Baseline immunoglobulin G and immune function in non-Hodgkin lymphoma: a retrospective analysis.

Introduction: Non-Hodgkin's lymphoma (NHL) encompasses a diverse group of lymphoma subtypes with a wide range in disease course. Previous studies show that hypogammaglobulinemia in treatment-naïve patients is associated with poorer survival in high grade B-cell non-Hodgkin's lymphomas, though it is not known how this applies across all B-cell lymphoid malignancies. Methods: We conducted a retrospective study of immunoglobulin levels and clinical outcomes including survival, hospitalization, and infection rates in patients diagnosed with B-cell non-Hodgkin lymphomas of all grades at our institution. Results: Two-hundred twenty-three adults (aged = 18 years) with available pre-treatment IgG levels were selected, with hypogammaglobulinemia defined as IgG< 500 mg/mL. For this analysis, we grouped DLBCL (n=90), Primary CNS (n=5), and Burkitt lymphoma (n=1) together as high-grade, while CLL (n=52), mantle cell (n=20), marginal zone (n=25), follicular (n=21), and Waldenstrom macroglobulinemia (n=5) were low-grade. The incidence of hypogammaglobulinemia in our cohort of both high and low-grade lymphoma patients was 13.5% (n=30). Across all NHL subtypes, individuals with baseline IgG< 500 mg/dL showed an increased rate of hospitalization (4.453, CI: 1.955-10.54, p= 0.0005) and higher mortality (3.325, CI: 1.258, 8.491, p= 0.013), yet no association in number of infections when compared with those with IgG=500 mg/dL. There was a higher hospitalization rate (3.237, CI: 1.77-6.051, p=0.0017) in those with high-grade lymphoma with hypogammaglobulinemia when compared with low-grade. There was no statistically significant difference in individuals who were alive after three years in those with baseline IgG<500 mg/dL. Discussion: Our study is the first to analyze incidence of hypogammaglobulinemia at the time of diagnosis of NHL as a potential biomarker of interest for future outcomes including hospitalization and infection.

Interventions to mitigate cancer-related medical financial hardship: A systematic review and meta-analysis.

BACKGROUND: This study systematically reviewed interventions mitigating financial hardship in patients with cancer and assessed effectiveness using a meta-analytic method. METHODS: PubMed, Cochrane, Scopus, CINAHL, and Web of Science were searched for articles published in English during January 2000-April 2023. Two independent reviewers selected prospective clinical trials with an intervention targeting and an outcome measuring financial hardship. Quality appraisal and data extraction were performed independently by two reviewers using a quality assessment tool. A random-effects model meta-analysis was performed. Reporting followed the preferred reporting items for systematic review and meta-analyses guidelines. RESULTS: Eleven studies (2211 participants; 55% male; mean age, 59.29 years) testing interventions including financial navigation, financial education, and cost discussion were included. Financial worry improved in only 27.3% of 11 studies. Material hardship and cost-related care nonadherence remained unchanged in the two studies measuring these outcomes. Four studies (373 participants; 37% male, mean age, 55.88 years) assessed the impact of financial navigation on financial worry using the comprehensive score of financial toxicity (COST) measure (score range, 0-44; higher score = lower financial worry) and were used for meta-analysis. There was no significant change in the mean of pooled COST score between post- and pre-intervention (1.21; 95% confidence interval, -6.54 to 8.96; p = .65). Adjusting for pre-intervention COST, mean change of COST significantly decreased by 0.88 with every 1-unit increase in pre-intervention COST (p = .02). The intervention significantly changed COST score when pre-intervention COST was ≤14.5. CONCLUSION: A variety of interventions have been tested to mitigate financial hardship. Financial navigation can mitigate financial worry among high-risk patients.

A Pilot Study of Pembrolizumab Combined With Stereotactic Ablative Radiotherapy for Patients With Advanced or Metastatic Sarcoma.

OBJECTIVES: Immunotherapy with immune checkpoint inhibitors has shown only limited success in the management of metastatic soft tissue sarcoma. Overall response rates (ORR) with single agent pembrolizumab were 18% and median PFS was 18 weeks on the clinical trial SARC028. One strategy to improve the responses to immunotherapy is with stereotactic body radiation therapy (SBRT), which can enhance the antitumor CD8 T cell response through the release of tumor-specific antigens, potentially priming a more diverse class of T cell receptors. METHODS: This is a phase 0, pilot prospective study taking place at a single center with 2 arms. In Arm A, patients are treated with pembrolizumab 400 mg IV infusion on day 1 of a 42-day cycle. Stereotactic body radiation therapy (SBRT) is delivered in 1-5 fractions starting on C1D15-28 and given every other day. In Arm B, patients who have started an immune checkpoint inhibitor within 60 days are treated with SBRT in addition to the current therapy. RESULTS: In this study we outline testing the feasibility of adding SBRT to pembrolizumab. CONCLUSION: The ultimate goal of combination therapy is improved overall response, including tumors not treated with SBRT. This trial can be found registered online: NCT05488366.

A phase I study of docetaxel plus synthetic lycopene in metastatic prostate cancer patients.

PURPOSE: Our preclinical studies showed that lycopene enhanced the anti-prostate cancer efficacy of docetaxel in animal models. A phase I trial (NCT0149519) was conducted to identify an optimum dose of synthetic lycopene in combination with docetaxel (and androgen blockade [androgen deprivation therapy, ADT]), and to evaluate its effect on the safety and pharmacokinetics of docetaxel in men with metastatic prostate cancer. METHODS: Subjects were treated with 21-day cycles of 75 mg/m2 docetaxel (and ADT), plus lycopene at 30, 90 or 150 mg/day. A Bayesian model averaging continual reassessment method was used to guide dose escalation. Pharmacokinetics of docetaxel and multiple correlative studies were carried out. RESULTS: Twenty-four participants were enrolled, 18 in a dose escalation cohort to define the maximum tolerated dose (MTD), and six in a pharmacokinetic cohort. Docetaxel/ADT plus 150 mg/day synthetic lycopene resulted in dose-limiting toxicity (pulmonary embolus) in one out of 12 participants with an estimated probability of .106 and thus was chosen as the MTD. Lycopene increased the AUCinf and Cmax of plasma docetaxel by 9.5% and 15.1%, respectively. Correlative studies showed dose-related changes in circulating endothelial cells and vascular endothelial growth factor A, and reduction in insulin-like growth factor 1R phosphorylation, associated with lycopene therapy. CONCLUSIONS: The combination of docetaxel/ADT and synthetic lycopene has low toxicity and favourable pharmacokinetics. The effects of lycopene on biomarkers provide additional support for the toxicity-dependent MTD definition. HIGHLIGHTS: The maximum tolerated dose was identified as 150 mg/day of lycopene in combination with docetaxel/ADT for the treatment of metastatic prostate cancer patients. Small increases in plasma exposure to docetaxel were observed with lycopene co-administration. Mechanistically significant effects were seen on angiogenesis and insulin-like growth factor 1 signalling by lycopene co-administration with docetaxel/ADT.

A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome.

Hoyeraal-Hreidarsson syndrome (HHS) is the most severe form of dyskeratosis congenita (DC) and is caused by mutations in genes involved in telomere maintenance. Here, we identified male siblings from a family with HHS carrying a hemizygous mutation (c.1345C > G, p.R449G), located in the C-terminal nuclear localization signal (NLS) of the DKC1 gene. These patients exhibit progressive cerebellar hypoplasia, recurrent infections, pancytopenia due to bone marrow failure, and short leukocyte telomere lengths. Single-cell RNA sequencing analysis suggested defects in the NLRP3 inflammasome in monocytes and the activation and maturation of NK cells and B cells. In experiments using induced pluripotent stem cells (iPSCs) from patients, DKC1_R449G iPSCs had short telomere lengths due to reduced levels of human telomerase RNA (hTR) and increased cytosolic proportions of DKC1. Treatment with dihydroquinolizinone RG7834 and 3'deoxyanosine cordycepin rescued telomere length in patient-derived iPSCs. Together, our findings not only provide new insights into immunodeficiency in DC patients but also provide treatment options for telomerase insufficiency disorders.

High-Throughput Optical Controlling and Recording Calcium Signal in iPSC-Derived Cardiomyocytes for Toxicity Testing and Phenotypic Drug Screening.

Understanding how excitable cells work in health and disease and how that behavior can be altered by small molecules or genetic manipulation is important. Genetically encoded calcium indicators (GECIs) with multiple emission windows can be combined (e.g., for simultaneous observation of distinct subcellular events) or used in extended applications with other light-dependent actuators in excitable cells (e.g., combining genetically encoded optogenetic control with spectrally compatible calcium indicators). Such approaches have been used in primary or stem cell-derived neurons, cardiomyocytes, and pancreatic beta-cells. However, it has been challenging to increase the throughput, or duration of observation, of such approaches due to limitations of the instruments, analysis software, indicator performance, and gene delivery efficiency. Here, a high-performance green GECI, mNeonGreen-GECO (mNG-GECO), and red-shifted GECI, K-GECO, is combined with optogenetic control to achieve all-optical control and visualization of cellular activity in a high-throughput imaging format using a High-Content Imaging System. Applications demonstrating cardiotoxicity testing and phenotypic drug screening with healthy and patient-derived iPSC-CMs are shown. In addition, multi-parametric assessments using combinations of spectral and calcium affinity indicator variants (NIR-GECO, LAR-GECO, and mtGCEPIA or Orai1-G-GECO) are restricted to different cellular compartments are also demonstrated in the iPSC-CM model.

Multifocal confocal microscopy using a volume holographic lenslet array illuminator.

Multifocal illumination can improve image acquisition time compared to single point scanning in confocal microscopy. However, due to an increase in the system complexity, obtaining uniform multifocal illumination throughout the field of view with conventional methods is challenging. Here, we propose a volume holographic lenslet array illuminator (VHLAI) for multifocal confocal microscopy. To obtain uniform array illumination, a super Gaussian (SG) beam has been incorporated through VHLAI with an efficiency of 43%, and implemented in a confocal microscope. The design method for a photo-polymer based volume holographic beam shaper is presented and its advantages are thoroughly addressed. The proposed system can significantly improve image acquisition time without sacrificing the quality of the image. The performance of the proposed multifocal confocal microscopy was compared with wide-field images and also evaluated by measuring optically sectioned microscopic images of fluorescence beads, florescence pollen grains, and biological samples. The proposed multifocal confocal system generates images faster without any changes in scanning devices. The present method may find important applications in high-speed multifocal microscopy platforms.

Metasurface-Based Abrupt Autofocusing Beam for Biomedical Applications.

Manipulation and precise delivery of optical energies in the regions of interest within specimens require different strategies. Hence, proper control of input beam parameters is a prerequisite. One of the prominent methods is metasurface optics, capable of crafting properties of light at nanoscales. Here, the generation of an abrupt autofocusing (AAF) beam by a nanophotonic metasurface for biomedical applications is demonstrated. Fluorescence guided laser microprofiling of mouse cardiac samples is experimentally investigated, using the AAF beam to deliver optical energy selectively to specific locations. In addition, photocoagulation of ex vivo swine skin tissue is performed and observed through optical coherence tomography. The results show great potentials for integrating metasurface optics to realize miniature laser surgery instruments for wide applications in biomedicine.

Hip, vertebral, and wrist fracture risks and schizophrenia: a nationwide longitudinal study.

BACKGROUND: Fractures are a great health issue associated with morbidity, quality of life, life span, and health care expenditure. Fractures are correlated with cardiovascular disease, type 2 diabetes mellitus, cerebrovascular disease, and some psychiatric disorders. However, representative national data are few, and longitudinal cohort studies on the association between schizophrenia and the subsequent fracture risk are scant. We designed a nationwide population-based cohort study to investigate the association of schizophrenia with hip, vertebral, and wrist fractures over a 10-year follow-up. METHODS: Data of patients with schizophrenia (International Classification of Diseases, Ninth Revision, Clinical Modification code 295) and matched over January 2000-December 2009) were extracted from Taiwan National Health Insurance Research Database. A Cox proportional-hazards regression model was constructed to calculate hazard ratios (HRs) for fractures between the schizophrenia and control cohorts. RESULTS: Of 2028 people with schizophrenia (mean age: 36.3 years, 49.4% female), 89 (4.4%) reported newly diagnosed fractures-significantly higher than the proportion in the control population (257, 3.2%; P = 0.007). The incidences of hip (1.2%, P = 0.009) and vertebral (2.6%, P = 0.011) fractures were significantly higher in the schizophrenia cohort than in the control cohort. In Cox regression analysis, hip (adjusted HR: 1.78, 95% confidence interval [CI]: 1.08-2.93) and vertebral (adjusted HR: 1.40, 95% CI: 1.01-1.95) fracture risks were significantly higher in patients with schizophrenia. Furthermore, a sex-based subgroup analysis revealed that the risk of hip fracture remained significantly higher in female patients with schizophrenia (HR: 2.68, 95% CI: 1.32-5.44) than in female controls. On the other hand, there was no significant interaction between effects of sex and schizophrenia on the risk of fractures. CONCLUSIONS: Over a 10-year follow-up, hip and vertebral fracture risks were higher in the people with schizophrenia than in the controls. The risk of fractures in patients with schizophrenia does not differ between female and male.

Impact of genetic tests on survivors of paediatric sudden cardiac arrest.

OBJECTIVE: To retrospectively investigate the clinical spectrum, genetic profiles and outcomes of survivors of paediatric sudden cardiac arrest (SCA). DESIGN AND PATIENTS: All 66 patients (aged 1-20 years), with unexpected SCA or syncope related to ventricular tachycardia (VT)/fibrillation and who survived to discharge from a tertiary centre, were enrolled from 1995 to 2018. Of these, 30 with underlying diseases prior to the events were excluded. Whole-exome sequencing targeting 384 channelopathy and cardiomyopathy-related genes (composite panel) was conducted to identify the possible genetic variants/mutations. RESULTS: A total of 36 patients were enrolled. Male adolescents predominated (66.7%), and the median age at onset was 13.3 years. Events occurred most often during exercise and daily activities. The yield rate of the genetic test was 84.6% (22/26); 14 had pathogenic variants; and 8 had likely pathogenic variants. The most common diagnoses were long QT in nine (25%), catecholaminergic polymorphic VT in six patients (16.7%), but other long QT and cardiomyopathy genes were also detected in eight patients (30.7%). The 10-year transplantation-free survival rate was 87.8% and was better for those who received genetic tests initially at the disease onset. An implantable cardioverter-defibrillator was implanted in 55.6% of the patients, with an appropriate shock rate of 61.1%. The defibrillator shock rate was lower for those who received composite panel initially. CONCLUSION: Survivors of SCA in the paediatric population had favourable long-term outcomes aided by genetic test. A broad composite genetic panel brings extra diagnostic value in the investigation of ventricular fibrillation/sudden cardiac death.

Psychological stress and cortisol during pregnancy: An ecological momentary assessment (EMA)-Based within- and between-person analysis.

BACKGROUND: Although the linkage between psychological stress and cortisol is believed to mediate the association of stress with health outcomes, several studies have been unable to demonstrate this association. We suggest this inability may be a consequence of limitations in the measurement approach and/or reliance on analytic strategies that focus on associations across, rather than within individuals. The link between psychological stress and cortisol is of particular interest in the context of pregnancy and fetal development. Using an ecological momentary assessment (EMA) design, we examined the association between psychological stress and cortisol at the between- and the within-person level. METHODS: 152 participants completed a 4-day long EMA protocol serially in early, mid and late pregnancy to provide momentary stress appraisals (average of 150 measures/subject) and saliva samples (average of 55 samples/subject) for quantification of cortisol. The association between stress and cortisol was estimated using linear mixed models. RESULTS: After accounting for the effects of key determinants of variation in cortisol, momentary stress was significantly and positively associated with cortisol at the within-person level (B = .030, p = .031), but not at the between-person level. No association was evident for traditional retrospective measures of stress with cortisol at either the between- or the within-person level. CONCLUSIONS: Our study highlights the value of EMA methods and linear mixed-modeling approaches in linking maternal psychological and physiological states across pregnancy. These findings may have important implications for the development of personalized risk identification and "just-in-time" intervention strategies to optimize maternal and child health.

Increased frequency of GNPAT p.D519G in compound HFE p.C282Y/p.H63D heterozygotes with elevated serum ferritin levels.

Glyceronephosphate O-acyltransferase (GNPAT) p.D519G (rs11558492) was identified as a genetic modifier correlated with more severe iron overload in hemochromatosis through whole-exome sequencing of HFE p.C282Y homozygotes with extreme iron phenotypes. We studied the prevalence of p.D519G in HFE p.C282Y/p.H63D compound heterozygotes, a genotype associated with iron overload in some patients. Cases were Australian participants with elevated serum ferritin (SF) levels ≥300µg/L (males) and ≥200µg/L (females); subjects whose SF levels were below these cut-offs were designated as controls. Samples were genotyped for GNPAT p.D519G. We compared the allele frequency of the present subjects, with/without elevated SF, to p.D519G frequency in public datasets. GNPAT p.D519G was more prevalent in our cohort of p.C282Y/p.H63D compound heterozygotes with elevated SF (37%) than European public datasets: 1000G 21%, gnomAD 20% and ESP 21%. We conclude that GNPAT p.D519G is associated with elevated SF in Australian HFE p.C282Y/p.H63D compound heterozygotes.

A Phase IIa Trial of Metformin for Colorectal Cancer Risk Reduction among Individuals with History of Colorectal Adenomas and Elevated Body Mass Index.

Obesity is associated with risk of colorectal adenoma (CRA) and colorectal cancer. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPK, decreased pmTOR/mTOR ratio, and decreased pS6Ser235/S6Ser235 ratio in polyps. We hypothesized that metformin would affect colorectal tissue S6Ser235 among obese patients with recent history of CRA. A phase IIa clinical biomarker trial was conducted via the U.S. National Cancer Institute-Chemoprevention Consortium. Nondiabetic, obese subjects (BMI ≥30) ages 35 to 80 with recent history of CRA were included. Subjects received 12 weeks of oral metformin 1,000 mg twice every day. Rectal mucosa biopsies were obtained at baseline and end-of-treatment (EOT) endoscopy. Tissue S6Ser235 and Ki-67 immunostaining were analyzed in a blinded fashion using Histo score (Hscore) analysis. Among 32 eligible subjects, the mean baseline BMI was 34.9. Comparing EOT to baseline tissue S6Ser235 by IHC, no significant differences were observed. Mean (SD) Hscore at baseline was 1.1 (0.57) and 1.1 (0.51) at EOT; median Hscore change was 0.034 (P = 0.77). Similarly, Ki-67 levels were unaffected by the intervention. The adverse events were consistent with metformin's known side-effect profile. Among obese patients with CRA, 12 weeks of oral metformin does not reduce rectal mucosa pS6 or Ki-67 levels. Further research is needed to determine what effects metformin has on the target tissue of origin as metformin continues to be pursued as a colorectal cancer chemopreventive agent.

Deficiency of nuclear receptor interaction protein leads to cardiomyopathy by disrupting sarcomere structure and mitochondrial respiration.

BACKGROUND: Cardiomyopathy is a common and lethal complication in patients with limb-girdle muscular dystrophy (LGMD), one of the most prevalent forms of muscular dystrophy. The pathogenesis underlying LGMD-related cardiomyopathy remains unclear. NRIP (gene name DCAF6), a Ca2+-dependent calmodulin binding protein, was reduced in dystrophic muscles from LGMD patients. Mice lacking NRIP exhibit a myopathic phenotype resembling that in LGMD patients, making NRIP deficiency a potential culprit leading to cardiomyopathy. This study aimed to determine if NRIP deficiency leads to cardiomyopathy and to explore the underlying molecular mechanisms. METHODS AND RESULTS: NRIP expression was reduced in both human and mouse failing hearts. Muscle-specific NRIP knockout (MCK-Cre::Dcaf6flox/flox) mouse heart and isolated cardiomyocytes exhibited markedly reduced contractility. Transmission electron microscopy revealed abnormal sarcomere structures and mitochondrial morphology in MCK-Cre::Dcaf6flox/flox hearts. Protein co-immunoprecipitation and confocal imaging revealed that NRIP interacts with α-actinin 2 (ACTN2) at the Z-disc. We found that NRIP facilitated ACTN2-mediated F-actin bundling, and that NRIP deficiency resulted in reduced binding between Z-disc proteins ACTN2 and Cap-Z. In addition, NRIP-deficiency led to increased mitochondrial ROS and impaired mitochondrial respiration/ATP production owing to elevated cellular NADH/NAD+ ratios. Treatment with mitochondria-directed antioxidant mitoTEMPO or NAD+ precursor nicotinic acid restored mitochondrial function and cardiac contractility in MCK-Cre::Dcaf6flox/flox mice. CONCLUSIONS: NRIP is essential to maintain sarcomere structure and mitochondrial/contractile function in cardiomyocytes. Our results revealed a novel role for NRIP deficiency in the pathogenesis of LGMD and heart failure. Targeting NRIP, therefore, could be a powerful new approach to treat myocardial dysfunction in LGMD and heart failure patients.

Diffuse optical spectroscopic imaging for the investigation of human lactation physiology: a case study on mammary involution.

Relatively few imaging and sensing technologies are employed to study human lactation physiology. In particular, human mammary development during pregnancy as well as mammary involution after lactation have been poorly described, despite their importance for breast cancer diagnosis and treatment during these phases. Our case study shows the potential of diffuse optical spectroscopic imaging (DOSI) to uniquely study the spatiotemporal changes in mammary tissue composition during the involution of the lactating breast toward its pre-pregnant state. At nine time intervals over a period of eight months after the cessation of breastfeeding, we reconstructed 2-D maps of mammary water content, lipid content, total hemoglobin (THb) concentration, oxygen saturation (StO2), and tissue optical scattering. Mammary lipid content in the nonareolar region showed a significant relative increase of 59%, whereas water content and THb concentration showed a significant relative decrease of 50% and 48%, respectively. Significant changes were also found in StO2 and tissue optical scattering. Our findings are consistent with the gradual replacement of fibroglandular tissue by adipose tissue and vascular regression during mammary involution. Moreover, our data provide unique insight into the dynamics of breast tissue composition and demonstrate the effectiveness of DOSI as a technique to study human lactation physiology.

Bivariate mixture models for the joint distribution of repeated serum ferritin and transferrin saturation measured 12 years apart in a cohort of healthy middle-aged Australians.

Homozygosity for the p.C282Y substitution in the HFE protein encoded by the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. McLaren et al. used bivariate mixture modeling to analyze the joint population distribution of transferrin saturation (TS) and serum ferritin concentration (SF) measured for participants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. They identified four components (C1, C2, C3, and C4) with successively increasing means for TS and SF. They demonstrated that bivariate mixture modeling in TS and SF reflect the genetic locus of HFE and may isolate p.C282Y homozygotes from the general population. In the current study we used data from the another large cohort, the Australian HealthIron study of genetic and environmental modifiers of hereditary hemochromatosis, to validate the component analysis approach, to examine stability of component proportions over time and to determine if TS and SF values from an individual move between components at baseline and follow-up. Because sampling fractions from each p.C282Y / p.H63D genotype stratum are not equal, we used frequency weights based on the inverse of the probability of selection for invitation to participate. In the weighted female analytic cohorts, C4 captured most of C282Y homozygotes, and C2 was the largest component. We identified four components from the weighted male analytic cohort and C4 captured most of p.C282Y homozygotes. The bivariate mixture modeling approach suggested that the model is transferable from one white population to another, although estimated means within components may differ.

Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes.

INTRODUCTION AND AIM: We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. MATERIAL AND METHODS: We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. RESULTS: Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metacarpophalangeal joints, mean serum ferritin, elevated alanine aminotransferase, elevated aspartate aminotransferase, and mean iron removed; and significantly fewer mean blood pints/units donated. GNPAT p.D519G positivity was detected in 82 of 188 participants (43.6%). In a multivariable model for cirrhosis, there were four significant positive associations: age (10-y intervals) (odds ratio 2.2 [95% confidence interval 1.5, 3.3]); diabetes (3.3; [1.1, 9.7]); alcohol intake (14 g alcohol drinks/d) (1.5 [1.2, 1.8]); and iron removed, g (1.3 [1.2, 1.4]). There was no statistical evidence of two-way interactions between these variables. CONCLUSION: In conclusion, cirrhosis in HFE p.C282Y homozygotes is significantly associated with age, diabetes, daily alcohol intake, and iron removed by phlebotomy, taking into account the effect of other variables.

External light activates hair follicle stem cells through eyes via an ipRGC-SCN-sympathetic neural pathway.

Changes in external light patterns can alter cell activities in peripheral tissues through slow entrainment of the central clock in suprachiasmatic nucleus (SCN). It remains unclear whether cells in otherwise photo-insensitive tissues can achieve rapid responses to changes in external light. Here we show that light stimulation of animals' eyes results in rapid activation of hair follicle stem cells with prominent hair regeneration. Mechanistically, light signals are interpreted by M1-type intrinsically photosensitive retinal ganglion cells (ipRGCs), which signal to the SCN via melanopsin. Subsequently, efferent sympathetic nerves are immediately activated. Increased norepinephrine release in skin promotes hedgehog signaling to activate hair follicle stem cells. Thus, external light can directly regulate tissue stem cells via an ipRGC-SCN autonomic nervous system circuit. Since activation of sympathetic nerves is not limited to skin, this circuit can also facilitate rapid adaptive responses to external light in other homeostatic tissues.

Non-invasive Dual-Channel Broadband Diffuse Optical Spectroscopy of Massive Hemorrhage and Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in Swine.

Objective: To quantitatively measure tissue composition and hemodynamics during resuscitative endovascular balloon occlusion of the aorta (REBOA) in two tissue compartments using non-invasive two-channel broadband diffuse optical spectroscopy (DOS). Methods: Tissue concentrations of oxy- and deoxyhemoglobin (HbO2 and HbR), water, and lipid were measured in a porcine model (n = 10) of massive hemorrhage (65% total blood volume over 1 h) and 30-min REBOA superior and inferior to the aortic balloon. Results: After hemorrhage, hemoglobin oxygen saturation (StO2 = HbO2/[HbO2 + HbR]) at both sites decreased significantly (-29.9% and -42.3%, respectively). The DOS measurements correlated with mean arterial pressure (MAP) (R2 = 0.79, R2 = 0.88), stroke volume (SV) (R2 = 0.68, R2 = 0.88), and heart rate (HR) (R2 = 0.72, R2 = 0.88). During REBOA, inferior StO2 continued to decline while superior StO2 peaked 12 min after REBOA before decreasing again. Inferior DOS parameters did not associate with MAP, SV, or HR during REBOA. Conclusions: Dual-channel regional tissue DOS measurements can be used to non-invasively track the formation of hemodynamically distinct tissue compartments during hemorrhage and REBOA. Conventional systemic measures MAP, HR, and SV are uncorrelated with tissue status in inferior (downstream) sites. Multi-compartment DOS may provide a more complete picture of the efficacy of REBOA and similar resuscitation procedures.