γ-6-Phosphogluconolactone, a Byproduct of the Oxidative Pentose Phosphate Pathway, Contributes to AMPK Activation through Inhibition of PP2A.

The oxidative pentose phosphate pathway (oxiPPP) contributes to cell metabolism through not only the production of metabolic intermediates and reductive NADPH but also inhibition of LKB1-AMPK signaling by ribulose-5-phosphate (Ru-5-P), the product of the third oxiPPP enzyme 6-phosphogluconate dehydrogenase (6PGD). However, we found that knockdown of glucose-6-phosphate dehydrogenase (G6PD), the first oxiPPP enzyme, did not affect AMPK activation despite decreased Ru-5-P and subsequent LKB1 activation, due to enhanced activity of PP2A, the upstream phosphatase of AMPK. In contrast, knockdown of 6PGD or 6-phosphogluconolactonase (PGLS), the second oxiPPP enzyme, reduced PP2A activity. Mechanistically, knockdown of G6PD or PGLS decreased or increased 6-phosphogluconolactone level, respectively, which enhanced the inhibitory phosphorylation of PP2A by Src. Furthermore, γ-6-phosphogluconolactone, an oxiPPP byproduct with unknown function generated through intramolecular rearrangement of δ-6-phosphogluconolactone, the only substrate of PGLS, bound to Src and enhanced PP2A recruitment. Together, oxiPPP regulates AMPK homeostasis by balancing the opposing LKB1 and PP2A.

Serine restriction alters sphingolipid diversity to constrain tumour growth.

Serine, glycine and other nonessential amino acids are critical for tumour progression, and strategies to limit their availability are emerging as potential therapies for cancer1-3. However, the molecular mechanisms driving this response remain unclear and the effects on lipid metabolism are relatively unexplored. Serine palmitoyltransferase (SPT) catalyses the de novo biosynthesis of sphingolipids but also produces noncanonical 1-deoxysphingolipids when using alanine as a substrate4,5. Deoxysphingolipids accumulate in the context of mutations in SPTLC1 or SPTLC26,7-or in conditions of low serine availability8,9-to drive neuropathy, and deoxysphinganine has previously been investigated as an anti-cancer agent10. Here we exploit amino acid metabolism and the promiscuity of SPT to modulate the endogenous synthesis of toxic deoxysphingolipids and slow tumour progression. Anchorage-independent growth reprogrammes a metabolic network involving serine, alanine and pyruvate that drives the endogenous synthesis and accumulation of deoxysphingolipids. Targeting the mitochondrial pyruvate carrier promotes alanine oxidation to mitigate deoxysphingolipid synthesis and improve spheroid growth, similar to phenotypes observed with the direct inhibition of SPT or ceramide synthesis. Restriction of dietary serine and glycine potently induces the accumulation of deoxysphingolipids while decreasing tumour growth in xenograft models in mice. Pharmacological inhibition of SPT rescues xenograft growth in mice fed diets restricted in serine and glycine, and the reduction of circulating serine by inhibition of phosphoglycerate dehydrogenase (PHGDH) leads to the accumulation of deoxysphingolipids and mitigates tumour growth. The promiscuity of SPT therefore links serine and mitochondrial alanine metabolism to membrane lipid diversity, which further sensitizes tumours to metabolic stress.

CalScope: methodology and lessons learned for conducting a remote statewide SARS-CoV-2 seroprevalence study in California using an at-home dried blood spot collection kit and online survey.

BACKGROUND: To describe the methodology for conducting the CalScope study, a remote, population-based survey launched by the California Department of Public Health (CDPH) to estimate SARS-CoV-2 seroprevalence and understand COVID-19 disease burden in California. METHODS: Between April 2021 and August 2022, 666,857 randomly selected households were invited by mail to complete an online survey and at-home test kit for up to one adult and one child. A gift card was given for each completed survey and test kit. Multiple customized REDCap databases were used to create a data system which provided task automation and scalable data management through API integrations. Support infrastructure was developed to manage follow-up for participant questions and a communications plan was used for outreach through local partners. RESULTS: Across 3 waves, 32,671 out of 666,857 (4.9%) households registered, 6.3% by phone using an interactive voice response (IVR) system and 95.7% in English. Overall, 25,488 (78.0%) households completed surveys, while 23,396 (71.6%) households returned blood samples for testing. Support requests (n = 5,807) received through the web-based form (36.3%), by email (34.1%), and voicemail (29.7%) were mostly concerned with the test kit (31.6%), test result (26.8%), and gift card (21.3%). CONCLUSIONS: Ensuring a well-integrated and scalable data system, responsive support infrastructure for participant follow-up, and appropriate academic and local health department partnerships for study management and communication allowed for successful rollout of a large population-based survey. Remote data collection utilizing online surveys and at-home test kits can complement routine surveillance data for a state health department.

Adopting, implementing and assimilating coproduced health and social care innovations involving structurally vulnerable populations: findings from a longitudinal, multiple case study design in Canada, Scotland and Sweden.

BACKGROUND: Innovations in coproduction are shaping public service reform in diverse contexts around the world. Although many innovations are local, others have expanded and evolved over time. We know very little, however, about the process of implementation and evolution of coproduction. The purpose of this study was to explore the adoption, implementation and assimilation of three approaches to the coproduction of public services with structurally vulnerable groups. METHODS: We conducted a 4 year longitudinal multiple case study (2019-2023) of three coproduced public service innovations involving vulnerable populations: ESTHER in Jönköping Region, Sweden involving people with multiple complex needs (Case 1); Making Recovery Real in Dundee, Scotland with people who have serious mental illness (Case 2); and Learning Centres in Manitoba, Canada (Case 3), also involving people with serious mental illness. Data sources included 14 interviews with strategic decision-makers and a document analysis to understand the history and contextual factors relating to each case. Three frameworks informed the case study protocol, semi-structured interview guides, data extraction, deductive coding and analysis: the Consolidated Framework for Implementation Research, the Diffusion of Innovation model and Lozeau's Compatibility Gaps to understand assimilation. RESULTS: The adoption of coproduction involving structurally vulnerable populations was a notable evolution of existing improvement efforts in Cases 1 and 3, while impetus by an external change agency, existing collaborative efforts among community organizations, and the opportunity to inform a new municipal mental health policy sparked adoption in Case 2. In all cases, coproduced innovation centred around a central philosophy that valued lived experience on an equal basis with professional knowledge in coproduction processes. This philosophical orientation offered flexibility and adaptability to local contexts, thereby facilitating implementation when compared with more defined programming. According to the informants, efforts to avoid co-optation risks were successful, resulting in the assimilation of new mindsets and coproduction processes, with examples of how this had led to transformative change. CONCLUSIONS: In exploring innovations in coproduction with structurally vulnerable groups, our findings suggest several additional considerations when applying existing theoretical frameworks. These include the philosophical nature of the innovation, the need to study the evolution of the innovation itself as it emerges over time, greater attention to partnered processes as disruptors to existing power structures and an emphasis on driving transformational change in organizational cultures.

Waning of 2-Dose BNT162b2 and mRNA-1273 Vaccine Effectiveness Against Symptomatic SARS-CoV-2 Infection Accounting for Depletion-of-Susceptibles Bias.

Concerns about the duration of protection conferred by coronavirus disease 2019 (COVID-19) vaccines have arisen in postlicensure evaluations. "Depletion of susceptibles," a bias driven by differential accrual of infection among vaccinated and unvaccinated individuals, may obscure vaccine effectiveness (VE) estimates, hindering interpretation. We enrolled California residents who received molecular SARS-CoV-2 tests in a matched, test-negative design, case-control study to estimate VE of mRNA-based COVID-19 vaccines between February 23 and December 5, 2021. We analyzed waning protection following 2 vaccine doses using conditional logistic regression models. Additionally, we used data from a population-based serological study to adjust for "depletion-of-susceptibles" bias and estimated VE for 3 doses, by time since second dose receipt. Pooled VE of BNT162b2 and mRNA-1273 against symptomatic SARS-CoV-2 infection was 91.3% (95% confidence interval (CI): 83.8, 95.4) at 14 days after second-dose receipt and declined to 50.8% (95% CI: 19.7, 69.8) at 7 months. Adjusting for depletion-of-susceptibles bias, we estimated VE of 53.2% (95% CI: 23.6, 71.2) at 7 months after primary mRNA vaccination series. A booster dose of BN162b2 or mRNA-1273 increased VE to 95.0% (95% CI: 82.8, 98.6). These findings confirm that observed waning of protection is not attributable to epidemiologic bias and support ongoing efforts to administer additional vaccine doses to mitigate burden of COVID-19.

Evaluating the association between in-person work and the risk of SARS-CoV-2 infection through June 2021.

OBJECTIVES: Recent studies have evaluated COVID-19 outbreaks and excess mortality by occupation sectors. Studies on SARS-CoV-2 infection across occupation and occupation-related factors remain lacking. In this study, we estimate the effect of in-person work on SARS-CoV-2 infection risk and describe SARS-CoV-2 seroprevalence among working adults. METHODS: We used Wave 1 data (May to June 2021) from CalScope, a population-based seroprevalence study in California. Occupation data were coded using the National Institute for Occupational Safety and Health Industry and Occupation Computerized Coding System. Dried blood spot specimens were tested for antibodies to establish evidence of prior infection. We estimated the causal effect of in-person work on SARS-CoV-2 infection risk using the g-formula and describe SARS-CoV-2 seroprevalence across occupation-related factors. RESULTS: Among 4335 working adults, 53% worked in person. In-person work was associated with increased risk of prior SARS-CoV-2 infection (risk difference: 0.03; [95% CI: 0.02-0.04]) compared with working remotely. Workers that reported job loss or who were without medical insurance had higher evidence of prior infection. Amongst in-person workers, evidence of prior infection was highest within farming, fishing, and forestry (55%; [95% CI: 26%-81%]); installation, maintenance, and repair (23%; [12%-39%]); building and grounds cleaning and maintenance (23%; [13%-36%]); food preparation and serving related (22% [13%-35%]); and healthcare support (22%; [13%-34%]) occupations. Workers who identified as Latino, reported a household income of <$25K, or who were without a bachelor's degree also had higher evidence of prior infection. CONCLUSIONS: SARS-CoV-2 infection risk varies by occupation. Future vaccination strategies may consider prioritizing in-person workers.

Serine biosynthesis as a novel therapeutic target for dilated cardiomyopathy.

AIMS: Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. Despite significant progress in understanding the genetic aetiologies of DCM, the molecular mechanisms underlying the pathogenesis of familial DCM remain unknown, translating to a lack of disease-specific therapies. The discovery of novel targets for the treatment of DCM was sought using phenotypic sceening assays in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) that recapitulate the disease phenotypes in vitro. METHODS AND RESULTS: Using patient-specific iPSCs carrying a pathogenic TNNT2 gene mutation (p.R183W) and CRISPR-based genome editing, a faithful DCM model in vitro was developed. An unbiased phenotypic screening in TNNT2 mutant iPSC-derived cardiomyocytes (iPSC-CMs) with small molecule kinase inhibitors (SMKIs) was performed to identify novel therapeutic targets. Two SMKIs, Gö 6976 and SB 203580, were discovered whose combinatorial treatment rescued contractile dysfunction in DCM iPSC-CMs carrying gene mutations of various ontologies (TNNT2, TTN, LMNA, PLN, TPM1, LAMA2). The combinatorial SMKI treatment upregulated the expression of genes that encode serine, glycine, and one-carbon metabolism enzymes and significantly increased the intracellular levels of glucose-derived serine and glycine in DCM iPSC-CMs. Furthermore, the treatment rescued the mitochondrial respiration defects and increased the levels of the tricarboxylic acid cycle metabolites and ATP in DCM iPSC-CMs. Finally, the rescue of the DCM phenotypes was mediated by the activating transcription factor 4 (ATF4) and its downstream effector genes, phosphoglycerate dehydrogenase (PHGDH), which encodes a critical enzyme of the serine biosynthesis pathway, and Tribbles 3 (TRIB3), a pseudokinase with pleiotropic cellular functions. CONCLUSIONS: A phenotypic screening platform using DCM iPSC-CMs was established for therapeutic target discovery. A combination of SMKIs ameliorated contractile and metabolic dysfunction in DCM iPSC-CMs mediated via the ATF4-dependent serine biosynthesis pathway. Together, these findings suggest that modulation of serine biosynthesis signalling may represent a novel genotype-agnostic therapeutic strategy for genetic DCM.

A Small Molecule Fluorogenic Probe for the Detection of Sphingosine in Living Cells.

The single-chained sphingolipid sphingosine is an essential structural lipid and signaling molecule. Abnormal sphingosine metabolism is observed in several diseases, including cancer, diabetes, and Alzheimer's. Despite its biological importance, there is a lack of tools for detecting sphingosine in living cells. This is likely due to the broader challenge of developing highly selective and live-cell compatible affinity probes for hydrophobic lipid species. In this work, we have developed a small molecule fluorescent turn-on probe for labeling sphingosine in living cells. We demonstrate that this probe exhibits a dose-dependent response to sphingosine and is able to detect endogenous pools of sphingosine. Using our probe, we successfully detected sphingosine accumulation in cells from patients with Niemann-Pick type C1 (NPC1), a lipid transport disorder in which increased sphingosine mediates disease progression. This work provides a simple and accessible method for the detection of sphingosine and should facilitate study of this critical signaling lipid in biology and disease.

Risk mitigation of shared electronic records system in campus institutions: medical social work practice in singapore.

In 2013, the Singapore General Hospital (SGH) Campus initiated a shared electronic system where patient records and documentations were standardized and shared across institutions within the Campus. The project was initiated to enhance quality of health care, improve accessibility, and ensure integrated (as opposed to fragmented) care for best outcomes in our patients. In mitigating the risks of ICT, it was found that familiarity with guiding ethical principles, and ensuring adherence to regulatory and technical competencies in medical social work were important. The need to negotiate and maneuver in a large environment within the Campus to ensure proactive integrative process helped.

Tracing the Diverse Paths of One-Carbon Metabolism in Cancer and Beyond.

One-carbon (1C) metabolism is a network of biochemical reactions distributed across organelles that delivers folate-activated 1C units to support macromolecule synthesis, methylation, and reductive homeostasis. Fluxes through these pathways are up-regulated in highly proliferative cancer cells, and anti-folates, which target enzymes within the 1C pathway, have long been used in the treatment of cancer. In this work, we review fundamental aspects of 1C metabolism and place it in context with other biosynthetic and redox pathways, such that 1C metabolism acts to bridge pathways across compartments. We further discuss the importance of stable-isotope-tracing techniques combined with mass spectrometry analysis to study 1C metabolism and conclude by highlighting therapeutic approaches that could exploit cancer cells' dependency on 1C metabolism.

A prospective case-control and molecular epidemiological study of human cases of Shiga toxin-producing Escherichia coli in New Zealand.

BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) O157:H7 and related non-O157 STEC strains are enteric pathogens of public health concern worldwide, causing life-threatening diseases. Cattle are considered the principal hosts and have been shown to be a source of infection for both foodborne and environmental outbreaks in humans. The aims of this study were to investigate risk factors associated with sporadic STEC infections in humans in New Zealand and to provide epidemiological information about the source and exposure pathways. METHODS: During a national prospective case-control study from July 2011 to July 2012, any confirmed case of STEC infection notified to regional public health units, together with a random selection of controls intended to be representative of the national demography, were interviewed for risk factor evaluation. Isolates from each case were genotyped using pulsed-field gel electrophoresis (PFGE) and Shiga toxin-encoding bacteriophage insertion (SBI) typing. RESULTS: Questionnaire data from 113 eligible cases and 506 controls were analysed using multivariate logistic regression. Statistically significant animal and environmental risk factors for human STEC infections were identified, notably 'Cattle livestock present in meshblock' (the smallest geographical unit) (odds ratio 1.89, 95% CI 1.04-3.42), 'Contact with animal manure' (OR 2.09, 95% CI 1.12-3.90), and 'Contact with recreational waters' (OR 2.95, 95% CI 1.30-6.70). No food-associated risk factors were identified as sources of STEC infection. E. coli O157:H7 caused 100/113 (88.5%) of clinical STEC infections in this study, and 97/100 isolates were available for molecular analysis. PFGE profiles of isolates revealed three distinctive clusters of genotypes, and these were strongly correlated with SBI type. The variable 'Island of residence' (North or South Island of New Zealand) was significantly associated with PFGE genotype (p = 0.012). CONCLUSIONS: Our findings implicate environmental and animal contact, but not food, as significant exposure pathways for sporadic STEC infections in humans in New Zealand. Risk factors associated with beef and dairy cattle suggest that ruminants are the most important sources of STEC infection. Notably, outbreaks of STEC infections are rare in New Zealand and this further suggests that food is not a significant exposure pathway.

An Evaluation of the Relationship between Training of Health Practitioners in a Person-Centred Care Model and their Person-Centred Attitudes.

Introduction: The Esther Network (EN) person-centred care (PCC) advocacy training aims to promote person-centred attitudes among health practitioners in Singapore. This study aimed to assess the relationship between the training and practitioners' PCC attributes over a 3-month period, and to explore power sharing by examining the PCC dimensions of "caring about the service user as a whole person" and the "sharing of power, control and information". Methods: A repeated-measure study design utilising the Patient-Practitioner Orientation Scale (PPOS), was administered to 437 training participants at three time points - before training (T1), immediately after (T2) and three months after training (T3). A five-statement questionnaire captured knowledge of person-centred care at T1 and T2. An Overall score, Caring and Sharing sub-scores were derived from the PPOS. Scores were ranked and divided into three groups (high, medium and low). Ordinal Generalised Estimating Equation (GEE) model analysed changes in PPOS scores over time. Results: A single, short-term training appeared to result in measurable improvements in person-centredness of health practitioners, with slight attenuation at T3. There was greater tendency to "care" than to "share power" with service users across all three time points, but the degree of improvement was larger for sharing after training. The change in overall person-centred scores varied by sex and profession (females score higher than males, allied health showed a smaller attenuation at T3). Conclusion: Training as a specific intervention, appeared to have potential to increase health practitioners' person-centredness but the aspect of equalising power was harder to achieve within a hierarchical structure and clinician-centric culture. An ongoing network to build relationships, and a supportive system to facilitate individual and organisational reflexivity can reinforce learning.

How the Esther Network model for coproduction of person-centred health and social care was adopted and adapted in Singapore: a realist evaluation.

OBJECTIVES: The Esther Network (EN) model, a person-centred care innovation in Sweden, was adopted in Singapore to promote person-centredness and improve integration between health and social care practitioners. This realist evaluation aimed to explain its adoption and adaptation in Singapore. DESIGN: An organisational case study using a realist evaluation approach drawing on Greenhalgh et al (2004)'s Diffusion of Innovations in Service Organisations to guide data collection and analysis. Data collection included interviews with seven individuals and three focus groups (including stakeholders from the macrosystem, mesosystem and microsystem levels) about their experiences of EN in Singapore, and field notes from participant observations of EN activities. SETTING: SingHealth, a healthcare cluster serving a population of 1.37 million residents in Eastern Singapore. PARTICIPANTS: Policy makers (n=4), EN programme implementers (n=3), practitioners (n=6) and service users (n=7) participated in individual interviews or focus group discussions. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcome data from healthcare institutions (n=13) and community agencies (n=59) were included in document analysis. RESULTS: Singapore's ageing population and need to transition from a hospital-based model to a more sustainable community-based model provided an opportunity for change. The personalised nature and logic of the EN model resonated with leaders and led to collective adoption. Embedded cultural influences such as the need for order and hierarchical structures were both barriers to, and facilitators of, change. Coproduction between service users and practitioners in making care improvements deepened the relationships and commitments that held the network together. CONCLUSIONS: The enabling role of leaders (macrosystem level), the bridging role of practitioners (mesosystem level) and the unifying role of service users (microsystem level) all contributed to EN's success in Singapore. Understanding these roles helps us understand how staff at various levels can contribute to the adoption and adaptation of EN and similar complex innovations systemwide.

CalScope: Monitoring Severe Acute Respiratory Syndrome Coronavirus 2 Seroprevalence From Vaccination and Prior Infection in Adults and Children in California May 2021-July 2021.

Background: Understanding the distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies from vaccination and/or prior infection is critical to the public health response to the pandemic. CalScope is a population-based serosurvey in 7 counties in California. Methods: We invited 200 000 randomly sampled households to enroll up to 1 adult and 1 child between April 20, 2021 and June 16, 2021. We tested all specimens for antibodies against SARS-CoV-2 nucleocapsid and spike proteins, and each participant completed an online survey. We classified participants into categories: seronegative, antibodies from infection only, antibodies from infection and vaccination, and antibodies from vaccination only. Results: A total of 11 161 households enrolled (5.6%), with 7483 adults and 1375 children completing antibody testing. As of June 2021, 33% (95% confidence interval [CI], 28%-37%) of adults and 57% (95% CI, 48%-66%) of children were seronegative; 18% (95% CI, 14%-22%) of adults and 26% (95% CI, 19%-32%) of children had antibodies from infection alone; 9% (95% CI, 6%-11%) of adults and 5% (95% CI, 1%-8%) of children had antibodies from infection and vaccination; and 41% (95% CI, 37%-45%) of adults and 13% (95% CI, 7%-18%) of children had antibodies from vaccination alone. Conclusions: As of June 2021, one third of adults and most children in California were seronegative. Serostatus varied regionally and by demographic group.

Concomitant Obstructive Sleep Apnoea in Patients with Meniere's Disease: A Case Report and Literature Review.

Meniere's disease (MD) is a condition characterised by fluctuating and progressive hearing loss, aural fullness, tinnitus, and intermittent attacks of vertigo. The disabling vertigo symptoms can be controlled in most patients by lifestyle changes and medications such as diuretics. Should standard medical therapy fail, the patient may require surgery in order to control the disease, but such surgical procedures can be functionally destructive. Obstructive sleep apnoea syndrome (OSAS) is common, especially in people who are grossly overweight. Up to 15% of patients with MD may have concomitant OSA. Unless the OSA is well controlled, such patients may continue to experience MD symptoms despite receiving adequate standard medical therapy for MD. Moreover, MD patients may experience insomnia as a result of vertigo and/or tinnitus where sedatives are indicated. The use of sedatives with muscle relaxant properties may inadvertently further aggravate OSA resulting in a vicious cycle of symptoms. Symptoms suggestive of concomitant OSA must be proactively sought as these patients do not necessarily exhibit the obvious phenotypic features of OSA. This is especially so in Asians where OSAS is commonly observed in people who are not overly obese. We report a case of a female patient who presented with recalcitrant MD disease and was later found to have concomitant OSA. The relevant literature will be reviewed, and learning points will be discussed from the perspective of the otologist/neurotologist. The clinician must always be mindful of the existence of concomitant "silent" OSAS as this impacts the management of patients with MD.

Synchronous caecal and sigmoid volvulus: a surprise twist.

Traditionally, caecal volvulus (CV) and sigmoid volvulus (SV) have been thought of as largely separate clinical entities with distinct clinical features, radiological findings and treatment strategies. We present a rare case of synchronous CV and SV. To our knowledge, this represents only the ninth such case in the literature. This posed a diagnostic challenge as the seemingly textbook features of SV, such as the classical 'coffee-bean' sign on plain abdominal X-ray, masked the simultaneous occurrence of CV which only became apparent after the patient continued to deteriorate despite the successful endoscopic decompression of the SV. The diagnosis of SV should be made cautiously, with a period of close clinical observation post-intervention and a low threshold for re-evaluation should symptoms persist or recur to ensure accurate diagnosis.

Progressive alterations in amino acid and lipid metabolism correlate with peripheral neuropathy in PolgD257A mice.

Mitochondria are central to metabolic homeostasis, and progressive mitochondrial defects have diverse metabolic consequences that could drive distinct pathophysiological states. Here, we comprehensively characterized metabolic alterations in PolgD257A mice. Plasma alanine increased markedly with time, with other organic acids accumulating to a lesser extent. These changes were reflective of increased Cori and Cahill cycling in PolgD257A mice and subsequent hypoglycemia, which did not occur during normal mouse aging. Tracing with [15N]ammonium further supported this shift in amino acid metabolism with mild impairment of the urea cycle. We also measured alterations in the lipidome, observing a reduction in canonical lipids and accumulation of 1-deoxysphingolipids, which are synthesized from alanine via promiscuous serine palmitoyltransferase activity and correlate with peripheral neuropathy. Consistent with this metabolic link, PolgD257A mice exhibited thermal hypoalgesia. These results highlight the longitudinal changes that occur in intermediary metabolism upon mitochondrial impairment and identify a contributing mechanism to mitochondria-associated neuropathy.

A Multifunctional, Low-Volume Resuscitation Cocktail Improves Vital Organ Blood Flow and Hemostasis in a Pig Model of Polytrauma with Traumatic Brain Injury.

The resuscitation of polytrauma with hemorrhagic shock and traumatic brain injury (TBI) is a balance between permissive hypotension and maintaining vital organ perfusion. There is no current optimal solution. This study tested whether a multifunctional resuscitation cocktail supporting hemostasis and perfusion could mitigate blood loss while improving vital organ blood flow during prolonged limited resuscitation. Anesthetized Yorkshire swine were subjected to fluid percussion TBI, femur fracture, catheter hemorrhage, and aortic tear. Fluid resuscitation was started when lactate concentration reached 3-4 mmol/L. Animals were randomized to one of five groups. All groups received hydroxyethyl starch solution and vasopressin. Low- and high-dose fibrinogen (FBG) groups additionally received 100 and 200 mg/kg FBG, respectively. A third group received TXA and low-dose FBG. Two control groups received albumin, with one also including TXA. Animals were monitored for up to 6 h. Blood loss was decreased and vital organ blood flow was improved with low- and high-dose fibrinogen compared to albumin controls, but survival was not improved. There was no additional benefit of high- vs. low-dose FBG on blood loss or survival. TXA alone decreased blood loss but had no effect on survival, and combining TXA with FBG provided no additional benefit. Pooled analysis of all groups containing fibrinogen vs. albumin controls found improved survival, decreased blood loss, and improved vital organ blood flow with fibrinogen delivery. In conclusion, a low-volume resuscitation cocktail consisting of hydroxyethyl starch, vasopressin, and fibrinogen concentrate improved outcomes compare to controls during limited resuscitation of polytrauma.

Qualitative and quantitative analysis of Arnebiae Radix and Dictamni Cortex and efficacy study of herbal extracts on allergic contact dermatitis using 3D human reconstructed epidermis.

Objective: To evaluate the quality of Arnebiae Radix (AR) and Dictamni Cortex (DC) and study the efficacy of herbal extracts of these two herbs on the treatment of allergic contact dermatitis (ACD). Methods: Qualitative and quantitative analysis of effective components was performed using High Performance Thin Layer Chromatography (HPTLC), High Performance Liquid Chromatography (HPLC), and HPLC-Quadrupole Time of Flight-Mass Spectrometry (HPLC-QTOF-MS). In vitro allergic ACD 3D model was established by incubating 3D reconstructed human epidermis (RHE) with skin sensitizer, potassium dichromate. A total of 65 gene expression that were associated with ACD, which included 24 antioxidant responsive element (ARE) and 41 SENS-IS genes were quantified by qRT-PCR. More than or equal to 10 ARE genes and 18 SENN-IS genes were induced by 1.3-fold, demonstrating the successful establishment of in vitro ACD model. Oil extracts of AR and DC were applied on the in vitro ACD model to study the efficacy. Results: Batch 3 of AR and batch 2 of DC showed presence of all active ingredients with the highest concentrations. Active ingredients of the herbs were extracted using a special oil and formulated into herbal oil extracts. The herbal oil extracts were able to down regulate the induced genes in the in-vitro ACD skin model, bringing the tissue back to homeostatic status. Conclusion: The oil extracts showed the potent efficacy of using AR and DC in ACD treatment. The combination study will be done to optimize the formulation ratio which will be developed into a topical cream.

SARS-CoV-2 Cumulative Incidence and Period Seroprevalence: Results From a Statewide Population-Based Serosurvey in California.

BACKGROUND: California has reported the largest number of coronavirus disease 2019 (COVID-19) cases of any US state, with more than 3.5 million confirmed as of March 2021. However, the full breadth of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in California is unknown as reported cases only represent a fraction of all infections. METHODS: We conducted a population-based serosurvey, utilizing mailed, home-based SARS-CoV-2 antibody testing along with a demographic and behavioral survey. We weighted data from a random sample to represent the adult California population and estimated period seroprevalence overall and by participant characteristics. Seroprevalence estimates were adjusted for waning antibodies to produce statewide estimates of cumulative incidence, the infection fatality ratio (IFR), and the reported fraction. RESULTS: California's SARS-CoV-2 weighted seroprevalence during August-December 2020 was 4.6% (95% CI, 2.8%-7.4%). Estimated cumulative incidence as of November 2, 2020, was 8.7% (95% CrI, 6.4%-11.5%), indicating that 2 660 441 adults (95% CrI, 1 959 218-3 532 380) had been infected. The estimated IFR was 0.8% (95% CrI, 0.6%-1.0%), and the estimated percentage of infections reported to the California Department of Public Health was 31%. Disparately high risk for infection was observed among persons of Hispanic/Latinx ethnicity and people with no health insurance and who reported working outside the home. CONCLUSIONS: We present the first statewide SARS-CoV-2 cumulative incidence estimate among adults in California. As of November 2020, ~1 in 3 SARS-CoV-2 infections in California adults had been identified by public health surveillance. When accounting for unreported SARS-CoV-2 infections, disparities by race/ethnicity seen in case-based surveillance persist.