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The phenolic natural product magnolol exhibits neuroprotective properties through β-amyloid toxicity in PC-12 cells and ameliorative effects against cognitive deficits in a TgCRND8 transgenic mice model. Its bioavailability and blood–brain barrier crossing ability have been significantly improved using the metal–organic framework (MOF) UiO-66(Zr) as a drug delivery system (DDS). To investigate the neuroprotective effects of the Zr-based DDS, magnolol and magnolol-loaded-UiO-66(Zr) (Mag@UiO-66(Zr)) were evaluated for inhibitory activity against β-secretase and AlCl3-induced neurotoxicity. Due to the moderate inhibition observed for magnolol in vitro, in silico binding studies were explored against β-secretase along with 11 enzymes known to affect Alzheimer’s disease (AD). Favorable binding energies against CDK2, CKD5, MARK, and phosphodiesterase 3B (PDE3B) and dynamically stable complexes were noted through molecular docking and molecular dynamic simulation experiments, respectively. The magnolol-loaded DDS UiO-66(Zr) also showed enhanced neuroprotective activity against two pathological indices, namely, neutrophil infiltration and apoptotic neurons, in addition to damage reversal compared to magnolol. Thus, MOFs are promising drug delivery platforms for poorly bioavailable drugs.

Background: Sargassum polycystum C. Agardh has potent antioxidant and antiinflammatory properties. However, its anti-allergic effect has not yet been reported. In this study, we investigated the anti-allergic effects of sulfated polysaccharide of S. polycystum (SPSP) in Dinitrofluorobenzene (DNFB)- induced allergic contact dermatitis animal model. Methods: SPSP was extracted through the hot water extraction method and was subjected to compositional analyses. For the Allergic Contact Dermatitis (ACD) model, symptoms were induced by the topical application of 0.5% DNFB on the shaved ventral skin of mice. SPSP (500, 1000, and 2000 mg/kg) and Prednisolone were orally administered for seven days after sensitization. Elicitation was performed seven days later with 0.2% DNFB. After this, ear thickness was measured at baseline and 24 hours post elicitation using a dial thickness gauge. Serum of mice was obtained 24 hours post elicitation, and the level of IFNγ and TNFα was quantified by enzyme-linked immunosorbent assays (ELISA). Results: SPSP afforded 33.6% carbohydrates, 23.7% sulfate, 7.5% protein, and 1.5% uronic acid contents. SPSP inhibited the ear swelling and cytokines (IFNγ and TNFα) production in DNFBinduced mice in a dose-dependent manner. In comparison with Prednisolone (p>0.05), the highest concentration (2000 mg/kg) of SPSP showed a comparable anti-allergic effect. Conclusion: These findings showed that the sulfated polysaccharide from S. polycystum is a potential natural source to treat allergic contact dermatitis. The effect is attributed to the polysaccharideprotein complex present in the extract, but further studies are needed to establish the exact mechanism of action of SPSP in the treatment of the disease.

We observed bacterial or fungal coinfections in COVID-19 patients admitted between March 1 and April 18, 2020 (152 of 4,267, 3.6%). Among these patients, mortality was 57%; 74% were intubated; 51% with bacteremia had central venous catheters. Time to culture positivity was 6–7 days, and 79% had received prior antibiotics. Metallo-β-lactamase–producing E. cloacae coinfections occurred in 5 patients.

Introduction: With better medical care, patients with Duchenne muscular dystrophy (DMD) now live longer but face more complex medical and social needs. This study described the perceptions of DMD patients and their families of disease-specific palliative care services in Singapore. Materials and Methods: A multicentre, crosssectional study involving DMD patients and their families was carried out. Structured questionnaires were administered to them to collect data on their understanding of palliative care, health services accessed and desired by them and quality of life. Results: A total of 30 pairs of DMD patients and their caregivers responded. Mostpatients were >13 years old (70%) and non-ambulant (86%). Most of them and their families (70%) were also not aware of palliative care and support services that were available to them in Singapore. Additionally, they perceived greater financial assistance and better transport services as resources that could better meet their care needs. The presence of scoliosis and need for ventilatory support were associated with lower quality of life in patients. Conclusion: There is a need to improve awareness and provision of palliative care services for DMD patients in Singapore where discussion of end-of-life care is often considered taboo. Prevention and correction of scoliosis and provision of appropriate ventilatory support may improve quality of life in DMD patients. Key words: Advance care planning, Palliative support services, Quality of life.

Two of the main pathologies characterizing dysferlinopathies are disrupted muscle membrane repair and chronic inflammation, which lead to symptoms of muscle weakness and wasting. Here, we used recombinant human Galectin-1 (rHsGal-1) as a therapeutic for LGMD2B mouse and human models. Various redox and multimerization states of Gal-1 show that rHsGal-1 is the most effective form in both increasing muscle repair and decreasing inflammation, due to its monomer-dimer equilibrium. Dose-response testing shows an effective 25-fold safety profile between 0.54 and 13.5 mg/kg rHsGal-1 in Bla/J mice. Mice treated weekly with rHsGal-1 showed downregulation of canonical NF-κB inflammation markers, decreased muscle fat deposition, upregulated anti-inflammatory cytokines, increased membrane repair, and increased functional movement compared to non-treated mice. Gal-1 treatment also resulted in a positive self-upregulation loop of increased endogenous Gal-1 expression independent of NF-κB activation. A similar reduction in disease pathologies in patient-derived human cells demonstrates the therapeutic potential of Gal-1 in LGMD2B patients.

Mood disorders and anxiety significantly impact the prognosis and disease course of Parkinson’s disease. Non-motor symptoms of Parkinson’s disease such as apathy, anhedonia, and fatigue overlap with diagnostic criteria for anxiety and depression, thus making accurate diagnosis of mood disorders in Parkinson’s disease patients difficult. Furthermore, treatment options for mood disorders can produce motor complications leading to poor adherence and impaired quality of life in Parkinson’s disease patients. This review aims to clarify the current state of diagnostic and treatment options pertaining to anxiety and mood disorders in Parkinson’s disease. It explores both the pharmacologic and non-pharmacologic treatment modalities for various mood disorders in comorbid Parkinson’s disease with a brief discussion of the future outlook of the field given the current state of the literature.

The global prevalence of myopia has brought to the attention of the different eye and vision specialists, who make way to control its progression. Evidence have shown that a proactive reshaping of the eyeball is the core point of myopia developing process, which particularly includes the weakening, thinning, and expanding of the sclera. Thus, the sclera is considered to be a prime target for therapeutic manipulation in halting progressive myopia. In the past decades, corneal collagen cross-linking has been applied in clinical practice for treating aberrant corneal remodeling diseases. In this article, we hypothesize that scleral collagen cross-linking (SXL) has a huge potential in stabilizing myopic process by shaping the eyeball and preventing the aberrant scleral remodeling. In contrast with the current methods of optometry correction, such as physiotherapy, pharmacotherapy, spectacles, contact lenses, refractive surgeries, etc., eyeball-shaping method using SXL is a fundamental intervention which aims at the pathogenesis of progressive visual loss of myopia. Compared with the current posterior scleral reinforcement, the most advantage of SXL is that there is no allotransplant into the myopic eye, which means less expenditure, lower risk, and easier to handle in operating.

Introduction: With the increasing prevalence of diabetes mellitus (DM), there is an increasing burden of DM among pregnant women. Gestational DM (GDM), is a known complication of pregnancy which could affect the outcome for mother and child. This study looked into the burden of DM related gestations and readmissions. Methods: Data was obtained from the US National Readmissions Database for 2018, the largest database for readmissions in the US, which approximates yearly estimates. Index hospitalizations for DM complicating pregnancy and the postpartum period were obtained using ICD-10 codes. Hospitalizations less than 18 years of age and elective admissions were excluded. Outcomes included the rate of 30-day readmission (30DR) as well as identifying the commonest reasons for readmission among the studied cohort. Results: A total of 61,675 hospitalizations were included in the study as index admissions. Of these hospitalizations, 2,768 (4.50%) were readmitted within 30 days of discharge. The top reasons for readmission included severe pre-eclampsia, gestational DM, pre-existing DM type 1 in pregnancy, maternal care for scar from previous cesarean delivery, pre-existing DM type 2 in pregnancy and endometritis following delivery. Readmission was associated with increased healthcare utilization. Conclusion: Among pregnancies complicated by DM that led to hospitalization, a small proportion of patients get readmitted within 30 days for known complications of pregnancy. These could be associated with mortality, hence, research into factors and predictors of readmission in this population should be encouraged. Disclosure M. C. Aguilera: None. H. Shaka: None. C. D. Corpuz: None. M. Ramirez: None. S. T. Yap: None. P. O. Eseaton: None. M. Murthi: None.

Background: Diabetes mellitus (DM) is a multisystem metabolic disorder shown to have adverse effects on lung physiology, immune responses, and antimicrobial defenses. However, the impact of DM on the development of poor in-hospital outcomes in patients with Acute COPD exacerbation (AECOPD) is unclear. We aimed to assess this very impact in our study. Methods: A retrospective cohort study was conducted using the Nationwide Inpatient Sample from 2018. About 394,929 hospitalizations had AECOPD as a primary diagnosis and were stratified based on the presence of DM using ICD-10 codes. Multivariate regression analysis was used to adjust for confounders and analyze variables. The selection of covariates was done with a univariate screen and literature review. Results: Out of the 394,929 hospitalized patients with AECOPD, 123,425 patients had DM. In-hospital mortality in AECOPD patients with DM was lower than those without (0.78% vs. 1.17%, p Conclusion: DM in AECOPD did not have worse outcomes in terms of in-hospital mortality, LOS, and PC. DM patients had lower risk of MI, PE, and stroke, however, had higher risk of AKI. Further investigation is needed to understand the exact correlation between the paradoxical nature of outcomes in AECOPD in those with DM. Disclosure R. Atluri: None. M. Ramirez: None. H. Shaka: None. M. Murthi: None. C. D. Corpuz: None. S. Velagapudi: None. G. Velazquez: None.

Introduction: Hyperglycemic hyperosmolar state is an endocrinological emergency associated with type 2 diabetes (T2DM) patients. HHS is associated with significant morbidity and mortality. The burden of HHS, however, does not end with the index admission. This study sought to determine the rate, reasons and predictors of 30-day readmissions (30DR) in T2DM patients with index admission for HHS with the goal of identifying potentially modifiable factors to decrease the burden of readmissions. Methods: The US Readmission database for 2018 was searched for index hospitalizations involving adult patients with T2DM who had HHS in 2018. Outcomes assessed included 30DR rates, top principal diagnosis for readmitted patients, comparison of mortality, length of stay (LOS), and hospitalization costs (THC), and predictors of 30DR. Results: A total of 21,721 hospitalizations involved adults with T2DM with HHS during the index admissions. The 30DR rate was 13.77%. The most common reasons for readmission was DM type 2 with hyperglycemia (8.6%), DKA (8.1%), HHS (8.0%), sepsis unspecified (7.9%), and acute renal failure (4.2%). Readmission was associated with higher odds of mortality (2.55% vs. 0.65%, OR: 4.00, 95% CI: 2.63 - 6.07), longer LOS (5.8 vs. 3.9 days, p Conclusion: HHS is associated with significant complications following the index admission. 30DR is associated with increased mortality and healthcare utilization in this population. Proper discharge planning and addressing factors associated with readmissions would likely improve outcome in this population. Disclosure H. Shaka: None. M. C. Aguilera: None. S. T. Yap: None. M. Ramirez: None. C. D. Corpuz: None. E. Edigin: None. P. E. Ojemolon: None. I. R. Asemota: None. E. Akuna: None.

Introduction: Diabetes mellitus (DM) is the commonest cause of nontraumatic amputation worldwide. With increasing prevalence of DM, there has been an increase in the rate of below the knee amputations (BKA), usually in the setting of severe soft tissue infections and osteomyelitis. Readmissions are often related to prior admissions and account for significant and usually preventable healthcare cost burden. This study assessed the rate and reasons for 30-day readmissions (30DR) in DM patients with BKA with the aim of identifying preventable factors for readmissions. Methods: The National Readmission Database for 2018 was queried for hospitalizations involving adult patients with DM who had BKA from January 1 to November 30, 2018. Elective and traumatic admissions were excluded. Outcomes assessed were 30DR rates, mortality, length of stay (LOS), hospitalization costs (THC) and top principal diagnosis for readmitted patients following BKA. Results: A total of 15,090 hospitalizations involved adults with DM who had DKA as index admissions. The 30DR rate was 13.79%. The most common reasons for readmission were sepsis unspecified (18.4%), hypertension with CKD and heart failure (7.0%), DM angiopathy with gangrene (4.2%), acute renal failure (3.0%), and hypertension with heart failure (2.1%). Readmission was associated with higher odds of mortality (6.1% vs. 4.3%, OR: 1.45, 95% CI: 1.11 - 1.89, p=0.007) compared to the index admission. In patients with DM with BKA, readmissions accounted for a cumulative 18,078 days of hospitalization, which cost patients over $40 million within the period. Conclusion: A significant proportion of patients with DM with BKA are readmitted for various complications. 30DR is associated with higher mortality and result in a significant cost burden to the patient and healthcare system. Mitigating the rate or readmissions would significantly improve patient outcomes. Disclosure C. D. Corpuz: None. H. Shaka: None. M. Ramirez: None. M. C. Aguilera: None. S. T. Yap: None. A. Kichloo: None. M. Murthi: None. R. Atluri: None. S. Gonakoti: None.

Corynebacterium kroppenstedtii is a difficult pathogen associated with granulomatous mastitis and recurrent breast abscesses. Despite over a dozen studies, there is no guidance on surgical interventions, steroid use, or dosing or duration of antibiotic treatment.Initially seen in predominantly Maori and Pacific Islander multiparous, postlactating women, C. kroppenstedtii breast infection has since been reported throughout the world, including in nulliparous women. Additionally, emerging data suggest that hyperprolactinemia is a modifiable risk factor for these infections. This article reviews a patient case and data from 87 other cases to compile current best practices for diagnosis, treatment, and monitoring, and provides areas for future study.In cases of granulomatous mastitis and breast abscess, especially if recurrent, infection with C. kroppenstedtii should be considered. Microbiologists should be alerted to the specialized growth conditions and tools needed for appropriate culturing, identification, and antibiotic susceptibility testing. Clinicians should utilize a multimodal approach with surgical and antibiotic treatment to maximize clinical cure and reduce recurrence.

Objective: The primary purpose of this study is to characterize Codium edule crude sulfated polysaccharide (CSP) and its fractions and to determineits potential antiproliferative and apoptotic properties.Methods: The CSP was obtained through hot water extraction followed by precipitation with absolute ethanol. CSP was further purified using ionexchangechromatography, Sepharose DEAE Fast Flow column and yielded three fractions (F1, F2, and F3). The CSP and fractions were characterizedfor their sulfate, protein, carbohydrate, and uronic acid content. Fourier-transformed infrared spectroscopy (FT-IR) was used to determine thefunctional groups present in CSP and SP fractions. Antiproliferative activity against human breast adenocarcinoma (MCF-7) was analyzed using MTTassay with doxorubicin as positive control. Apoptotic activity of C. edule was analyzed using caspase 3/7 and annexin V-FITC assay.Results: CSP afforded 6.3% sulfate, 4.1% protein, and 68.7% carbohydrate. F1 has the highest content of sulfate, protein, carbohydrate, and uronicacid among the fractions. FT-IR shows a broadband around 3400 cm−1 indicates the presence of hydroxyl stretching vibration of polysaccharide (-OH)and a band at 2922 cm−1 suggests a C-H stretch (alkane). 1658 cm−1 may be attributed to the C=O stretches of amide C=N group. Peak around 1259 cm−1is a characteristic band for S=O sulfate ester. The antiproliferative activity of C. edule against MCF-7 showed significant difference in the mean percentinhibition between CSP and F3 (p=0.001), F1 and F3 (p≤0.001), F2 and doxorubicin (p=0.025), and F3 and doxorubicin (p≤0.000). F1 of C. edule hasthe lowest IC50 of 5.54 μg/ml and displayed apoptotic phase and caspase 3/7 activity.Conclusion: The investigation revealed that SP from green seaweed, C. edule, could be used as potential anticancer treatment against breast canceradenocarcinoma.

Emergency response personnel (ERP) hold a vital role in disaster management. They respond to victims in stressful situations yet there is limited information about their psychological well-being. T...

The emergence of coronavirus disease-2019 (COVID-19) pandemic has stimulated governments to an extensive discussion on the necessity of COVID-19 vaccination certificate (CVC) to help monitor and manage the rollout of vaccinations and revive the economy. A recent correspondence highlighted the ethical issues concerning COVID-19 diagnostic test results and vaccination certificates. This paper highlights the potential benefits and harms of implementing CVC in the ASEAN region.

A recent correspondence published in this journal rightly argues the meaning of creative ritual practices during the coronavirus disease 2019 (COVID-19) pandemic. Recent researches revealed the ‘creative ways’ to augment the need for spiritual and religious longing, complicated grief and different ways of coping with loss and coping mental health issues during the COVID-19 pandemic. This paper further adds the ways on how to mitigate the reality of dying alone during COVID-19 pandemic.

Myeloid neoplasms, including acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), and myelodysplastic syndromes (MDS), feature clonal dominance and remodeling of the bone marrow niche in a manner that promotes malignant over non-malignant hematopoiesis. This take-over of hematopoiesis by the malignant clone is hypothesized to include hyperactivation of inflammatory signaling and overproduction of inflammatory cytokines. In the Ph-negative MPNs, inflammatory cytokines are considered to be responsible for a highly deleterious pathophysiologic process: the phenotypic transformation of polycythemia vera (PV) or essential thrombocythemia (ET) to secondary myelofibrosis (MF), and the equivalent emergence of primary myelofibrosis (PMF). Bone marrow fibrosis itself is thought to be mediated heavily by the cytokine TGF-β, and possibly other cytokines produced as a result of hyperactivated JAK2 kinase in the malignant clone. MF also features extramedullary hematopoiesis and progression to bone marrow failure, both of which may be mediated in part by responses to cytokines. In MF, elevated levels of individual cytokines in plasma are adverse prognostic indicators: elevated IL-8/CXCL8, in particular, predicts risk of transformation of MF to secondary AML (sAML). Tumor necrosis factor (TNF, also known as TNFα), may underlie malignant clonal dominance, based on results from mouse models. Human PV and ET, as well as MF, harbor overproduction of multiple cytokines, above what is observed in normal aging, which can lead to cellular signaling abnormalities separate from those directly mediated by hyperactivated JAK2 or MPL kinases. Evidence that NFκB pathway signaling is frequently hyperactivated in a pan-hematopoietic pattern in MPNs, including in cells outside the malignant clone, emphasizes that MPNs are pan-hematopoietic diseases, which remodel the bone marrow milieu to favor persistence of the malignancy. Clinical evidence that JAK2 inhibition by ruxolitinib in MF neither reliably reduces malignant clonal burden nor eliminates cytokine elevations, suggests targeting cytokine mediated signaling as a therapeutic strategy, which is being pursued in new clinical trials. Greater knowledge of inflammatory pathophysiology in MPNs can therefore contribute to the development of more effective therapy.

Recently, there has been an increased demand for functional foods, to reduce the risk of age-related cognitive impairment, dementia, and Alzheimer's disease. Among them, plant-derived bioactive compounds, such as phytochemicals and peptides, have notable potential in improving memory and cognitive functions. Many studies have provided potential data concerning the characteristics and structure-activity relationships of memory-enhancing peptides. When considering the proof of efficacy of these plant-based peptides in humans as neurological treatment options, it is necessary to accumulate evidence concerning their bioavailability and permeability through blood-brain barrier (BBB). This review focuses on the memory-enhancing effects of peptides derived from plant proteins and presents a current perspective on their structure-activity relationships and BBB permeability.

Purpose: Sulfated polysaccharide (SP) from Codium species has been reported for its anti-inflammatory activities. However, the effect of SP from C. edule on allergic responses has not been studied. The study was conducted to determine the effect of SP (F1) from C. edule on allergic contact dermatitis (ACD) induced by 2,4-dinitrofluorobenzene (DNFB) in female BALB/c mice. Methods: F1 was isolated using DEAE Sepharose Gel Chromatography and chemically identified by LC-MS analyses. The effects of F1 on changes in ear thickness, allergic responses, and histology were evaluated. The effects of F1 on the production of inflammatory cytokines IFN- γ and TNF-α in serum were also quantified and compared with standard prednisolone therapy. Results: F1 was identified as a heteropolysaccharide with β-D-galactans and β-L-arabinans units. F1 was non-toxic at 2000 mg/kg. Administration of F1 in DNFB-challenged mice significantly suppressed the increase in ear thickness, erythema, desquamation, and proliferation of inflammatory cells. F1 significantly decreased the production of inflammatory markers, IFN- γ and TNF-α in a dose-dependent manner when compared to the untreated group (p

This paper is a response to the recent correspondence published in this journal where the author rightly stated that need to redirect one’s perception on the different realities of life such as death. This paper discusses the difficulties associated with loss, grief and healing in the time of COVID-19 pandemic. This paper further adds the importance of accompaniment to people experiencing the complicated grief process. The COVID-19 pandemic is affecting the way one overcome grief where the bereaved are required to grieve without the support of usual social, cultural and religious rituals.

Background Central line-associated bloodstream infections (CLABSI) carry serious risks for patients and financial consequences for hospitals. Avoiding unnecessary temporary central venous catheters (CVC) can reduce CLABSI. Critical Care Medicine (CCM) is often consulted to insert CVC when alternatives are unavailable. We aim to describe clinical and financial implications of a CCM-driven vascular access model. Methods In this retrospective, observational cohort study, all CLABSI and a sample of CCM consults for CVC insertion on adult medical-surgical inpatient units were reviewed in 2019. Assessment of CVC appropriateness and financial analysis of labor, reimbursement, and attributable CLABSI cost was conducted. Results Of 554 CCM consult requests, 75 (13.5%) were for CVC and 36 (48.0%) resulted in CVC insertion; 6 (16.7%) CVC were avoidable. Three CLABSI occurred in avoidable CVC with estimated annual attributable cost of $165,099. Estimated annual CCM consultant cost for CVC was $78,094 generating $110,733 in reimbursement. Overall estimated annual loss was $132,460. Discussion Reliance on CCM for intravenous access resulted in avoidable CVC, CLABSI, inefficient physician effort, and financial losses; nurse-driven vascular access models offer potential cost savings and risk reduction. Conclusions CCM-driven vascular access models may not be cost-effective; alternatives should be considered for utilization reduction, CLABSI prevention, and financial viability.

Azotemia is a disease that is easy to be treated, but when left undiagnosed and untreated could lead to more fatal diseases like those of Kidney failure or Renal Diseases. Azotemia is a common disease; however, the lack of information from urinalysis showed to be one of the problems, detecting Azotemia thru urinalysis could prevent more hazardous diseases to develop. This study aims to gather more information about Azotemia through urinalysis using Electronic Nose and help diagnose Azotemia faster using urinalysis. Based from the result, The Electronic Nose system proved that there is a difference on the odor of a Healthy Urine sample and an Azotemic Urine sample. The Electronic Nose is made of common MQ Gas sensors and Raspberry Pi for its hardware, while for its software the system used Principal Component Analysis. Using the E-Nose chamber the system gathers data from the pre-classified urine sample provided by the hospital to test and differentiate the Azotemic urine and Healthy urine. The result shows that there are four sensors that are very responsive to the system namely: Combustible Gas, Carbon Monoxide, Hydrogen Gas and Air Quality. Based from the result the system has an accuracy of 90% and an error rate of 10%. In conclusion, the researches successfully developed a system that can differentiate Healthy Urine to an Azotemic Urine sample using Electronic Nose System with Principal Component Analysis.

Transforming growth factor-β (TGFβ) is a key driver of fibrogenesis. Three TGFβ isoforms (TGFβ1, TGFβ2, and TGFβ3) in mammals have distinct functions in embryonic development; however, the postnatal pathological roles and activation mechanisms of TGFβ2 and TGFβ3 have not been well characterized. Here, we show that the latent forms of TGFβ2 and TGFβ3 can be activated by integrin-independent mechanisms and have lower activation thresholds compared to TGFβ1. Unlike TGFB1, TGFB2 and TGFB3 expression is increased in human lung and liver fibrotic tissues compared to healthy control tissues. Thus, TGFβ2 and TGFβ3 may play a pathological role in fibrosis. Inducible conditional knockout mice and anti-TGFβ isoform-selective antibodies demonstrated that TGFβ2 and TGFβ3 are independently involved in mouse fibrosis models in vivo, and selective TGFβ2 and TGFβ3 inhibition does not lead to the increased inflammation observed with pan-TGFβ isoform inhibition. A cocrystal structure of a TGFβ2-anti-TGFβ2/3 antibody complex reveals an allosteric isoform-selective inhibitory mechanism. Therefore, inhibiting TGFβ2 and/or TGFβ3 while sparing TGFβ1 may alleviate fibrosis without toxicity concerns associated with pan-TGFβ blockade.

Non-alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is associated with metabolic dysregulation. Although G protein-coupled receptor 84 (GPR84) has been associated with inflammation, its role in metabolic regulation remains elusive. The aim of our study was to evaluate the potential of PBI-4547 for the treatment of NAFLD and to validate the role of its main target receptor, GPR84. We report that PBI-4547 is a fatty acid mimetic, acting concomitantly as a GPR84 antagonist and GPR40/GPR120 agonist. In a mouse model of diet-induced obesity, PBI-4547 treatment improved metabolic dysregulation, reduced hepatic steatosis, ballooning and NAFLD score. PBI-4547 stimulated fatty acid oxidation and induced gene expression of mitochondrial uncoupling proteins in the liver. Liver metabolomics revealed that PBI-4547 improved metabolic dysregulation induced by a high-fat diet regimen. In Gpr84−/− mice, PBI-4547 treatment failed to improve various key NAFLD-associated parameters, as was observed in wildtype littermates. Taken together, these results highlight a detrimental role for the GPR84 receptor in the context of meta-inflammation and suggest that GPR84 antagonism via PBI-4547 may reflect a novel treatment approach for NAFLD and its related complications.

Body weight is regulated by interoceptive neural circuits that track energy need, but how the activity of these circuits is altered in obesity remains poorly understood. Here we describe the in vivo dynamics of hunger-promoting AgRP neurons during the development of diet-induced obesity in mice. We show that high-fat diet attenuates the response of AgRP neurons to an array of nutritionally-relevant stimuli including food cues, intragastric nutrients, cholecystokinin and ghrelin. These alterations are specific to dietary fat but not carbohydrate or protein. Subsequent weight loss restores the responsiveness of AgRP neurons to exterosensory cues but fails to rescue their sensitivity to gastrointestinal hormones or nutrients. These findings reveal that obesity triggers broad dysregulation of hypothalamic hunger neurons that is incompletely reversed by weight loss and may contribute to the difficulty of maintaining a reduced weight.

Background: Sargassum polycystum C. Agardh is brown seaweed abundant in the Philippines. Recent studies showed that it has an anti-inflammatory property. However, its efficacy against allergic contact dermatitis (ACD) has not yet been studied and there are no established data regarding its physicochemical properties yet. Objectives: The objectives of this study were to evaluate the topical efficacy of S. polycystum crude polysaccharide (Spcp) using dinitrofluorobenzene (DNFB)-induced ACD murine model and to conduct physicochemical characterization on Spcp. Methods: ACD was induced by sensitizing the BALB/c mice through topical application of 0.5% DNFB on the shaved ventral skin. Spcp (25%, 12.5%, 6.25% w/w) and standard drug (Betamethasone 0.10%) were topically applied on the right ear of the mice for seven days after sensitization and right after the challenge on the eighth day. Seven days after sensitization, the right ear was challenged with 0.2% DNFB. Ear thickness was measured at baseline and 24-hrs post-challenge using a dial thickness gauge. Physicochemical characterization was also performed. Results: The results showed that topical application of Spcp inhibited the swelling produced during 24-hrs post-challenge. The analysis revealed that the 25% Spcp exhibited a statistically significant effect and was comparable with the inhibitory effect of the standard drug, betamethasone (p

Diabetes mellitus (DM) is a known risk factor for morbidity and mortality among patients with COVID-19 based on recent studies. While there are many local and international guidelines on inpatient management of diabetes, the complicated pathology of the virus, the use of glucose-elevating drugs such as glucocorticoids, antivirals and even inotropes, and various other unique problems has made the management of in-hospital hyperglycemia among patients with COVID-19 much more difficult than in other infections. The objective of this guidance is to collate and integrate the best available evidence that has been published regarding in-patient management of diabetes among patients with COVID-19. A comprehensive review of literature was done and recommendations have been made through a consensus of expert endocrinologists from the University of the Philippines-Philippine General Hospital (UP-PGH) Division of Endocrinology, Diabetes and Metabolism. These recommendations are evolving as we continue to understand the pathology of the disease and how persons with diabetes are affected by this virus.

BackgroundSex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences.MethodsCombining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients. Pretreatment MR images of 494 glioblastoma patients (299 males and 195 females) were segmented to quantify tumor volumes. Cox proportional hazard (CPH) models and Student’s t-tests were used to assess which variables were associated with survival outcomes.ResultsAmong males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, pConclusionDespite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes, which emphasizes the importance of considering sex as a biological factor when determining patient prognosis and treatment approach.

The nongenomic mechanisms by which glucocorticoids modulate β2 agonist-induced-bronchodilation remain elusive. Our studies aimed to elucidate mechanisms mediating the beneficial effects of glucocorticoids on agonist-induced bronchodilation. Utilizing human precision-cut lung slices (hPCLS), we measured bronchodilation to formoterol, prostaglandin E2 (PGE2), cholera toxin (CTX), or forskolin in the presence and absence of budesonide. Using cultured human airway smooth muscle (HASM), intracellular cAMP was measured in live cells following exposure to formoterol, PGE2, or forskolin in the presence or absence of budesonide. We showed that simultaneous budesonide administration amplified formoterol-induced bronchodilation and attenuated agonist-induced phosphorylation of myosin light chain, a necessary signaling event mediating force generation. In parallel studies, cAMP levels were augmented by simultaneous exposure of HASM cells to formoterol and budesonide. Budesonide, fluticasone, and prednisone alone rapidly increased cAMP levels, but steroids alone had little effect on bronchodilation in hPCLS. Bronchodilation induced by PGE2, CTX, or forskolin was also augmented by simultaneous exposure to budesonide in hPCLS. Furthermore, HASM cells expressed membrane-bound glucocorticoid receptors that failed to translocate with glucocorticoid stimulation and that potentially mediated the rapid effects of steroids on β2 agonist-induced bronchodilation. Knockdown of glucocorticoid receptor-α had little effect on budesonide-induced and steroid-dependent augmentation of formoterol-induced cAMP generation in HASM. Collectively, these studies suggest that glucocorticoids amplify cAMP-dependent bronchodilation by directly increasing cAMP levels. These studies identify a molecular mechanism by which the combination of glucocorticoids and β2 agonists may augment bronchodilation in diseases such as asthma or chronic obstructive pulmonary disease.

Severe asthma patients with low type 2 inflammation derive less clinical benefit from therapies targeting type 2 cytokines and have significant unmet medical needs. We show that mast cell tryptase is elevated in severe asthma patients, correlating with greater disease severity, but independent of type 2 biomarker status. Active β-tryptase allele count correlates with blood tryptase levels, and asthma patients carrying more active alleles benefit less from anti-IgE treatment. We generated a noncompetitive inhibitory antibody against human β-tryptase, which dissociates active tetramers into inactive monomers. A 2.15 A crystal structure of a β-tryptase/antibody complex coupled with biochemical studies reveals the molecular basis for allosteric destabilization of both small and large interfaces required for tetramerization. Anti-tryptase potently blocks tryptase-dependent activity in a humanized mouse model, reducing IgE-mediated systemic anaphylaxis, and has favorable pharmacokinetics in cynomolgus monkeys. Our data provide the foundation for developing anti-tryptase as a clinical therapy for severe asthma.

Male testosterone (T) decreases in response to childbirth. Longitudinal support for this has come from samples across cultures. In this study, we look at individual differences in this phenomenon. Utilizing a sample of U.S. fathers, we employ life history theory to investigate the influence of a father's early experience on his neuroendocrine response to fatherhood. We conducted three home visits (n = 226 fathers) from the third trimester of pregnancy to when infants were 10 months old. In this sample, T declined from the third trimester of (a partner's) pregnancy to the early months of the postnatal period. T recovered to pre-birth levels by the time infants reached 10 months old. We did not find any evidence that one's subjective experience of their early environment could account for any meaningful variability in T calibration. Objective, “event” measures of early harshness (i.e., death of a sibling/friend) and unpredictability (i.e., parent upheaval) each uniquely predicted a younger age of sexual debut. Neither harshness nor unpredictability had any (direct or indirect) effects on T calibration. Age of sexual debut did predict the rate of T recovery from 3 to 10 months postnatal. The younger one's sexual debut, the more accelerated their T ascent during this period. We discuss the potential reasons for, and implications of our mixed results.

Introduction: Nonalcoholic Fatty Liver Diseases (NAFLD), characterized by fatty acid and glucose metabolism dysregulation, is highly prevalent in all regions of the world. PBI-4547 is an orally active compound which displays pleiotropic activities and has been shown to reduce NASH, diabetes and fibrosis in different rodent models. The goal of the current study was to investigate the effects of PBI-4547 in a mouse model of high-fat diet-induced obesity and metabolic syndrome. Methods: C57BL/6 mice were fed with either a standard or a high-fat diet (HFD, Harlan, TD.06414) for 14 weeks. Mice fed with the HFD were then treated or not with PBI-4547 (10 mg/kg, oral once a day) for 6 weeks. Liver/WAT histology and mRNA gene profile were examined. HepG2 hepatocytes were also used for in vitro experiments. Blood glucose, serum insulin level, serum triglyceride and adiponectin were followed over the 6 weeks of treatment. Results: PBI-4547 treatment led to a significant reduction of hepatic steatosis, ballooning and total NAFLD score. Inflammation and fibrosis in white adipose tissues were also significantly reduced by PBI-4547. Adiponectin levels were also increased by PBI-4547. Metabolomic study from liver extracts revealed that PBI-4547 restored back to normal the levels of amino acids, Krebs cycle and energy-related intermediates. Uncoupling Proteins (Ucp2/3 in liver and Ucp1 in WAT) were also increased by PBI-4547 suggesting that PBI-4547 could affect mitochondria and increase energy expenditure. Oxygen consumption rate analyses confirmed that PBI-4547 reduces Oxphos-related ATP production and increased proton leak in HepG2 hepatocytes. In such way, PBI-4547 increased glucose and fatty acid metabolism improving insulin resistance and β-cell function. Conclusions: These results indicate that PBI-4547 offers the potential as a novel therapy for NAFLD, diabetes and associated metabolic syndrome. Disclosure J. Simard: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Thibodeau: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Leduc: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Tremblay: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Laverdure: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. R. Corpuz: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc.

Background Black sexual minority men (BSMM) are disproportionately affected by HIV. Los Angeles County (LAC) carries a substantial burden of the HIV epidemic in California. Negative effects of both psychosocial and structural barriers highlight the timely need to increase HIV treatment among BSMM. Successful HIV interventions based on social media and mobile phone technology have been demonstrated. This protocol describes LINX LA, a study that tests LINX, a web-based mobile app that provides tailored social services, legal resources, and peer support for BSMM living with HIV (BSMM+) in LAC using a randomized comparison trial. Objective During phase 1, the LINX LA study aims to engage in an iterative design process to develop the LINX App using qualitative data to inform and tailor the mobile app technology and its functionality. In phase 2 of LINX LA, we will test the efficacy of the LINX App compared with the LINX App Plus to improve HIV treatment outcomes (ie, antiretroviral therapy adherence, viral suppression) among BSMM+ in LAC by addressing social work and legal needs and developing a forum for peer support. Methods In this study funded by the California HIV/AIDS Research Program, we will recruit and enroll BSMM+ participants (aged ≥18 years) in LAC (N=400) to participate in a 12-month study that includes access to the LINX App, which provides a forum for peer support and tailored content aimed at improving the use of social and legal resources. All participants will also receive survey-based interviews at 3 time points (at baseline and 6- and 12-month intervals) and weekly text message surveys that assess medication and treatment adherence. Treatment adherence and viral suppression will be extracted from medical record data. Half of the participants will also be randomly assigned to receive 3 individualized coaching sessions (at 1-, 3-, and 6-month intervals) and the ability to directly message their coach via the LINX App. Over the course of the study, LINX App participants will receive a minimum of US $130 in cash and LINX App Plus participants will receive a minimum of US $190. We hypothesize that participants enrolled in LINX App Plus will demonstrate greater improvement in HIV outcomes compared with LINX App participants. Results The LINX study will test the efficacy of a web-based mobile app intervention for BSMM+ in LAC (N=400). The LINX App seeks to increase participants’ knowledge of HIV; to facilitate access to necessary social and legal services, including information and referrals; and to increase social support across participants by providing a mediated forum for engagement. Conclusions The implementation of LINX LA aims to develop and test a culturally tailored approach to improve the HIV treatment outcomes of BSMM+. International Registered Report Identifier (IRRID) PRR1-10.2196/19770

• Critically-ill COVID-19 patients with New Delhi Metallo-beta-lactamase producing Enterobacterales infections at our medical center had poor outcomes, including death in 4 of 5 cases • Multiple insults contributed to the occurrence of co-infection in these patients, including prolonged hospitalization, intubation, invasive devices, extensive antibiotic use, immunosuppressive therapy and environmental factors • There are few antibiotic options for treatment of infections with New Delhi Metallo-beta-lactamase producing Enterobacterales, contributing to poor outcomes • Hospitals and public health authorities should be vigilant for extensively drug resistant bacterial co-infections in patients hospitalized with COVID-19

Secondary cerebral folate deficiency (CFD) has been described in various neurodegenerative diseases, for example, Aicardi–Goutieres syndrome, Kearns–Sayre syndrome, and other mitochondriopathies. The importance of associated CFD lies in the possibility that treatment with folinic acid may improve the outcome of these diseases, or its presence may affect the course of the disease. We describe a patient with neuronal ceroid lipofuscinosis (NCL) type 2 due to tripeptidyl-peptidase I (TPP1) deficiency with an atypical presentation of chorea and dystonia. She was subsequently found to have low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5-MTHF). TPP1 level in skin fibroblast cultures was

Chikungunya virus (CHIKV) often co-circulates with dengue virus (DENV). A cross-sectional surveillance study was conducted at a tertiary hospital in Manila, Philippines, to describe the prevalence and characteristics of DENV and CHIKV infections among patients seeking care for dengue-like illness. Acute blood samples from patients ≥ 6 months of age clinically diagnosed with dengue from November 2012 to December 2013 underwent reverse transcription polymerase chain reaction (RT-PCR) to detect DENV and CHIKV RNA. A total of 118 patients with clinically diagnosed dengue (age range = 1-89 years, mean = 22 years; male-to-female ratio = 1.51) were tested by DENV RT-PCR; 40 (34%) were DENV PCR-positive (age range = 1-45 years, mean = 17 years). All DENV serotypes were detected: 11 (28%) DENV-1, 6 (15%) DENV-2, 6 (15%) DENV-3, and 17 (42%) DENV-4. Of 112 patients clinically diagnosed with dengue and tested by CHIKV RT-PCR, 11 (10%) were CHIKV PCR-positive (age range = 2-47 years, mean = 20.3 years). No coinfections were detected. Presenting signs/symptoms did not differ between DENV- and CHIKV-positive cases. Sequencing of envelope 1 gene from two CHIKV PCR-positive samples showed Asian genotype. This study highlights the potential for misdiagnosis of medically attended CHIKV infections as DENV infection and the difficulty in clinically differentiating dengue and chikungunya based on presenting signs/symptoms alone. This underscores the necessity for diagnostic laboratory tests to distinguish CHIKV infections in the background of actively co-circulating DENV.

Anti-PD1/L1 has become the backbone of immune therapy for many cancer types. However, the majority of patients do not respond due to a myriad of mechanisms affecting the tumor microenvironment, including low tumor mutational burden and low immune cell infiltrate. Innate immune agonists can potentially address both issues by increasing tumor antigen presentation and tumor microenvironment inflammation, thereby turning cold tumors hot. As clinical proof-of-concept, many intratumoral TLR/STING agonists have shown promising anti-tumor responses as single agents and in combination with checkpoint inhibitors; however, successful clinical applications have been limited to cutaneous-accessible tumor types. APR003 is an orally-administered GI/liver-targeted small molecule TLR7 agonist designed for the treatment of visceral colorectal and liver cancers. Studies in mice and monkeys demonstrate robust Type-1 Interferon pathway activation with good tolerability. APR003 is efficacious in several syngeneic orthotopic models of liver and colon cancer, both as single agent and in combination with anti-PDL1. Mechanistic studies show enhancement of CD103+ dendritic cells in tumor draining lymph nodes and tumor antigen-specific T cells in the tumor microenvironment. Pre-clinical pharmacology data will be presented. Citation Format: Andrew T. Miller, Evelyn Rodrigo, Manny Corpuz, David Plouffe, Tom Y.-H. Wu. Gastrointestinal/liver-targeted TLR7 agonist for treatment of colorectal and liver cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 684.

Tuberculosis treatment failure is not uncommon in patients with AIDS. Treatment failure is defined as a positive sputum smear or culture at month 5 or later in the course of the treatment. The clinical presentations in these patients show remarkable heterogeneity. In this report, we chronicle the case of a patient with treatment failure presenting as the disseminated disease, specifically ocular and renal tuberculosis. Additionally, we undertake here a brief literature review highlighting the increased resistance to tuberculosis treatment in patients with AIDS, the rarity of ocular tuberculosis and the importance of tailoring drug regimens on an individual basis in these coinfected patients.

Interferons-alpha (IFN-α) are the expressed gene products comprising thirteen type I interferons with protein pairwise sequence similarities in the 77-96% range. Three other widely expressed human type I interferons, IFN-β, IFN-κ and IFN-ω have sequences 29-33%, 29-32% and 56-60% similar to the IFN-αs, respectively. Type I interferons act on immune cells by producing subtly different immune-modulatory effects upon binding to the extracellular domains of a heterodimeric cell-surface receptor composed of IFNAR1 and IFNAR2, most notably anti-viral effects. IFN-α has been used to treat infection by hepatitis-virus type C (HCV) and a correlation between hyperactivity of IFN-α-induced signaling and systemic lupus erythematosis (SLE), or lupus, has been noted. Anti-IFN-α antibodies including rontalizumab have been under clinical study for the treatment of lupus. To better understand the rontalizumab mechanism of action and specificity, we determined the X-ray crystal structure of the Fab fragment of rontalizumab bound to human IFN-α2 at 3A resolution and find substantial overlap of the antibody and IFNA2 epitopes on IFN-α2.

Compared with lymphoid tissues, the immune cell compartment at mucosal sites is enriched with T cells bearing the γδ T-cell receptor (TCR). The female reproductive tract, along with the placenta and uterine decidua during pregnancy, are populated by γδ T cells predominantly expressing the invariant Vγ6+ Vδ1+ receptor. Surprisingly little is understood about the function of these cells. We found that the majority of γδ T cells in the non-pregnant uterus, pregnant uterus, decidua and placenta of mice express the transcription factor RORγt and produce interleukin-17 (IL-17). In contrast, IFNγ-producing γδ T cells were markedly reduced in gestational tissues compared with uterine-draining lymph nodes and spleen. Both uterine-resident invariant Vγ6+ and Vγ4+ γδ T cells which are more typically found in lymphoid tissues and circulating blood, were found to express IL-17. Vγ4+ γδ T cells were particularly enriched in the placenta, suggesting a pregnancy-specific recruitment or expansion of these cells. A small increase in IL-17-producing γδ T cells was observed in allogeneic compared with syngeneic pregnancy, suggesting a contribution to regulating the maternal response to paternally-derived alloantigens. However, their high proportions also in non-pregnant uteri and gestational tissues of syngeneic pregnancy imply a role in the prevention of intrauterine infection or quality control of fetal development. These data suggest the need for a more rigorous evaluation of the role of IL-17 in sustaining normal pregnancy, particularly as emerging data points to a pathogenic role for IL-17 in pre-eclampsia, pre-term birth, miscarriage and maternal immune activation-induced behavioral abnormalities in offspring. Refereed/Peer-reviewed

Background and aims Spontaneous hepatic rupture (SHR) is a rare peripartum complication and usually occurs among patients with pre-eclampsia, eclampsia or HELLP syndrome. We report a case of a 29 year old primigravid woman with fetal death in utero and spontaneous hepatic rupture secondary to undiagnosed Antiphospholipid Antibody Syndrome (APAS). Despite its uncommonness, a high index of suspicion for an autoimmune disease such as APAS to prevent maternal and fetal complications is recommended. Presenting a 29 year old, primigravid of 32 weeks age of gestation was admitted due to epigastric pain, hypotension and decreased fetal movement. She delivered to a dead male neonate via Emergency Low Segment Transverse Caesarean Section. Hemoperitonium and active bleeding from the liver were noted intraoperatively. Methods Patient was managed as spontaneous hepatic rupture. APAS was considered and diagnosed via the Revised SAPPORO Criteria. HELLP syndrome and pre-eclampsia were ruled out by clinical and laboratory parameters. Results Hepatic packing with drainage and blood pressure control were done. Patient received Low Molecular Weight Heparin and Aspirin and improved after 13 days without bleeding. Conclusions Spontaneous hepatic rupture is a rare, life-threatening presentation of APAS that warrants timely diagnosis and effective control of haemorrhage to prevent maternal and fetal mortality. Early initiation of anticoagulation is both safe and effective in preventing APAS complications. Aspirin should be initiated to prevent future thrombosis and pregnancy loss.

Introduction Patients with cancer are at increased risk of thrombosis, particularly those with central venous catheter (CVC) placement, which may predispose to the development of upper extremity deep vein thrombosis (UEDVT). Standard treatment includes low molecular weight heparin (LMWH) or LMWH bridged to warfarin. The direct oral anticoagulants (DOACs) have become standard of care for uncomplicated venous thromboembolism (VTE), but research in patients with cancer is ongoing. Objectives To assess rivaroxaban monotherapy in patients with cancer who develop UEDVT due to CVC for preservation of line function, and safety outcomes of VTE recurrence, bleeding risk and death. Materials and methods Patients ≥ 18 years of age with active malignancy and symptomatic proximal UEDVT with or without pulmonary embolism (PE), associated with a CVC, were eligible. Treatment included rivaroxaban 15 mg oral twice daily for 3 weeks, followed by 20 mg oral daily for 9 weeks. Patients were followed clinically for 12 weeks to assess for line function, recurrent VTE and bleeding. Results Seventy patients (47 women) were included, with mean age 54.1 years. The most common malignancy was breast cancer (41%). Preservation of line function was 100% at 12 weeks. The risk of recurrent VTE at 12 weeks was 1.43%, with one episode of fatal PE. 9 patients (12.9%) experienced 11 total bleeding episodes. Conclusions Rivaroxaban showed promise in treating CVC-UEDVT in cancer patients, resulting in preserved line function. However, bleeding rates and a fatal pulmonary embolism on treatment are concerning safety outcomes necessitating further study before rivaroxaban can be recommended.

Influenza myocarditis is an underappreciated and severe complication of influenza infection, estimated to be present in about 10% of all influenza cases. We present a case of a woman who precipitously died of fulminant influenza myocarditis and then review the historical data, literature and expert recommendations for suspecting and managing influenza myocarditis.

Multiple Sclerosis (MS) is a neurodegenerative autoimmune disorder caused by chronic inflammation and demyelination within the central nervous system (CNS). Clinical studies in MS patients have demonstrated efficacy with B cell targeted therapies such as anti-CD20. However, the exact role that B cells play in the disease process is unclear. Activation Induced cytidine deaminase (AID) is an essential enzyme for the processes of antibody affinity maturation and isotype switching. To evaluate the impact of affinity maturation and isotype switching, we have interrogated the effect of AID-deficiency in an animal model of MS. Here, we show that the severity of experimental autoimmune encephalomyelitis (EAE) induced by the extracellular domain of human myelin oligodendrocyte glycoprotein (MOG1-125) is significantly reduced in Aicda deficient mice, which, unlike wild-type mice, lack serum IgG to myelin associated antigens. MOG specific T cell responses are comparable between wild-type and Aicda knockout mice suggesting an active role for antigen experienced B cells. Thus affinity maturation and/or class switching are critical processes in the pathogenesis of EAE.

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma. Cancer Res; 71(24); 7568–75. ©2011 AACR.

This study seeks to ascertain whether a culturally tailored art calendar could improve participation in cancer screening activities. We conducted a randomized, controlled calendar mail-out in which a Native art calendar was sent by first class mail to 5,633 patients seen at an urban American Indian clinic during the prior 2 years. Using random assignment, half of the patients were mailed a "message" calendar with screening information and reminders on breast, colorectal, lung, and prostate cancer; the other half received a calendar without messages. The receipt of cancer screening services was ascertained through chart abstraction in the following 15 months. In total, 5,363 observations (health messages n = 2,695; no messages n = 2,668) were analyzed. The calendar with health messages did not result in increased receipt of any cancer-related prevention outcome compared to the calendar without health messages. We solicited clinic input to create a culturally appropriate visual intervention to increase cancer screening in a vulnerable, underserved urban population. Our results suggest that printed materials with health messages are likely too weak an intervention to produce the desired behavioral outcomes in cancer screening.