Cedars-Sinai Medical Center

BACKGROUND The development of thoracic aortic calcium (TAC) temporally precedes coronary artery calcium more often in women versus men. Whether TAC density and area confer sex-specific differences in atherosclerotic cardiovascular disease (ASCVD) risk is unknown. METHODS We studied 5317 primary prevention patients who underwent coronary artery calcium scoring on noncontrast cardiac gated computed tomography with TAC >0. The Agatston TAC score (Agatston units), density (Hounsfield units), and area (mm ² ) were compared between men and women. Cox proportional hazards regression calculated adjusted hazard ratios for TAC density-area groups with ASCVD mortality, adjusting for traditional risk factors, coronary artery calcium, and TAC. Multinomial logistic regression calculated adjusted odds ratios for the association between traditional risk factors and TAC density-area groups. RESULTS The mean age was 60.7 years, 38% were women, and 163 ASCVD deaths occurred over a median of 11.7-year follow-up. Women had higher median TAC scores (97 versus 84 Agatston units; P =0.004), density (223 versus 210 Hounsfield units; P <0.001), and area (37 versus 32 mm ² ; P =0.006) compared with men. There was a stepwise higher incidence of ASCVD deaths across increasing TAC density-area groups in men though women with low TAC density relative to TAC area (3.6 per 1000 person-years) had survival probability commensurate with the high-density-high-area group (4.8 per 1000 person-years). Compared with low TAC density-area, low TAC density/high TAC area conferred a 3.75-fold higher risk of ASCVD mortality in women (adjusted hazard ratio, 3.75 [95% CI, 1.13–12.44]) but not in men (adjusted hazard ratio, 1.16 [95% CI, 0.48–2.84]). Risk factors most strongly associated with low TAC density/high TAC area differed in women (diabetes: adjusted odds ratio, 2.61 [95% CI, 1.34–5.07]) versus men (hypertension: adjusted odds ratio, 1.45 [95% CI, 1.11–1.90]). CONCLUSIONS TAC density-area phenotypes do not consistently associate with ASCVD mortality though low TAC density relative to area may be a marker of increased ASCVD risk in women.

Background Fibronectin glomerulopathy is a rare genetic nephropathy with only a few cases of post-transplant recurrence being reported previously. We highlight a case that was initially misdiagnosed and emphasize the importance of full immunofluorescence and electron microscopy evaluation in allograft biopsies. Case presentation A 36-year-old male with a history of end-stage kidney disease secondary to biopsy-proven type 1 membranoproliferative glomerulonephritis (MPGN) status-post living unrelated donor kidney transplant 12 years prior, presented with increasing creatinine and proteinuria. Biopsy was performed and was consistent with fibronectin glomerulopathy. Subsequent genetic testing revealed an FN1 mutation, the primary gene associated with this condition. Conclusions Full histologic evaluation of the allograft biopsy corrected the diagnosis and additionally suggested that the patient's mother, who had expired in her 30s and had received a diagnosis of type 1 MPGN on autopsy, likely also had fibronectin glomerulopathy, enabling appropriate genetic counseling for the family.

Purpose of Review Breast cancer is a major health issue with over 2 million new cases diagnosed annually. The burden of this disease is much higher in low- to middle-income countries (LMIC) secondary to lack of access to health care, screening, diagnostic services, as well as options for treatment. Moreover, there is a lack of awareness about breast diseases, and cultural barriers often lead to late detection and patient’s presenting with stages of breast cancer. Recent Findings The incidence of breast cancer is increasing in Pakistan. To address the challenges of lack of awareness including cultural factors, limited resources, and importance of screening, NGOs have established free cancer screening and clinical breast exams (CBE) for women. In Gilgit, a mountainous region in Pakistan, local family doctors are being trained on how to perform effective breast exams and provide mammograms for women who meet criteria for mammography. Summary Women who have breast masses in Gilgit are now realizing the importance of seeking care at local clinics and hospitals as a result of this new screening program. Future research will need to focus on whether these programs are successful in identifying women with breast cancer who have early-stage disease.

Acne is a dermatologic disease with a strong pathologic association with human commensal Cutibacterium acnes. Conspicuously, certain C. acnes phylotypes are associated with acne, whereas others are associated with healthy skin. Here we investigate if the evolution of a C. acnes enzyme contributes to health or acne. Two hyaluronidase variants exclusively expressed by C. acnes strains, HylA and HylB, demonstrate remarkable clinical correlation with acne or health. We show that HylA is strongly pro-inflammatory, and HylB is modestly anti-inflammatory in a murine (female) acne model. Structural and phylogenic studies suggest that the enzymes evolved from a common hyaluronidase that acquired distinct enzymatic activity. Health-associated HylB degrades hyaluronic acid (HA) exclusively to HA disaccharides leading to reduced inflammation, whereas HylA generates large-sized HA fragments that drive robust TLR2-dependent pathology. Replacing an amino acid, Serine to Glycine near the HylA catalytic site enhances the enzymatic activity of HylA and produces an HA degradation pattern intermediate to HylA and HylB. Selective targeting of HylA using peptide vaccine or inhibitors alleviates acne pathology. We suggest that the functional divergence of HylA and HylB is a major driving force behind C. acnes health- and acne- phenotype and propose targeting of HylA as an approach for acne therapy.

Background Hypertensive disorders of pregnancy (HDP) are associated with long-term maternal risks for cardiovascular disease for reasons that remain incompletely understood. Methods The HCHS/SOL (Hispanic Community Health Study/Study of Latinos), a multi-center community-based cohort of Hispanic/Latino adults recruited 2008 to 2011, was used to evaluate the associations of history of de novo HDP (gestational hypertension, preeclampsia, eclampsia) with echocardiographic measures of cardiac structure and function in Hispanic/Latina women with ≥1 prior pregnancy and the proportion of association mediated by current hypertension (>140/90 mm Hg or antihypertensive therapy). Results The study cohort included 5168 Hispanic/Latina women with an average age (SD) of 58.7 (9.7) years at time of echocardiogram. Prior de novo HDP was reported by 724 (14%) of the women studied and was associated with lower left ventricle (LV) ejection fraction −0.66 (95% confidence interval [CI], −1.21 to −0.11), higher LV relative wall thickness 0.09 (95% CI, 0–0.18), and 1.39 (95% CI, 1.02–1.89) higher risk of abnormal LV geometry after adjusting for blood pressure and other confounders. The proportion of the association mediated by current hypertension between HDP and LV ejection fraction was 0.09 (95% CI, 0.03–0.45), LV relative wall thickness was 0.28 (95% CI, 0.16–0.51), abnormal LV geometry was 0.14 (95% CI, 0.12–0.48), concentric left ventricular hypertrophy was 0.31 (95% CI, 0.19–0.86), and abnormal LV diastolic dysfunction was 0.58 (95% CI, 0.26–0.79). Conclusions In a large cohort of Hispanic/Latina women those with history of de novo HDP had detectable and measurable subclinical alterations in cardiac structure and both systolic and diastolic dysfunction that were only partially mediated by current hypertension.

Purpose Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma. Patients and Methods Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers. Results Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4–31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months–undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms. Conclusions High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.

Background Eicosanoids are derivatives of polyunsaturated fatty acids (PUFAs) and participate in the inflammatory response as well as the maintenance of endothelial function. Specific eicosanoids have been linked to various diseases, including hypertension and asthma, and may also reduce renal blood flow. A systematic investigation of eicosanoid-related metabolites and adverse kidney outcomes could identify key mediators of kidney disease and inform ongoing work in drug development. Methods Profiling of eicosanoid-related metabolites was performed in 9,650 participants in the Atherosclerosis Risk in Communities (ARIC) Study (visit 2; mean age, 57 years). The associations between metabolite levels and the development of end-stage kidney disease (ESKD) was investigated using a series of progressively adjusted models and Cox proportional hazards regression (N= 256 events; median follow-up, 25.5 years). Metabolites with statistically significant associations with ESKD were evaluated for a potential causal role using bidirectional Mendelian randomization techniques, linking genetic instruments for eicosanoid levels to genome-wide association study summary statistics of estimated glomerular filtration rate (eGFR). Results The 223 eicosanoid-related metabolites that were profiled and passed QC were generally uncorrelated with eGFR in cross-sectional analyses (median Spearman correlation, -0.03; IQR -0.05 to 0.002). In models adjusted for multiple covariates, including baseline eGFR, three metabolites had statistically significant associations with ESKD (p-value <0.05/223). These included a hydroxyoctadecenoic acid, a dihydroxydocosapentaenoic acid, and arachidonic acid, with higher levels of the former two protective against ESKD and higher levels of arachidonic acid having a positive association with risk of ESKD. Mendelian randomization analyses suggested a causal role for the hydroxyoctadecenoic and arachidonic acid in determining eGFR. Spectral analysis identified the former metabolite as either 11-hydroxy-9-octadecenoic acid or 10-hydroxy-11-octadecenoic acid. Conclusions High throughput eicosanoid profiling can identify metabolites that may play a protective role in the development of kidney disease.

Objective Dravet Syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment‐resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. Methods ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants ( SCN1A + DS) enrolled at age <5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition (BSID‐III) and the parent‐reported Vineland Adaptive Behavior Scales 3rd Edition (VABS‐III). We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6–2:0 years:months (youngest), 2:1–3:6 years:months (middle) and 3:7–5:0 years:months (oldest). Results Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow‐up was 17.5 months (range: 0.0–24.0), with 54/58 (93.1%) followed for at least 6 months and 51/58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [min–max]: 1.0 in the youngest [1.0–70.0] and middle [1.0–242.0] age groups and 4.5 [0.0–2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size 0.52, P=0.024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. Significance In infants and young children with SCN1A + DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.

Silicone is utilized widely in medical devices for its compatibility with tissues and bodily fluids, making it a versatile material for implants and wearables. To effectively bond silicone devices to biological tissues, a reliable adhesive is required to create a strong and long‐lasting interface. This study introduces BioAdheSil, a silicone‐based bioadhesive designed to provide robust adhesion on both sides of the interface, facilitating bonding between dissimilar substrates, namely silicone devices and tissues. The adhesive's design focuses on two key aspects: wet tissue adhesion capability and tissue‐infiltration‐based long‐term integration. BioAdheSil is formulated by mixing soft silicone oligomers with siloxane coupling agents and absorbents for bonding the hydrophobic silicone device to hydrophilic biological tissues. Incorporation of biodegradable absorbents eliminates surface water and controls porosity, while silane crosslinkers provide interfacial strength. Over time, BioAdheSil transitions from non‐permeable to permeable through enzyme degradation, creating a porous structure that facilitates cell migration and tissue integration, potentially enabling long‐lasting adhesion. Experimental results demonstrate that BioAdheSil outperforms commercial adhesives and elicits no adverse response in rats. BioAdheSil offers practical utility for adhering silicone devices to wet tissues, including long‐term implants and transcutaneous devices. In this study, we demonstrate its functionality through applications such as tracheal stents and LVAD (Left Ventricular Assist Device) lines. This article is protected by copyright. All rights reserved

Background Memory CD8⁺ T cells expand with age. We previously demonstrated an age-associated expansion of effector memory (EM) CD8⁺ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) and the presence of its gene signature (i.e., IL-7Rαlow aging genes) in peripheral blood of older adults without Alzheimer’s disease (AD). Considering age as the strongest risk factor for AD and the recent finding of EM CD8⁺ T cell expansion, mostly IL-7Rαlow cells, in AD, we investigated whether subjects with AD have alterations in IL-7Rαlow aging gene signature, especially in relation to genes possibly associated with AD and disease severity. Results We identified a set of 29 candidate genes (i.e., putative AD genes) which could be differentially expressed in peripheral blood of patients with AD through the systematic search of publicly available datasets. Of the 29 putative AD genes, 9 genes (31%) were IL-7Rαlow aging genes (P < 0.001), suggesting the possible implication of IL-7Rαlow aging genes in AD. These findings were validated by RT-qPCR analysis of 40 genes, including 29 putative AD genes, additional 9 top IL-7R⍺low aging but not the putative AD genes, and 2 inflammatory control genes in peripheral blood of cognitively normal persons (CN, 38 subjects) and patients with AD (40 mild cognitive impairment and 43 dementia subjects). The RT-qPCR results showed 8 differentially expressed genes between AD and CN groups; five (62.5%) of which were top IL-7Rαlow aging genes (FGFBP2, GZMH, NUAK1, PRSS23, TGFBR3) not previously reported to be altered in AD. Unbiased clustering analysis revealed 3 clusters of dementia patients with distinct expression levels of the 40 analyzed genes, including IL-7Rαlow aging genes, which were associated with neurocognitive function as determined by MoCA, CDRsob and neuropsychological testing. Conclusions We report differential expression of “normal” aging genes associated with IL‐7Rαlow EM CD8⁺ T cells in peripheral blood of patients with AD, and the significance of such gene expression in clustering subjects with dementia due to AD into groups with different levels of cognitive functioning. These results provide a platform for studies investigating the possible implications of age-related immune changes, including those associated with CD8⁺ T cells, in AD.

Precision cancer care, for essentially all cancer types, now requires molecular diagnostics to assess mutations, chromosomal alterations, and gene expression to personalize treatments for individual patients. Advances in the diagnostics and treatment options have moved the field forward from fundamental discoveries beginning in the 1960s to the development of many targeted therapies that can be as specific as targeting a single-base-pair mutation. Herein is a brief historical perspective on cancer precision medicine with current diagnostic, prognostic, and treatment stratification guidance for early- and late-stage cancers.

Smoking and high fat diet (HFD) consumption are two modifiable risk factors for cardiovascular (CV) diseases, and individuals who are overweight or obese due to unhealthy diet are more likely to use tobacco products. In this study, we aim to investigate the combined effects of nicotine (the addictive component of all tobacco products) and HFD on CV health, which are poorly understood. C57BL/6N male mice were placed on either HFD (60 kcal% fat) or regular diet (22 kcal% fat) and exposed to air or nicotine vapor for 10-12 weeks. CV function was monitored by echocardiography and radiotelemetry, with left ventricular (LV) catheterization and aortic ring vasoreactivity assays performed at endpoint. Mice on HFD exhibited increased heart rate and impaired parasympathetic tone, whereas nicotine exposure increased sympathetic vascular tone as evidenced by increased blood pressure (BP) response to ganglionic blockade. Although neither nicotine nor HFD alone or in combination significantly altered BP, nicotine exposure disrupted circadian BP regulation with reduced BP dipping. LV catheterization revealed that combined exposure to nicotine and HFD led to LV diastolic dysfunction with increased LV end-diastolic pressure (LVEDP). Moreover, combined exposure resulted in increased inhibitory phosphorylation of endothelial nitric oxide synthase and greater impairment of endothelium-dependent vasodilation. Finally, a small cohort of C57BL/6N females with combined exposure exhibited similar increases in LVEDP, indicating that both sexes are susceptible to the combined effect of nicotine and HFD. In summary, combined exposure to nicotine and HFD leads to greater CV harm, including both additive and new-onset CV dysfunction.

Hemodilution of bone marrow (BM) aspirates is a limitation of multiparameter flow cytometry (MFC) in plasma cell disorders. There is a need for a validated approach for assessing sample quality and the distribution of non-plasma cell BM populations by MFC could provide a solution. We evaluated BM-associated cell populations, assessed by next-generation flow cytometry (NGF) and white blood cell (WBC) count in 351 BM aspirated samples from 219 participants with plasma cell disorders in the Iceland Screens, Treats, or Prevents MM study (iStopMM), as markers of hemodilution by their discriminatory ability between first and (generally more hemodiluted) second pull BM aspirated samples. The most discriminating markers were used to derive a novel BM quality index (BMQI). Nucleated red blood cells and myeloid precursors provided the greatest discriminatory ability between first vs second pull samples (area under the curve (AUC): 0.87 and 0.85, respectively), significantly better than B cell precursors (AUC = 0.64; p < 0.001), mast cells (AUC = 0.65; p < 0.001), and the BM WBC count (AUC = 0.77; p < 0.05). We generated a novel BMQI that is intrinsic to current NGF protocols, for evaluating quality of diagnostic BM samples and suggest the use of a BMQI scoring system for interpreting results and guiding appropriate actions.

Purpose of Review The surge in orthopedic surgeries strains the US healthcare system, necessitating innovative rehabilitation solutions. This review examines the potential of virtual reality (VR)-based interventions for orthopedic rehabilitation. Recent Findings The effectiveness of VR-based interventions in orthopedic surgery patients is scrutinized. While some studies suggest better patient-reported outcomes and satisfaction, mixed results emerge from others, demonstrating comparable or varied results compared to traditional rehabilitation. The underlying mechanisms of VR-based rehabilitation are elucidated, showing its positive impact on proprioception, pain management, agency, and balance. Challenges of unfamiliarity, patient engagement, and drop-out rates are identified, emphasizing the need for tailored approaches. Summary VR technology’s immersive environments and multisensory experiences offer a novel approach to addressing functional deficits and pain post-surgery. The conclusion drawn is that VR-based rehabilitation complements rather than replaces conventional methods, potentially aiding in pain reduction and functional improvement. VR-based rehabilitation holds promise for enhancing orthopedic surgery outcomes, presenting a dynamic approach to recovery. Its potential to reshape healthcare delivery and reimbursement structures underscores its significance in modern healthcare. Overall, VR-based rehabilitation offers a promising avenue for optimizing postoperative recovery in orthopedic surgery patients.