Algorithmic design of self-folding polyhedra

Self-assembly has emerged as a paradigm for highly parallel fabrication of complex three-dimensional structures. However, there are few principles that guide a priori design, yield, and defect tolerance of self-assembling structures. We examine with experiment and theory the geometric principles that underlie self-folding of submillimeter-scale higher polyhedra from two-dimensional nets. In particular, we computationally search for nets within a large set of possibilities and then test these nets experimentally. Our main findings are that (i) compactness is a simple and effective design principle for maximizing the yield of self-folding polyhedra; and (ii) shortest paths from 2D nets to 3D polyhedra in the configuration space are important for rationalizing experimentally observed folding pathways. Our work provides a model problem amenable to experimental and theoretical analysis of design principles and pathways in self-assembly.     

An uncommon cause of myocardial infarction

A 73 year-old lady with hypertension and chronic atrial fibrillation (AF) developed chest pain followed by ventricular fibrillation (VF) cardiac arrest. Her electrocardiogram post-cardioversion revealed inferior ST-elevation myocardial infarction (MI). Her coronary arteries were angiographically normal. Contrast-enhanced cardiac magnetic resonance(CE-CMR) demonstrated both an inferior subendocardial infarction and left atrial (LA) appendage thrombus suggesting cardioembolism as the most likely cause of her presentation.     

Clostridium difficile associated diarrhea: new rules for an old game

C. difficile associated diarrhea (CDAD) is now considered to be one of the commonest causes of nosocomial diarrhea. CDAD, once considered to be a "nuisance" disease, has lately become a "killer" disease with appearance of a hypervirulent strain, toxinotype III. Although the incidence and severity of CDAD have increased in the western world especially in health care settings; it still is under-recognized in India and Asia. Any episode of diarrhea with fever and leucocytosis in a patient on some antibiotics in a health care setting is strong pointer towards presence of CDAD. Clinical suspicion is usually confirmed by ELISA based C. difficile toxin assays in the stool sample. The aim of therapy is to restore normal colonic microflora, resulting in the elimination of C. difficile. Treatment of C.difficile needs to be individualized depending on the severity of the disease and patient characteristics. Majority of patients will require antibiotic therapy and, whenever possible, discontinuation of the predisposing antibiotics. Metronidazole and vancomycin are the mainstay of the treatment of CDAD, as both these agents are highly active against all strains of pathogenic C.difficile. Neither of these drugs is however effective for the carrier state of C. difficile. Approximately 15%-30% of patients experience a symptomatic recurrence after discontinuation of antibiotics. Control of health care associated CDAD involves a range of primarily preventive measures including proper hand hygiene, use of personal protective equipment, environmental decontamination, isolation or cohort nursing and adequate treatment of CDAD cases.     

Sequential testing with different tissue transglutaminase antibodies,a new approach for diagnosis of celiac disease

Background

The diagnosis of celiac disease (CeD) in clinical practice relies on serological testing for IgA antibodies to human tissue transglutaminase (anti-tTG) which diagnose CeD autoimmunity. We compared three kits for their performance in diagnosis of the disease and evaluated the point prevalence of CeD autoimmunity in a South Indian urban population.

Methods

In the first part of the study, sera from 90 patients with documented CeD and 92 healthy controls were tested for anti-tTG using three different kits. One thousand nine hundred and seventeen healthy adults residing in urban areas of Vellore and Kancheepuram districts were tested for CeD autoimmunity using a sequential two-test strategy.

Results

The sensitivity, specificity, false positivity, false negativity, positive predictive value, and negative predictive value for the three assays respectively were as follows: 95.5%, 82.6%, 17.3%, 4.4%, 84.3%, and 95% for the Aeskulisa New Generation Assay; 85.5%, 100%, 0%, 14.4%, 100%, and 87.6% for Quanta Lite; and 71.1%, 100%, 0%, 28.8%, 100%, and 71% for Celiac Microlisa. The ROC curves showed good discrimination for all three ELISAs with an AUC of 0.947, 0.950, and 0.886 for the Aeskulisa, Quanta Lite, and Celiac Microlisa, respectively. Of 1917 (males 908, females 1009) healthy adults, 113 (5.89%) were seropositive for IgA anti-htTG in the Aeskulisa test. Two of the latter tested positive in the Quanta Lite assay and/or the Celiac Microlisa assay. The CeD autoimmunity prevalence in this urban population was 1.0 per thousand (95% confidence interval 0.3 to 3.7 per thousand).

Conclusion

Sequential testing for anti-tTG using first a highly sensitive assay followed by a very specific assay is a new strategy for screening for CeD in clinical practice.

     

Impact of Obesity on Outcomes of Pregnancy in Women With Heart Disease

BackgroundWomen with heart disease are at risk for complications during pregnancy. This study sought to examine the effect of maternal obesity on pregnancy complications in women with heart disease.ObjectivesThe objective was to determine the incidence of adverse cardiac events (CE) in pregnant women with heart disease and obesity.MethodsAdverse CE during pregnancy were examined in a prospective cohort of women with heart disease. CE were a composite of the following: cardiac death/arrest, arrhythmias, heart failure, myocardial infarction, stroke, aortic dissection, and thromboembolic events. Pre-eclampsia and post-partum hemorrhage were also studied. Outcomes were examined according to body mass index (BMI). To identify additional predictors of CE, a baseline risk score (CARPREG [Canadian Cardiac Disease in Pregnancy Study] II score) for predicting cardiac complications was calculated for all pregnancies and included in a multivariable logistic regression model.ResultsOf 790 pregnancies, 19% occurred in women with BMI ≥30 kg/m² (obesity), 25% in women with BMI 25 to 29.9 kg/m² (overweight), 53% in women with BMI 18.5 to 24.9 kg/m² (normal weight), and 3% in women with BMI <18.5 kg/m² (underweight). Women with obesity were at higher risk of CE when compared with women with normal weight (23% vs. 14%; p = 0.006). In a multivariable model, obesity (odds ratio: 1.7; 95% confidence interval: 1.0 to 2.7) and higher CARPREG II risk scores (odds ratio: 1.7; 95% confidence interval: 1.5 to 1.9) predicted CE. Pre-eclampsia was more frequent in women with obesity compared with those with normal weight (8% vs. 2%; p = 0.001).ConclusionsObesity increases the risk of maternal cardiovascular complications in pregnant women with heart disease. This modifiable risk factor should be addressed at the time of preconception counseling.     

African League Against Rheumatism (AFLAR) preliminary recommendations on the management of rheumatic diseases during the COVID-19 pandemic

Objectives

To develop recommendations for the management of rheumatic and musculoskeletal diseases (RMDs) during the COVID-19 pandemic.

Method

A task force comprising of 25 rheumatologists from the 5 regions of the continent was formed and operated through a hub-and-spoke model with a central working committee (CWC) and 4 subgroups. The subgroups championed separate scopes of the clinical questions and formulated preliminary statements of recommendations which were processed centrally in the CWC. The CWC and each subgroup met by several virtual meetings, and two rounds of voting were conducted on the drafted statements of recommendations. Votes were online-delivered and recommendations were pruned down according to predefined criteria. Each statement was rated between 1 and 9 with 1–3, 4–6 and 7–9 representing disagreement, uncertainty and agreement, respectively. The levels of agreement on the statements were stratified as low, moderate or high according to the spread of votes. A statement was retired if it had a mean vote below 7 or a ‘low’ level of agreement.

Results

A total of 126 initial statements of recommendations were drafted, and these were reduced to 22 after the two rounds of voting.

Conclusions

The preliminary statements of recommendations will serve to guide the clinical practice of rheumatology across Africa amidst the changing practices and uncertainties in the current era of COVID-19. It is recognized that further updates to the recommendations will be needed as more evidence emerges.

Risk of malignancy in patients with celiac disease

PURPOSE: Studies from Europe have demonstrated an increased risk of malignancy, especially non-Hodgkin's lymphoma, in patients with celiac disease. However, there are no data on the risk for similar patients in the United States. Our aim was to estimate the risk of malignancy in a cohort of patients with celiac disease compared with the general U.S. population and to determine if a gluten-free diet is protective. METHODS: Patients with celiac disease seen between July 1981 and January 2000 at a referral center were included. Standardized morbidity ratios (SMRs) (ratio of observed to expected) and corresponding 95% confidence intervals (CI) were calculated, using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. RESULTS: Forty-three (11%) of 381 celiac disease patients had a diagnosis of cancer; 9 were after the diagnosis of celiac disease, 7 were simultaneous (during same month or admission), and 27 were before the diagnosis. The standardized morbidity ratio for all cancers combined was 1.5 (95% CI: 0.3 to 7.5), with significantly increased values for small bowel cancer (SMR = 34; 95% CI: 24 to 42), esophageal cancer (SMR = 12; 95% CI: 6.5 to 21), non-Hodgkin's lymphoma (SMR = 9.1; 95% CI: 4.7 to 13), and melanoma (SMR = 5.0; 95% CI: 2.1 to 12). Following the diagnosis of celiac disease, patients were at increased risk of non-Hodgkin's lymphoma only (SMR = 6.2; 95% CI: 2.9 to 14), despite adherence to a gluten-free diet. The non-Hodgkin's lymphoma included both T-cell and B-cell types and occurred in both gastrointestinal (n = 5) and extraintestinal sites (n = 4). CONCLUSION: In this cohort of patients with celiac disease, we observed increased risks of small intestinal adenocarcinoma, esophageal cancer, melanoma, and non-Hodgkin's lymphoma. The risk of non-Hodgkin's lymphoma persisted despite a gluten-free diet.     

Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis

The ubiquitin-proteasome system degrades viral oncoproteins and other microbial virulence factors; however, the role of endolysosomal degradation pathways in these processes is unclear. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma, and a constitutively active viral G protein-coupled receptor (vGPCR) contributes to the pathogenesis of KSHV-induced tumors. We report that a recently discovered autophagy-related protein, Beclin 2, interacts with KSHV GPCR, facilitates its endolysosomal degradation, and inhibits vGPCR-driven oncogenic signaling. Furthermore, monoallelic loss of Becn2 in mice accelerates the progression of vGPCR-induced lesions that resemble human Kaposi’s sarcoma. Taken together, these findings indicate that Beclin 2 is a host antiviral molecule that protects against the pathogenic effects of KSHV GPCR by facilitating its endolysosomal degradation. More broadly, our data suggest a role for host endolysosomal trafficking pathways in regulating viral pathogenesis and oncogenic signaling.Phagocytosis and autophagy are two processes that deliver microbes and their constituent proteins to the lysosome for degradation, thereby contributing to the clearance of pathogens and to the presentation of peptide antigens to T cells (1, 2). However, it is not known whether endocytic internalization and lysosomal targeting of virus-encoded cell-surface receptors contributes to the control of viral infection and disease.Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of AIDS-related and other forms of Kaposi’s sarcoma (KS), primary effusion lymphoma, and multicentric Castleman’s disease (3–5). KS is a multifocal tumor characterized by proliferating spindle cells (possibly of endothelial origin), angiogenesis, vascular slits, erythrocyte extravasation, and inflammatory cells. Proinflammatory signaling by the dominant KS cell, the spindle cell, is considered the driving force in KS lesions (6). The risk of KSHV-associated malignancies increases with increased lytic viral replication (7–9), suggesting that KSHV-induced oncogenesis may be related to the levels of expression of viral oncoproteins.The oncogenic KSHV G protein-coupled receptor (vGPCR), encoded by the KSHV ORF74 lytic gene, is a constitutively active chemokine receptor expressed in patients with KSHV-associated tumors (10). At least in animal studies, there are strong data that vGPCR substantially contributes to the onset and progression of KSHV-associated neoplasia in vivo (11–19). Although only a small proportion of tumor cells express vGPCR (10), they are both sufficient and necessary for KSHV-induced sarcomagenesis. The endothelial-specific expression of vGPCR (but of neither KSHV latent genes, such as vCyclin, vFlip, and Kaposin, nor other KSHV lytic genes, such as vBcl-2 or vIRF1) or injection of murine endothelial cells stably expressing vGPCR (but not other KSHV genes, such as vCyclin, vFlip, Kaposin, LANA, vIL-6, vBcl-2, and K1) causes multifocal KS-like tumors in mice (15, 18). Furthermore, injection of a small number of endothelial cells expressing vGPCR increases the tumorigenic potential, in a paracrine fashion, of endothelial cells expressing other KSHV latent genes (vCyclin and vFlip), whereas eradication of the small number of vGPCR-expressing cells in established mix-cell tumors induces tumor regression (15, 18). Moreover, in a nude mouse model of KS driven by transfection of a KSHV bacterial artificial chromosome into bone marrow endothelial-lineage cells, siRNA interference (RNAi)-mediated suppression of vGPCR expression dramatically reduces angiogenesis and tumor formation (19). In addition, immunocompetent mice that transgenically express doxycycline (DOX)-inducible KSHV GPCR in endothelial cells (hereafter referred to as ikGPCR⁺) manifest lesions that strongly resemble human Kaposi’s sarcoma (16, 17). Importantly, the progression of lesions in ikGPCR⁺ mice is reversible because DOX withdrawal leads to significant regression of vGPCR-induced lesions (17), suggesting that vGPCR-driven oncogenesis is highly dependent on sustained vGPCR expression and signaling.Based on these previous observations in animal models regarding KSHV GPCR and oncogenesis, we developed the hypothesis that cell-intrinsic mechanisms that decrease vGPCR protein levels may function as an important host defense mechanism for controlling viral oncogenesis. Recently, we showed that the autophagy protein, Beclin 2 (but not the related autophagy protein Beclin 1) is essential for the endolysosomal degradation of certain cellular GPCRs that are regulated by GASP1 rather than by ubiquitination and the endosomal sorting complexes required for the transport pathway (20). This function of Beclin 2, but not Beclin 1, regulates mouse brain cannabinoid receptor levels and metabolism in vivo (20). Therefore, we investigated whether Beclin 2 may play a role in the endolysosomal degradation of viral GPCRs and thereby represent an important host defense mechanism against KSHV GPCR-induced oncogenic effects. Our results demonstrate a crucial role for Beclin 2 in KSHV GPCR trafficking, proinflammatory signaling, and in vivo tumorigenicity, and thus represent a previously undescribed role for endolysosomal trafficking in innate immunity and the control of viral GPCR-driven oncogenesis.     

Asia Pacific Consensus Statements on Crohn's disease. Part 1: Definition,diagnosis, and epidemiology

Inflammatory bowel disease (IBD) was previously thought to be rare in Asia, but emerging data indicate rising incidence and prevalence of IBD in the region. The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology with the goal of developing best management practices, coordinating research, and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis with specific relevance to the Asia‐Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis, and management of Crohn's disease. The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia‐Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses, and treatment availability. It does not intend to be all comprehensive and future revisions are likely to be required in this ever‐changing field.