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Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC) n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC) n , which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD.

Health Canada approved pembrolizumab in the first-line setting for advanced non-small-cell lung cancer with PD-L1 ≥ 50% and no EGFR/ALK aberration. The keynote 024 trial showed 55% of such patients progress with pembrolizumab monotherapy. We propose that the combination of baseline CT and clinical factors can help identify those patients who may progress. In 138 eligible patients from our institution, we retrospectively collected their baseline variables, including baseline CT findings (primary lung tumor size and metastatic site), smoking pack years, performance status, tumor pathology, and demographics. The treatment response was assessed via RECIST 1.1 using the baseline and first follow-up CT. Associations between the baseline variables and progressive disease (PD) were tested by logistic regression analyses. The results showed 46/138 patients had PD. The baseline CT “number of involved organs” by metastasis and smoking pack years were independently associated with PD (p < 0.05), and the ROC analysis showed a good performance of the model that integrated these variables in predicting PD (AUC: 0.79). This pilot study suggests that the combination of baseline CT disease and smoking PY can identify who may progress on pembrolizumab monotherapy and can potentially facilitate decision-making for the optimal first-line treatment in the high PD-L1 cohort.

Antibodies directed against DNA in systemic lupus erythematosus are functionally diverse. This study demonstrates that DNAse1L3 is the primary target of a subset of autoantibodies previously considered specific for double-stranded DNA.

The increasing demand for novel natural compounds has prompted the exploration of innovative approaches in bioengineering. This study investigates the bioengineering potential of the marine diatom Phaeodactylum tricornutum through the introduction of cannabis genes, specifically, tetraketide synthase (TKS), and olivetolic acid cyclase (OAC), for the production of the cannabinoid precursor, olivetolic acid (OA). P. tricornutum is a promising biotechnological platform due to its fast growth rate, amenability to genetic manipulation, and ability to produce valuable compounds. Through genetic engineering techniques, we successfully integrated the cannabis genes TKS and OAC into the diatom. P. tricornutum transconjugants expressing these genes showed the production of the recombinant TKS and OAC enzymes, detected via Western blot analysis, and the production of cannabinoids precursor (OA) detected using the HPLC/UV spectrum when compared to the wild-type strain. Quantitative analysis revealed significant olivetolic acid accumulation (0.6–2.6 mg/L), demonstrating the successful integration and functionality of the heterologous genes. Furthermore, the introduction of TKS and OAC genes led to the synthesis of novel molecules, potentially expanding the repertoire of bioactive compounds accessible through diatom-based biotechnology. This study demonstrates the successful bioengineering of P. tricornutum with cannabis genes, enabling the production of OA as a precursor for cannabinoid production and the synthesis of novel molecules with potential pharmaceutical applications.

Macroscelidid afrotherians and canid carnivorans possess four premolar loci, the first of which is not replaced. Previous work suggests that the first premolar in macroscelidids is a retained deciduous tooth, but in Canis it is a successional tooth with no milk precursor. We tested this contrasting interpretation of first premolar homology with data from ontogenetic anatomy and with area predictions from the inhibitory cascade (IC) model. Our results based on anatomy support previous interpretations that the functional first premolar is a retained deciduous tooth (dp1) with no successor in macroscelidids, and a successional tooth (p1) with no precursor in Canis. Hyracoids are among the few placental mammals that show replacement at the first premolar locus and show less deviation than other taxa of actual from predicted areas across the deciduous and molar toothrow. However, predicted vs. actual tooth areas can depart substantially from one another. At least without a better means of representing tooth size, the inhibitory cascade does not help to distinguish the deciduous from successional first premolar. This observation does not rule out the possibility that factors such as a size-shift within the toothrow (e.g., carnivoran carnassials) help to explain deviations from the inhibitory cascade model.

The origin and mechanisms of autoantigen generation in systemic lupus erythematosus (SLE) are poorly understood. Here, we identified SLE neutrophils activated in vivo by IFN as a prominent source of Ro52, also known as tripartite motif–containing protein 21 (TRIM21), a critical autoantigen historically thought to be primarily generated by keratinocytes in SLE. Different from mononuclear cells and keratinocytes, SLE neutrophils are enriched in several unique Ro52 species containing a core sequence encoded by exon 4 (Ro52Ex4) in TRIM21. Ro52Ex4 is the main target of anti-Ro52 antibodies and is found in 2 Ro52 variants (Ro52α and an isoform termed Ro52γ) upregulated in SLE neutrophils. Further analysis of Ro52γ revealed a subset of autoantibodies against a unique C-terminal domain (Ro52γCT) generated from a frameshift due to the lack of exon 6 in Ro52γ. Antibodies to Ro52Ex4 and Ro52γCT distinguish SLE patient subsets characterized by distinct clinical, laboratory, treatment, and transcriptional profiles that are not discerned by the “classical” anti-Ro52 antibodies. These studies uncover IFN-activated neutrophils as a key source of unique immunogenic forms of Ro52 in SLE. Moreover, the finding of Ro52Ex4 and Ro52γCT as core targets of anti-Ro52 antibodies focus interest on Ro52γ as the potential isoform toward which immunological tolerance is initially lost in SLE.

Background: Emergency departments (EDs) are complex, sociotechnical, high-paced, safety-critical work systems that have been disproportionately affected by the COVID-19 pandemic. Despite training, consistent compliance with recommended PPE use during COVID-19 pandemic has been challenging. Healthcare workers (HCWs) have had adapt to overcome these challenges to ensure their own safety and patient safety. We sought to identify barriers in the work system that impede the recommended COVID-19 PPE use in EDs. Methods: We conducted semistructured, in-depth interviews over ZoomTM from August 2020–May 2021 with 45 HCWs from the ED (ie, physicians, nurses, ancillary support staff, etc) affiliated with a large, tertiary-care, academic medical center. These audio-recorded interviews were transcribed and analyzed using a hybrid (inductive and deductive) qualitative coding approach in NVivo software. The deductive portion was guided by the SEIPS work system model, a well-known human-factors conceptual framework. Results: We identified multiple work-system factors in the ED that impede compliance with the recommended COVID-19 PPE use. In addition, ED HCWs have reported making a variety of adaptations or developing strategies to overcome these barriers. Some of these adaptations were made to the PPE physically (eg, trimming portions of PPE), and others were related to the tasks and/or processes associated with PPE, such as filming their own training video demonstrating PPE donning and doffing techniques, and environment services staff checking a patient’s status with nurses prior to entering the patient’s room when there was no COVID-19 signage on the door. Conclusions: Consistent compliance with COVID-19 PPE use in ED clinical practice is challenging and can be negatively affected by a variety of work system factors. Resilience strategies developed by HCWs can provide critical information with regards to HCW needs and potential directions for innovation. Future efforts should focus on not only changing individual HCW behavior through training but also on improving the PPE and ED work system design.

Background: Nucleic acid binding proteins are frequently targeted as autoantigens in systemic lupus erythematosus (SLE) and other interferon (IFN)-linked rheumatic diseases. The AIM-like receptors (ALRs) are IFN-inducible innate sensors that form supramolecular assemblies along double-stranded (ds)DNA of various origins. Here, we investigate the ALR absent in melanoma 2 (AIM2) as a novel autoantigen in SLE, with similar properties to the established ALR autoantigen interferon-inducible protein 16 (IFI16). We examined neutrophil extracellular traps (NETs) as DNA scaffolds on which these antigens might interact in a pro-immune context. Methods: AIM2 autoantibodies were measured by immunoprecipitation in SLE and control subjects. Neutrophil extracellular traps were induced in control neutrophils and combined with purified ALR proteins in immunofluorescence and DNase protection assays. SLE renal tissues were examined for ALR-containing NETs by confocal microscopy. Results: AIM2 autoantibodies were detected in 41/131 (31.3%) SLE patients and 2/49 (4.1%) controls. Our SLE cohort revealed a frequent co-occurrence of anti-AIM2, anti-IFI16, and anti-DNA antibodies, and higher clinical measures of disease activity in patients positive for antibodies against these ALRs. We found that both ALRs bind NETs in vitro and in SLE renal tissues. We demonstrate that ALR binding causes NETs to resist degradation by DNase I, suggesting a mechanism whereby extracellular ALR-NET interactions may promote sustained IFN signaling. Conclusions: Our work suggests that extracellular ALRs bind NETs, leading to DNase resistant nucleoprotein fibers that are targeted as autoantigens in SLE. Funding: These studies were funded by NIH R01 DE12354 (AR), P30 AR070254, R01 GM 129342 (JS), K23AR075898 (CM), K08AR077100 (BA), the Jerome L. Greene Foundation and the Rheumatology Research Foundation. Dr. Antiochos and Dr. Mecoli are Jerome L. Greene Scholars. The Hopkins Lupus Cohort is supported by NIH grant R01 AR069572. Confocal imaging performed at the Johns Hopkins Microscopy Facility was supported by NIH Grant S10 OD016374.

Abstract Background Epidemiologic data suggest that patients with systemic lupus erythematosus (SLE) have a lower risk of breast cancer than women in the general population. In light of mechanistic studies suggesting that anti-DNA antibodies have anti-cancer effects, we sought to examine breast cancer risk in autoantibody strata in a well-characterized SLE cohort. Methods SLE patients without a cancer diagnosis prior to entry in the Hopkins Lupus Cohort were studied (N = 2431). Overall and site-specific cancer incidence was calculated in racial strata and compared with the US Surveillance, Epidemiology and End Results (SEER) registry. Breast cancer incidence was further examined in autoantibody subsets. Patients were considered positive for an autoantibody if they were ever positive for a specificity during their disease course. Results Patients with SLE had a 37% lower risk of breast cancer (SIR 0.63, 95% CI 0.39–0.95). The risk of HPV-associated cancers (SIR 4.39, 95% CI 2.87–6.44) and thyroid cancer (SIR 2.27, 95% CI 1.04–4.30) was increased. Cancer risk varied by race, with breast cancer protection occurring in non-African Americans (SIR 0.29, 95% CI 0.11–0.63) and the increased risk of HPV-associated cancers occurring in African Americans (SIR 7.23, 95% CI 4.35–11.3). Breast cancer risk was decreased in patients ever positive for anti-dsDNA (SIR 0.55, 95% CI 0.29–0.96), anti-La (SIR 0.00, 95% CI 0.00–0.78), and lupus anticoagulant (SIR 0.37, 95% CI 0.10–0.94). Patients who were positive for fewer (0–2) SLE autoantibodies did not have a lower risk of breast cancer (SIR 0.84, 95% CI 0.47–1.39), but patients with 3+ autoantibodies had a 59% decreased risk (SIR 0.41, 95% CI 0.16–0.84). Conclusions Positivity for multiple SLE autoantibodies was associated with a lower risk of breast cancer, supporting the hypothesis that a highly diversified immune response may exert an anti-cancer effect against some cancers. Validation of racial differences in cancer risk in SLE is required to determine whether cancer screening strategies should be targeted to racial subgroups.

Heterogeneous helper T (Th) cell responses contribute to differential susceptibility to immunological disorders. Here the authors perform haplotype-based computational screens of 16 inbred mouse strains to identify a transcription factor, p73, as an important negative regulator of Th1 differentiation, with p73 deficient mice manifesting alterations in two inflammatory disease models.

Abstract Background Dysfunctional autophagy is implicated in Alzheimer’s Disease (AD) pathogenesis. The alterations in the expression of many autophagy related genes (ATGs) have been reported in AD brains; however, the disparity of the changes confounds the role of autophagy in AD. Methods To further understand the autophagy alteration in AD brains, we analyzed transcriptomic (RNAseq) datasets of several brain regions (BA10, BA22, BA36 and BA44 in 223 patients compared to 59 healthy controls) and measured the expression of 130 ATGs. We used autophagy-deficient mouse models to assess the impact of the identified ATGs depletion on memory, autophagic activity and amyloid-β (Aβ) production. Results We observed significant downregulation of multiple components of two autophagy kinase complexes BECN1-PIK3C3 and ULK1/2-FIP200 specifically in the parahippocampal gyrus (BA36). Most importantly, we demonstrated that deletion of NRBF2, a component of the BECN1-PIK3C3 complex, which also associates with ULK1/2-FIP200 complex, impairs memory in mice, alters long-term potentiation (LTP), reduces autophagy in mouse hippocampus, and promotes Aβ accumulation. Furthermore, AAV-mediated NRBF2 overexpression in the hippocampus not only rescues the impaired autophagy and memory deficits in NRBF2-depleted mice, but also reduces β-amyloid levels and improves memory in an AD mouse model. Conclusions Our data not only implicates NRBF2 deficiency as a risk factor for cognitive impairment associated with AD, but also support the idea of NRBF2 as a potential therapeutic target for AD.

For many people seeking abortion during the continuing COVID-19 pandemic, telemedicine abortion is the safest and most acceptable method, posing lower risk of exposure to the virus. In addition, by reducing in-person visits with health care providers, increased use of telemedicine for abortion can reduce pressure on overburdened health systems. Given the benefits of telemedicine during the pandemic, government agencies in several countries took measures to temporarily allow telemedicine abortion. We conducted key-word English-language searches to identify examples of government action to remove regulatory barriers to the practice of telemedicine abortion in response to the pandemic. We found instances of government agencies in eight countries taking steps to ease regulatory barriers to telemedicine abortion. Telemedicine abortion is safe, cost-effective, and may be the preferred method of abortion during acute periods of COVID-19 transmission, as well as after the pandemic has abated. As one step to expanding access to abortion with medicine where abortion is legal, health agencies and other regulatory bodies can take steps to remove barriers specific to telemedicine abortion.

Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.

Background and aims We hypothesised that intracellular homocysteine and homocysteine metabolite levels in patients with SLE are disproportionately elevated compared with the levels seen in healthy subjects and that they are independently associated with coronary plaque in SLE.Methods A liquid chromatography–tandem mass spectrometry absolute quantification assay was used for the determination of six analytes in both plasma and peripheral blood mononuclear cells (PBMCs): homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), methionine (Met), cystathionine (Cysta) and 5-methyltetrahydrofolate (5m-THF). We then compared intracellular (PBMC) and extracellular (plasma) Hcy and Hcy metabolite (SAM, SAH, Met, Cysta and 5m-THF) concentrations in 10 patients with SLE and in 10 age, sex and ethnicity matched controls. Subjects with a history of diabetes mellitus, cardiovascular disease, hypertension, alcohol consumption in excess of 3 units per day, anaemia, renal insufficiency (serum creatinine >1.5 mg/dL) and pregnancy were excluded. All patients with SLE had two coronary CT angiography studies as screening for occult coronary atherosclerotic disease.Results Plasma from patients with SLE had higher levels of Hcy (p

Objective Retinoblastoma (Rb) protein is a nuclear protein with several important functions, including the ability to stabilize heterochromatin. Because antibodies against the nucleosome and chromatin are key in systemic lupus erythematosus (SLE), we sought to determine whether Rb was an autoantigen in SLE and to evaluate any associated clinical phenotypes. Methods Sera from 222 patients with SLE from the Hopkins longitudinal cohort were studied. Additional cohorts tested included sera from 100 patients with primary Sjögren syndrome (pSS) (disease controls) evaluated at the Johns Hopkins Jerome L. Greene Sjögren's Center and sera from 36 healthy individuals. Anti‐Rb antibodies were assayed by immunoprecipitation of 35S‐methionine–labeled Rb, which was generated by in vitro transcription/translation. Fisher's exact test was used for the univariate analysis. Multivariable exact logistic regression was used to model for the presence of proteinuria in patients with SLE. Results Anti‐Rb antibodies were present in 15 of 222 (6.8%) patients with SLE, in 3 of 100 patients with pSS (3%), and in 0 of 36 healthy individuals. Among patients with SLE, Rb antibodies were strongly negatively associated with proteinuria (P = 0.0031), renal involvement (odds ratio [OR] = 0.11; P = 0.01), and anemia (OR = 0.05; P < 0.0001) and were positively associated with stroke (OR = 7.65; P = 0.05). The negative association with lupus nephritis held true in multivariate models (adjusted OR = 0.11; P = 0.01). Conclusion Anti‐Rb antibodies are a novel specificity not previously described in SLE. These new data define a possible SLE subset that is protected against renal involvement, is positively associated with stroke, and is not associated with antiphospholipid antibodies.

The T cell-dependent bispecific (TDB) antibody, anti-CD79b/CD3, targets CD79b and CD3 cell-surface receptors expressed on B cells and T cells, respectively. Since the anti-CD79b arm of this TDB binds only to human CD79b, a surrogate TDB that binds to cynomolgus monkey CD79b (cyCD79b) was used for preclinical characterization. To evaluate the impact of CD3 binding affinity on the TDB pharmacokinetics (PK), we utilized non-tumor-targeting bispecific anti-gD/CD3 antibodies composed of a low/high CD3 affinity arm along with a monospecific anti-gD arm as controls in monkeys and mice. An integrated PKPD model was developed to characterize PK and pharmacodynamics (PD). This study revealed the impact of CD3 binding affinity on anti-cyCD79b/CD3 PK. The surrogate anti-cyCD79b/CD3 TDB was highly effective in killing CD79b-expressing B cells and exhibited nonlinear PK in monkeys, consistent with target-mediated clearance. A dose-dependent decrease in B cell counts in peripheral blood was observed, as expected. Modeling indicated that anti-cyCD79b/CD3 TDB’s rapid and target-mediated clearance may be attributed to faster internalization of CD79b, in addition to enhanced CD3 binding. The model yielded unbiased and precise curve fits. These findings highlight the complex interaction between TDBs and their targets and may be applicable to the development of other biotherapeutics.

Background Positive remodelling index and presence of low-attenuation non-calcified plaque (LANCP) are characteristic vessel changes in unstable coronary plaques. We sought to characterise these high-risk plaque features in patients with systemic lupus erythematosus (SLE) and to compare them with controls.Methods A total of 72 patients who satisfied the SLICC classification criteria for SLE had coronary CT angiography (CCTA) studies, 30 of which had follow-up CCTA, as screening for occult coronary atherosclerotic disease in asymptomatic individuals. A total of 100 consecutive controls with no known history of lupus, heart disease or revascularisation who had two coronary CT angiograms at least 1 year apart were included in the study. These were asymptomatic patients referred by their primary physicians for screening of coronary artery disease and the screening interval was decided by the primary physicians. The methodology for image acquisition was identical.Results LANCP burden at baseline was significantly greater in patients with SLE compared with controls. LANCP volume was significantly greater in patients over 60 years of age (p10 mg/day. LANCP burden remained stable over follow-up. There were no significant differences in remodelling index compared with controls.Conclusion This is the first study describing high-risk CCTA features of coronary plaque in patients with SLE. Both LANCP and positive remodelling are common in SLE. These characteristic vessel changes may identify patients with SLE at increased risk of cardiovascular events and those in need for more frequent cardiac monitoring.

This study explored the novel immune checkpoint poliovirus receptor- related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced naural killer (NK)-cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK-cell activation and degranulation in the context of patient primary AML blasts. However, in AML patient bone marrow, NK-cell PVRIG expression levels were not increased. In order to understand how PVRIG blockade might potentially be exploited therapeutically, we investigated the biology of PVRIG and revealed that NK-cell activation resulted in reduced PVRIG expression on the cell surface. This occurred whether NK cells were activated by tumor cell recognition, cytokines (interleukin 2 [IL-2] and IL-12) or activating receptor stimulation (CD16 and NKp46). PVRIG was present at higher levels in the cytoplasm than on the cell surface, particularly on CD56bright NK cells, which further increased cytoplasmic PVRIG levels following IL-2 and IL-12 activation. PVRIG was continually transported to the cell surface via the endoplasmic reticulum and Golgi in both unstimulated and activated NK cells. Taken together, our findings suggest that anti-PVRIG blocking antibody functions by binding to surface-bound PVRIG, which undergoes rapid turnover in both unstimulated and activated NK cells. We conclude that the PVRIG-PVRL2 immune checkpoint axis can feasibly be targeted with PVRIG blocking antibody for NK-mediated immunotherapy of PVRL2+ AML.

Abstract Background Globally, alcohol is causally related to 2.5 million deaths per year and 12.5% of these are due to cancer. Previous research has indicated that public awareness of alcohol as a risk factor for cancer is low and this may contribute to a lack of public support for alcohol policies. The aim of this study was to investigate the relationship between awareness of the alcohol-cancer link and support for a range of alcohol policies in an English sample and policy context. Methods A cross-sectional survey of 2100 adult residents in England was conducted in which respondents answered questions regarding awareness of the link between alcohol and cancer and support for 21 policy proposals. Principal component analysis (PCA) was used to reduce the 21 policy proposals down to a set of underlying factors. Multiple regression analyses were conducted to estimate the relationship between awareness of the alcohol-cancer link and each of these policy factors. Results Thirteen per cent of the sample were aware of the alcohol-cancer link unprompted, a further 34% were aware when prompted and 53% were not aware of the link. PCA reduced the policy items to four policy factors, which were named price and availability, marketing and information, harm reduction and drink driving. Awareness of the alcohol-cancer link unprompted was associated with increased support for each of four underlying policy factors: price and availability (Beta: 0.06, 95% CI: 0.01, 0.10), marketing and information (Beta: 0.05, 95% CI: 0.00, 0.09), harm reduction (Beta: 0.09, 95% CI: 0.05, 0.14), and drink driving (Beta: 0.16, 95% CI: 0.11, 0.20). Conclusions Support for alcohol policies is greater among individuals who are aware of the link between alcohol and cancer. At the same time, a large proportion of people are unaware of the alcohol-cancer link and so increasing awareness may be an effective approach to increasing support for alcohol policies.

Abstract The ‘crime drop’ refers to the substantial reductions in crime reported in many industrialised countries over at least the past quarter century. Asian countries are underrepresented in the crime drop literature. Little is therefore known about whether the same type and levels of crime reductions have been observed, and if prevailing explanations hold. In this study, we examine trends in burglary and car crime using police recorded crime data from Hong Kong, Japan and Taiwan. We show that Japan and Taiwan experienced crime drops similar to that reported elsewhere but occurring more recently in the early 2000s. Hong Kong appears anomalous, with a major crime decline emerging from the early 1980s. The study concludes that there is sufficient evidence to justify further research and sets out suggestions to that end.

Humans that reach high altitude soon after the first ascent show faster adaptation to hypoxia. Songet al. show that this adaptive response relies on decreased red blood cell uptake of plasma adenosine due to reduced levels of nucleoside transporter ENT1 resulting from coordinated adenosine generation by ectonucleotidase CD73 and activation of A2B receptors.

Abstract Background Public knowledge of the association between alcohol and cancer is reported to be low. We aimed to provide up-to-date evidence for England regarding awareness of the link between alcohol and different cancers and to determine whether awareness differs by demographic characteristics, alcohol use, and geographic region. Methods A representative sample of 2100 adults completed an online survey in July 2015. Respondents were asked to identify which health outcomes, including specific cancers, may be caused by alcohol consumption. Logistic regressions explored whether demographic, alcohol use, and geographic characteristics predicted correctly identifying alcohol-related cancer risk. Results Unprompted, 12.9% of respondents identified cancer as a potential health outcome of alcohol consumption. This rose to 47% when prompted (compared to 95% for liver disease and 73% for heart disease). Knowledge of the link between alcohol and specific cancers varied between 18% (breast) and 80% (liver). Respondents identified the following cancers as alcohol-related where no such evidence exists: bladder (54%), brain (32%), ovarian (17%). Significant predictors of awareness of the link between alcohol and cancer were being female, more highly educated, and living in North-East England. Conclusion There is generally low awareness of the relationship between alcohol consumption and cancer, particularly breast cancer. Greater awareness of the relationship between alcohol and breast cancer in North-East England, where a mass media campaign highlighted this relationship, suggests that population awareness can be influenced by social marketing.

Abstract Background Multimorbidity is increasingly being recognized as a serious public health concern. Research into its determinants, prevalence, and management is needed and as the risk of experiencing multiple chronic conditions increases over time, attention should be given to investigating the development of multimorbidity through prospective cohort design studies. Here we examine the baseline patterns of multimorbidity and their association with health outcomes for residents in Yorkshire, England using data from the Yorkshire Health Study. Methods Baseline data from the Yorkshire Health Study (YHS) was collected from 27,806 patients recruited between 2010 and 2012. A two-stage sampling strategy was implemented which first involved recruiting 43 general practice surgeries and then having them consent to mailing invitations to their patients to complete postal or online questionnaires. The questionnaire collected information on chronic health conditions, demographics, health-related behaviours, healthcare and medication usage, and a range of other health related variables. Descriptive statistics (chi-square and t tests) were used to examine associations between these variables and multimorbidity. Results In the YHS cohort, 10,332 participants (37.2 %) reported having at least two or more long-term health conditions (multimorbidity). Older age, BMI and deprivation were all positively associated with multimorbidity. Nearly half (45.7 %) of participants from the most deprived areas experienced multimorbidity. Based on the weighted sample, average health-related quality of life decreased with the number of health conditions reported; the mean EQ-5D score for participants with no conditions was 0.945 compared to 0.355 for participants with five or more. The mean number of medications used for those without multimorbidity was 1.81 (range 1-13, SD = 1.25) compared to 3.81 (range 1-14, SD = 2.44) for those with at least two long-term conditions and 7.47 (range 1-37, SD = 7.47) for those with 5+ conditions. Conclusion Patterns of multimorbidity within the Yorkshire Health Study support research on multimorbidity within previous observational cross-sectional studies. The YHS provides both a facility for participant recruitment to intervention trials, and a large population-based longitudinal cohort for observational research. It is planned to continue to record chronic conditions and other health related behaviours in future waves which will be useful for examining determinants and trends in chronic disease and multimorbidity.

Tetrandrine is a bisbenzylisoquinoline alkaloid found in Stephania tetrandra, a Chinese medicine commonly used as an anti-inflammatory. It has extensive pharmacological activity, including positive ion channel blockade and inhibition of multiple drug resistance proteins. These activities are very similar to that of salinomycin, a known drug targeting breast cancer initiation cells (TICs). Herein, we tested tetrandrine targeting of breast cancer TICs. SUM-149, an inflammatory breast cancer cell line and SUM-159, a non-inflammatory metaplastic breast cancer cell line were used in these studies. In proliferation assays using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), we found that the IC50 for inhibition of proliferation is 15.3 ± 4.1 µM for SUM-149 and 24.3 ± 2.1 µM for SUM-159 cells. Tetrandrine also inhibited mammosphere formation, a surrogate for breast cancer TICs growth in vitro with IC50 around 1 µM for SUM-149 and around 2 µM for SUM-159 cells. Tetrandrine has similar effects on the mammosphere formation from cells isolated from fresh patient sample. Moreover, tetrandrine decreases the aldehyde dehydrogenase (ALDH) positive population in SUM-159 by 45% ± 5.45% P = 0.005. In summary, tetrandrine demonstrates significant efficacy against in vitro surrogates for inflammatory and aggressive breast cancer TICs.

OBJECTIVES/SPECIFIC AIMS: Long-acting reversible contraception (LARC) has been well established as the most cost-effective form of contraception, but LARC usage in developing countries remains low. As part of a multi-center parent study on HIV incidence, we implemented an integrated family planning program to increase LARC uptake in single women in Rwanda and Zambia. We aim to evaluate rates of LARC uptake, LARC discontinuation and incident pregnancy following family planning counseling. METHODS/STUDY POPULATION: We enrolled 3 cohorts of single sexually active HIV-negative women between the ages of 18–45 years: single mothers (SM) in Zambia, female sex workers (FSW) in Zambia and FSW in Rwanda. Participants were followed every 3 months for up to 5 years. At each visit, we discussed fertility goals and counseled participants on HIV risk reduction and contraceptive options. Eligible participants (not pregnant, already using a LARC method, or using a permanent contraceptive method) were offered a LARC method, specifically the copper IUD or Jadelle implant. Data was collected on demographic factors, sexual behavior, sexual and reproductive history, and gynecological exams and laboratory tests were performed if necessary. RESULTS/ANTICIPATED RESULTS: In total, 458 Rwandan FSW, 555 Zambian FSW, and 521 Zambian SM were enrolled, with a median follow-up time of 6 months, 12 months, and 9 months, respectively. Accounting for any LARC uptake during longitudinal follow-up, our preliminary results show an increase in LARC usage from 21% at screening to 51% at the end of follow-up among Rwandan FSW, an increase from 12% to 42% in Zambian FSW and an increase from 18% to 44% in Zambian SM. We hypothesize that demographic factors (e.g., younger age, higher education level) and sexual history (e.g., greater number of sexual partners, any STIs or reproductive health disturbances) will be associated with increased rates of LARC uptake. We also hypothesize that LARC users will have significantly lower proportions of contraceptive method discontinuation and incident pregnancy compared to non-LARC users. DISCUSSION/SIGNIFICANCE OF IMPACT: FSW and SM are disproportionately affected by high rates of unintended pregnancy, which can lead to obstetric complications and poor psychosocial outcomes. It is imperative that family planning interventions in developing countries target these populations to overcome obstacles in reproductive health and promote gender equality. Our study will provide necessary insights to an integrated family planning program, which will guide future efforts to design, implement and evaluate family planning initiatives for high-risk populations.

Considering the limitations of traditional energy-saving policies, a kind of energy conservation method called the Information Feedback to Residential Electricity Load Customers, which could impact the demand response capacity, has increasingly received more attention. However, most of the current feedback programs provide the same feedback information to all customers regardless of their diverse characteristics, which may reduce the energy-saving effects or even backfire. This paper attempts to investigate how different types of customers may change their behaviors under a set of customized feedback. We conducted a field survey study in Qinhuangdao (QHD), China. First, we conducted semi-structured interviews to classify four groups of customers of different energy-saving awareness, energy-saving potential, and behavioral variability. Then, 156 QHD households were surveyed using scenarios to collect feedback of different scenarios. Social science theories were used to guide the discussion on the behavior changes as a result of different feedback strategies and reveal the reasons for customers’ behaviors. Using the Chi-Square test of independence, the variables that have strong correlations with the categories of residents are extracted to provide references for residents’ classification. Finally, the practical implications and needs for future research are discussed.

To examine HIV prevalence, HIV testing behaviour, undiagnosed infection and risk factors for HIV positivity among a community sample of gay men in Scotland.Cross-sectional survey of gay and bisexual men attending commercial gay venues in Glasgow and Edinburgh, Scotland with voluntary anonymous HIV testing of oral fluid samples in 2011. A response rate of 65.2% was achieved (1515 participants).HIV prevalence (4.8%, 95% confidence interval, CI 3.8% to 6.2%) remained stable compared to previous survey years (2005 and 2008) and the proportion of undiagnosed infection among HIV-positive men (25.4%) remained similar to that recorded in 2008. Half of the participants who provided an oral fluid sample stated that they had had an HIV test in the previous 12 months; this proportion is significantly higher when compared to previous study years (50.7% versus 33.8% in 2005, p25 years) was associated with HIV positivity (1.8% in those

OBJECTIVES:To investigate the awareness of, and willingness to use, HIV Pre-Exposure Prophylaxis (PrEP), and willingness to take part in a PrEP study among gay and bisexual men in Scotland. METHODS:Cross-sectional survey of 17 gay commercial venues in Glasgow and Edinburgh in May 2011 (N = 1515, 65.2% response rate); 1393 are included in the analyses. RESULTS:Just under one-third of participants had heard of PrEP (n = 434; 31.2%), with awareness associated with being aged older than 35 years, talking to UAI partners about HIV, and with having had an HIV or STI test in the previous 12 months. Around half were willing to take part in a PrEP study (n = 695; 49.9%) or to take PrEP on a daily basis (n = 756; 54.3%). In multivariate analysis, willingness to take PrEP was associated with lower levels of education, regular gay scene attendance, 'high-risk' unprotected anal intercourse (UAI) and testing for HIV or STI in the previous 12 months. Reasons for not wanting to participate in a PrEP study or take PrEP included perceptions of low personal risk of HIV and concerns with using medication as an HIV prevention method. CONCLUSIONS:There is a willingness to engage in new forms of HIV prevention and research amongst a significant number of gay and bisexual men in Scotland. Future biomedical HIV interventions need to consider the links between sexual risk behaviour, testing, and potential PrEP use.