough history taking and targeted psychosexual evaluation, we as practitioners can ensure a more holistic and comprehensive approach to caring for individuals with PD.

Background There is limited evidence on the epidemiology and prognostic significance of acid-base disorders in the cardiovascular intensive care unit (CICU). This study examines the association of acid-base status at admission with in-hospital mortality among CICU patients. Methods We conducted a retrospective analysis of adults admitted to the Mayo Clinic CICU from 2007-2018 with available blood gas data, utilizing values obtained closest to CICU admission. Arterial pH, serum bicarbonate, base excess, and partial pressure of carbon dioxide (PaCO 2 ) were examined as predictors of in-hospital mortality. Multivariable logistic regression was used to assess associations, with adjustment for demographics, comorbidities, illness severity, and interventions. Results Among 3229 patients included for analysis, acidemia (pH < 7.35) emerged as the strongest predictor of in-hospital mortality (adjusted odds ratio [aOR] 1.60, 95% confidence interval [CI] 1.29-1.98, P < .003). Metabolic acidosis (HCO3 < 20 mEq/L, aOR 1.55, 95% CI 1.24-1.95, P < .001) and respiratory acidosis (PaCO2 > 45 mm Hg, aOR 1.44, 95% CI 1.14-1.81, P = .002) were associated with higher in-hospital mortality, whereas metabolic and respiratory alkalosis were not. After adjustment, lower pH and more negative base excess were associated with higher in-hospital mortality (both P < .001), whereas HCO3 and PaCO2 were not ( P = .053 and P = .051, respectively). Patients with combined metabolic and respiratory acidosis had the highest in-hospital mortality (56.3%). Conclusions Short-term survival in CICU patients decreases progressively with worse acidemia, especially in the context of combined metabolic and respiratory acidosis. Incorporating metabolic acid-base disorders as key therapeutic targets in randomized cardiogenic shock trials may improve outcomes in this complex population by addressing hemometabolic shock.

Objective Assess the patient compliance rate for nasopharyngoscopy as documented in clinical reports. Design Cross-sectional. Setting Thirteen cleft teams in North America. Patients Patients aged 3 to 21 years old with a repaired cleft palate. Interventions Nasopharyngoscopy. Main Outcome Measure Patient compliance rate for nasopharyngoscopy. Results Patient compliance was documented in 128 of 158 reports (81%). Of the 128 reports, patient compliance was reported as “good/excellent” in 65% (n = 83), “marginal/fair” across 10% (n = 13), “poor” in 16% (n = 20), and “other” in 9% (n = 12). Patients with “poor” compliance had lower rates of documented imaging ratings, however 55% (n = 11) of reports included a surgical recommendation. Conclusions Among children completing nasopharyngoscopy for velopharyngeal insufficiency surgery planning, at least one-fourth of reports indicate significant compliance issues that limits velopharyngeal port imaging. These findings suggest that some cleft teams and surgeons may be proceeding with surgical management of velopharyngeal insufficiency without adequate visualization or ratings of velopharyngeal anatomy.

Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD). The pathogenesis of HLHS is poorly understood, and due to the likely oligogenic complexity of the disease, definitive HLHS-causing genes have not yet been identified. Postulating impaired cardiomyocyte proliferation as a likely important contributing mechanism to HLHS pathogenesis, and we conducted a genome-wide siRNA screen to identify genes affecting proliferation of human iPSC-derived cardiomyocytes (hPSC-CMs). This yielded ribosomal protein (RP) genes as the most prominent class of effectors of CM proliferation. In parallel, whole genome sequencing and rare variant filtering of a cohort of 25 HLHS proband-parent trios with poor clinical outcome revealed enrichment of rare variants of RP genes. In addition, in a familial CHD case we identified a rare, predicted-damaging promoter variant affecting RPS15A that was shared between the HLHS proband and a distant relative with CHD. Functional testing with an integrated multi-model system approach reinforced the idea that RP genes are major regulators of cardiac growth and proliferation, thus potentially contributing to the hypoplastic phenotype observed in HLHS patients. Cardiac knockdown (KD) of RP genes with promoter or coding variants (RPS15A, RPS17, RPL26L1, RPL39, RPS15) reduced proliferation in generic hPSC-CMs and caused malformed hearts, heart-loss or even lethality in Drosophila. In zebrafish, diminished rps15a function caused reduced CM numbers, heart looping defects, or weakened contractility, while reduced rps17 or rpl39 function caused reduced ventricular size or systolic atrial dysfunction of the atrium, respectively. Importantly, genetic interactions between RPS15A and core cardiac transcription factors TBX5 in CMs, Drosocross, pannier and tinman in flies, and tbx5 and nkx2-7 (nkx2-5 paralog) in fish, support a specific role for RP genes in heart development. Furthermore, RPS15A KD-induced heart/CM proliferation defects were significantly attenuated by p53 KD in both hPSC-CMs and zebrafish, and by Hippo activation (YAP/yorkie overexpression) in developing fly hearts. Based on these findings, we conclude that RP genes play novel critical roles in cardiogenesis and constitute an emerging class of gene candidates likely involved in HLHS.