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BackgroundEmergency departments (EDs) are the front line in providing suicide care. Expert consensus recommends the delivery of several suicide prevention evidence-based interventions for individuals with acute suicidal ideation in the ED. ED personnel demands and staff shortages compromise delivery and contribute to long wait times and unnecessary hospitalization. Digital technologies can play an important role in helping EDs deliver suicide care without placing further demands on the care team if their use is safe to patients in a routine care context. ObjectiveThis study evaluates the safety and effectiveness of an evidence-based digital technology (Jaspr Health) designed for persons with acute suicidal ideation seeking psychiatric crisis ED services when used as part of routine ED-based suicide care. This study deployed Jaspr Health for real-world use in 2 large health care systems in the United States and aimed to evaluate (1) how and whether Jaspr Health could be safely and effectively used outside the context of a researcher-facilitated clinical trial, and (2) that Jaspr’s use would be associated with improved patient agitation and distress. MethodsUnder the auspices of a nonsignificant risk device study, ED patients with acute suicidal ideation (N=962) from 2 health care systems representing 10 EDs received access to Jaspr Health as part of their routine suicide care. Primary outcome measures included how many eligible patients were assigned Jaspr Health, which modules were assigned and completed, and finally, the number of adverse events reported by patients or by medical staff. Secondary outcome measures were patient agitation, distress, and satisfaction. ResultsThe most frequent modules assigned were Comfort and Skills (98% of users; n=942) and lethal means assessment (90% of patient users; n=870). Patient task completion rates for all modules ranged from 51% to 79%. No adverse events were reported, suggesting that digital technologies can be safely used for people seeking ED-based psychiatric services. Statistically significant (P

Introduction: Shoulder pain is a common clinical presentation and can be attributed to an anatomically anomalous insertion of the Pectoralis Minor (PMn) muscle tendon into the glenohumeral joint capsule. Therefore, understanding these anomalous patterns is crucial for clinicians in diagnosing and treating patients to prevent misdiagnosis and iatrogenic injury. Aim: To analyse the morphological patterns in the origin and insertion of the PMn muscle and to assess the morphometric dimensions of the muscle. Materials and Methods: This observational cross-sectional study was conducted on 60 upper limbs from 30 embalmed cadavers of both sexes. The specimens were obtained from the Department of Anatomy, ESIC Medical College and Hospital, Hyderabad, Telangana, India, between November 2018 and January 2023. The PMn muscles were thoroughly examined, and the various patterns in the origin and insertion were recorded. The length of the muscle was measured from the sternocostal junction of the inferior aspect of the fourth rib to the medial border of the coracoid process. The width of the muscle was measured at the midclavicular line and at the insertion. The frequency and percentage of each pattern were recorded and statistically analysed. Results: The present study found that the origin of PMn Type-2 was predominantly observed, with an incidence of 86.6%. Type-1 was observed in 6.7% of the upper limbs, while Type-3 was observed in 6.7% as well. Regarding the insertion of the PMn, Type-1 was predominantly observed, with an incidence of 76.7%. Type-2 was observed in 20% of the upper limbs, and Type-3 in 3.3%. The average length of the muscle was 14.01 cm, while the average width at the midclavicular line and at the insertion were 6.16 cm and 1.69 cm, respectively. Conclusion: A high incidence of Type-2 patterns in the origin, and Type-1 was predominant in the insertion of the pectoralis minor muscle. Knowledge of the morphometric measurements of the PMn muscle would be valuable for surgeons performing surgeries in the shoulder and pectoral region.

The Aschner-Dagnini reflex, also known as the Oculocardiac Reflex (OCR) or Trigeminovagal Reflex (TVR), is characterised by a reduction in heart rate due to direct pressure on the globe or traction on the Extraocular Muscles (EOM). It was first described in 1908 and is observed during strabismus surgery. However, it has also been reported following other ophthalmic procedures such as pterygium surgery or gonioscopy, as well as after facial trauma or regional anaesthesia. Sinus bradycardia is the most common presentation, accompanied by nausea and dizziness in conscious patients. In severe cases, it may also result in reduced blood pressure and life-threatening emergencies, including cardiac arrhythmias and arrest. Hereby, the authors present a rare case report of a 34-year-old male with delayed onset OCR following pterygium surgery under topical anaesthesia. The case was managed conservatively, as described in the case report, and the patient had a good recovery. To the best of authors’ knowledge, the present is the first reported case of OCR in the early postoperative period, following pterygium surgery.

P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance and mediates the bioavailability and pharmacokinetics of many drugs (Juliano and Ling, 1976; Ueda et al., 1986; Sharom, 2011). Decades of structural and biochemical studies have provided insights into how Pgp binds diverse compounds (Loo and Clarke, 2000; Loo et al., 2009; Aller et al., 2009; Alam et al., 2019; Nosol et al., 2020; Chufan et al., 2015), but how they are translocated through the membrane has remained elusive. Here, we covalently attached a cyclic substrate to discrete sites of Pgp and determined multiple complex structures in inward- and outward-facing states by cryoEM. In conjunction with molecular dynamics simulations, our structures trace the substrate passage across the membrane and identify conformational changes in transmembrane helix 1 (TM1) as regulators of substrate transport. In mid-transport conformations, TM1 breaks at glycine 72. Mutation of this residue significantly impairs drug transport of Pgp in vivo, corroborating the importance of its regulatory role. Importantly, our data suggest that the cyclic substrate can exit Pgp without the requirement of a wide-open outward-facing conformation, diverting from the common efflux model for Pgp and other ABC exporters. The substrate transport mechanism of Pgp revealed here pinpoints critical targets for future drug discovery studies of this medically relevant system.

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

Halogen bonding has emerged as a promising tool in two-dimensional (2D) crystal engineering. Since halogen bonds are similar to hydrogen bonds in a number of aspects, the existing knowledge of hydrogen bonded systems can be applied to halogenated systems. Here we evaluate the applicability of a retrosynthetic approach based on topological similarity between hydrogen and halogen bonds to obtain predictable halogen bonded networks. The self-assembly of 1,3-dibromo-5-alkoxybenzene derivatives was studied in analogy with well-explored alkoxy isophthalic acids using a combination of experimental and theoretical tools. Scanning tunneling microscopy (STM) characterization of the networks formed at the liquid-graphite interface revealed that while the retrosynthetic approach works at the level of small clusters of molecules within the 2D network, the overall structure of the network deviates from the anticipated structure. The monolayers consist of fractured rows of halogen-bonded modules instead of the expected continuous lamellar structure. Each module consists of a discrete number of halogen-bonded molecules. The interactions responsible for the stabilization of halogen bonded dimers are delineated through detailed density functional theory (DFT) calculations coupled with natural bonding orbitals (NBO) and perturbation analysis. A modified force field that includes an extra charged site to imitate the σ hole on the halogen atom was developed and applied to extract total potential energies of the anticipated and observed networks. Plausible reasons for the deviation from the anticipated structure are discussed. Finally, a modified molecular design that allows successful application of the hydrogen bond-halogen bond analogy was tested experimentally.

Summary: Janus kinases (JAKs) mediate signal transduction downstream of cytokine receptors. Cytokine-dependent dimerization is conveyed across the cell membrane to drive JAK dimerization, trans-phosphorylation, and activation. Activated JAKs in turn phosphorylate receptor intracellular domains (ICDs), resulting in the recruitment, phosphorylation, and activation of signal transducer and activator of transcription (STAT)-family transcription factors. The structural arrangement of a JAK1 dimer complex with IFNλR1 ICD was recently elucidated while bound by stabilizing nanobodies. While this revealed insights into the dimerization-dependent activation of JAKs and the role of oncogenic mutations in this process, the tyrosine kinase (TK) domains were separated by a distance not compatible with the trans-phosphorylation events between the TK domains. Here, we report the cryoelectron microscopy structure of a mouse JAK1 complex in a putative trans-activation state and expand these insights to other physiologically relevant JAK complexes, providing mechanistic insight into the crucial trans-activation step of JAK signaling and allosteric mechanisms of JAK inhibition.

INTRODUCTION Post operative pain is the most common complaint in post anaesthesia care units (PACU). Lower abdominal surgeries are associated with severe post-operative pain and inadequate post-operative analgesia leads to many complications. Multimodality approach is used to treat postoperative pain. Transversus abdominus plane (TAP) block is a peripheral nerve block of the trunk that provides analgesia between T10 to L1 dermatomes with a single injection which was first described by A.N. Rafi 1 in 2001 . TAP Block is indicated in any lower abdominal surgeries. Local anaesthetic is deposited in the fascial sheath between the internal oblique and transverse abdominis muscle using either the blind or the ultrasound guided technique. Adjuvants are frequently used in regional analgesia for rapid onset to improve the quality and prolong the duration of block. Alpha 2 agonist dexmedetomidine speeds the onset of block and prolongs duration of analgesia. Aim : To assess whether addition of dexmedetomidine to ropivacaine may bring some improvements to the analgesic efficacy and quality of TAP blocks in patients undergoing appendicectomy surgeries . MATERIALS AND METHODS 30 Patients belonging to ASA Class I or II scheduled for appendicectomy were selected for the study . The patients were randomized into two groups: Group R - receiving plain ropivacaine (2ml of normal saline and 20ml 0.2%ropivacaine) Group R+D - receiving ropivacaine with dexmedetomidine (0.5 mcg /kg of dexmedetomidine dissolved in 2ml of normal saline and 20ml 0.2%ropivacaine). At the end of surgery, USG guided transversus abdominus plane block was performed. Results Addition of dexmedetomidine to ropivacine in TAP block lower pain scores after 3hrs in postoperative period and the same trend of analgesia continued for the first 24 hours. It confers better post operative analgesia with less analgesic requirement and adverse effects. Conclusion: The addition of dexmedetomidine to ropivacaine in TAP block confers better pain control and decreases the total dose of analgesics post-operatively without any major side-effects

Background: Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) can present with overlapping symptoms, making diagnosis and management challenging. Patients with IBD in remission may continue to experience IBS symptoms. Patients with IBS were found to have a disproportionately higher prevalence of abdominal and pelvic surgeries than the general population. Aims: The aim of this study was to determine whether IBS is a risk factor for undergoing surgical interventions in patients with IBD and explore the diagnostic implications of these findings. Methods: A population-based cohort analysis was performed using TriNetX. Patients with Crohn’s disease + IBS (CD + IBS) and ulcerative colitis + IBS (UC + IBS) were identified. The control groups consisted of patients with CD or UC alone without IBS. The main outcome was to compare the risks of undergoing surgical interventions between the cohorts. The secondary outcomes were to compare the risks of developing gastrointestinal symptoms and IBD-related complications between the cohorts. Results: Patients with IBD who subsequently developed IBS were more likely to experience gastrointestinal symptoms than those without IBS (p < 0.0001). Patients with concomitant IBD and IBS were more likely to develop IBD-related complications, including perforation of the intestine, gastrointestinal bleeding, colon cancer, and abdominal abscess (p < 0.05). Patients with concomitant IBD and IBS were more likely to undergo surgical interventions than patients without IBS, including colectomy, appendectomy, cholecystectomy, exploratory laparotomy, and hysterectomy (p < 0.05). Conclusions: IBS appears to be an independent risk factor for patients with IBD to develop IBD-related complications and undergo surgical interventions. Patients with concomitant IBD and IBS could represent a unique subgroup of IBD patients with more severe symptoms, highlighting the importance of accurate diagnosis and management in this population.

Sara Ghoneim,1 Aun Shah,1 Aneesh Dhorepatil,1 Muhammad Umer Butt,2 Nisheet Waghray3 1Department of Internal Medicine, Case Western Reserve University at MetroHealth Medical Center, Cleveland, OH 44109, USA; 2Division of Cardiology, Case Western Reserve University at MetroHealth Medical Center, Cleveland, OH 44109, USA; 3Division of Gastroenterology, Case Western Reserve University at MetroHealth Medical Center, Cleveland, OH 44109, USACorrespondence: Sara GhoneimDepartment of Internal Medicine, Case Western Reserve University at MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109, USATel +1-216-777-0498Email saragho@gmail.comBackground: Inflammatory bowel disease (IBD) has been associated with an increased risk of cardiovascular events, but the risk of cerebrovascular accidents (CVA) remains unknown. Hypercoagulability and systemic inflammation are two proposed mechanisms by which the presence of IBD might lead to the development of CVA.Objective: To assess the risk of CVA in patients with IBD compared to those without IBD with known traditional risk factors for CVA.Methods: We reviewed data from a large commercial database (Explorys, IBM) that aggregated records from 26 health-care systems nationwide. Using systemized nomenclature of medicine – clinical terms, we identified adult patients diagnosed with IBD (ulcerative colitis or Crohn’s disease) between September 1994 and September 2019. We then examined the risk of CVA in these patients. Known risk factors such as age ≥ 65-years old, diabetes mellitus (DM), hypertension (HTN), female gender, atrial fibrillation (Afib) were collected. A univariate binary logistic model was constructed using CVA as the dependent variable and other variables as independent variables. To adjust for possible confounding, a multivariable model adjusting for all covariates was created to test for CVA.Results: A total of 52,176,550 patients were included in this analysis, and 261,890 had IBD. The prevalence of CVA was higher in IBD patients compared to non-IBD patients (6.24% versus 0.48%, p < 0.0001). The univariate binary logistic regression showed 13.7 times higher odds of having CVA in IBD patients than without IBD (odds ratio (OR) 13.74, p < 0.0001). In multivariate binary logistic regression, after adjusting for traditional risk factors for CVA (Afib, HTN, female gender, DM, age ≥ 65 years), odds ratio of CVA in IBD patients remained significantly higher (OR 8.07, 95% CI: 7.9– 8.2, p< 0.0001).Conclusion: In our large cohort of patients, IBD appears to be an independent risk factor for CVA. Further prospective studies are needed to understand the underlying mechanisms by which IBD increases the risk of CVA. This may lead to early identification and intervention to reduce the risk of CVA in this highly heterogeneous group of patients.Keywords: inflammatory bowel disease, cerebrovascular accident, IBD, CVA

Introduction: Retinal arterio-venous malformations (AVMs) are rare, congenital, high-flow congenital developmental vascular anomalies without intervening capillary bed also known as racemose angioma, They are unilateral, nonhereditary lesions located anywhere in retina and may involve optic nerve. Case report: A 55 year old male was found to have abnormal congenital arterio-venous malformation over optic nerve head in his left eye, as an incidental clinical finding. He had reported for his routine fundus examination due to diabetes. He had no other relevant systemic findings. Further follow up was advised to see the progression of the lesion and structural damage to optic nerve. Discussion: The typical clinical picture, fluorescein angiogram findings, normal MRI brain and orbits, and normal base line blood investigations all points in favour of a congenital arterio-venous malformation. Conclusion: Arterio- venous malformations of Optic nerve head are very rare to find as compared to retinal malformations. This is the first such case report from India.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ≥10 years) and short-term survival patients (STS, survival

Abstract Follicular lymphoma of the colon is rare, accounting for 1% to 2% of cases in the gastrointestinal tract. Despite the absence of randomized clinical trials, NCCN stage III and IV colonic follicular lymphomas are routinely treated with chemotherapy with good clinical response. We present 2 cases of advanced stage follicular lymphoma of colon that were effectively treated with bendamustine‐based chemotherapy regimens.

Background and study aims Incidence of Post-ERCP pancreatitis (PEP) ranges from 1 % to 10 % in unselected patients and as high as 25 % to 30 % in high-risk patients. Rectal indomethacin administered before or immediately after an ERCP and prophylactic pancreatic duct stent placement (PPS) are associated with a reduction in the incidence of PEP. We sought to investigate the utilization rate for prophylactic rectal indomethacin and PPS in average and high-risk patients undergoing ERCP between 2014 and 2019. Patients and methods We performed a retrospective analysis in the IBM Explorys database, a pooled, national de-identified clinical database of over 72 million unique patients from 26 health care networks and 300 hospitals across the United States from 2014 to 2019. Average and high-risk patients undergoing ERCP were identified using Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) diagnosis codes. PEP was defined by the presence of SNOMED CT diagnosis of acute pancreatitis and an inpatient admission within 5 days of an ERCP procedure. Results Out of 31,050 adults who had undergone ERCP from 2014 to 2019, only 10,500 individuals (33.8 %) had a PEP prophylaxis. Rectal indomethacin and PPS accounted for 82.4 % and 12.9 % respectively. Individuals with three risk factors had the highest PEP rates followed by individuals with two risk factors. Conclusions Only one-third of all patients undergoing ERCP received prophylaxis in the form of rectal indothemacin and/or PPS in this large population-based data. Increased implementation of prophylactic use is needed in patients undergoing ERCP as supported by current guidelines.

Community-acquired bacterial pneumonia (CABP) is one of the leading causes of morbidity and mortality in India and worldwide. Evidence indicates that Gram-positive, Gram-negative, and atypical bacteria are encountered with near-equal frequency. Despite guideline recommendations and antibiotic options for the management of CABP, burden of morbidity and mortality is high, which is attributable to a variety of factors. Failure of empirical therapy, probably because of insufficient microbial coverage, increasing bacterial resistance, and adverse effects of existing treatments, underlies the unsuccessful treatment of CABP, especially in India. Multiple novel therapies that have entered clinical development phases have potential to address some of these issues. This article discusses the current treatment guidelines in CABP, management limitations, and emerging potential treatment options in the management of CABP.

Summary: Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.

Translation of hepatitis C viral proteins requires an internal ribosome entry site (IRES) located in the 5' untranslated region of the viral mRNA. The core domain of the hepatitis C virus (HCV) IRES contains a four-way helical junction that is integrated within a predicted pseudoknot. This domain is required for positioning the mRNA start codon correctly on the 40S ribosomal subunit during translation initiation. Here, we present the crystal structure of this RNA, revealing a complex double-pseudoknot fold that establishes the alignment of two helical elements on either side of the four-helix junction. The conformation of this core domain constrains the open reading frame's orientation for positioning on the 40S ribosomal subunit. This structure, representing the last major domain of HCV-like IRESs to be determined at near-atomic resolution, provides the basis for a comprehensive cryoelectron microscopy-guided model of the intact HCV IRES and its interaction with 40S ribosomal subunits.

Frizzleds (Fzd) are the primary receptors for Wnt morphogens, which are essential regulators of stem cell biology, yet the structural basis of Wnt signaling through Fzd remains poorly understood. Here we report the structure of an unliganded human Fzd5 determined by single-particle cryo-EM at 3.7 Å resolution, with the aid of an antibody chaperone acting as a fiducial marker. We also analyzed the topology of low-resolution XWnt8/Fzd5 complex particles, which revealed extreme flexibility between the Wnt/Fzd-CRD and the Fzd-TM regions. Analysis of Wnt/β-catenin signaling in response to Wnt3a versus a ‘surrogate agonist’ that cross-links Fzd to LRP6, revealed identical structure-activity relationships. Thus, canonical Wnt/β-catenin signaling appears to be principally reliant on ligand-induced Fzd/LRP6 heterodimerization, versus the allosteric mechanisms seen in structurally analogous class A G protein-coupled receptors, and Smoothened. These findings deepen our mechanistic understanding of Wnt signal transduction, and have implications for harnessing Wnt agonism in regenerative medicine.

Ultrathin metallic films are most often fabricated by atomic or molecular beam epitaxy under ultrahigh vacuum conditions, where it is difficult to control deposition and growth. Here, the authors describe a wet deposition method, using solution-borne gold nanocluster precursors, to regulate growth of atomically flat gold nanoislands on a surface.

The hepatitis C virus (HCV) genomic RNA contains an internal ribosome entry site (IRES) in its 5' untranslated region, the structure of which is essential for viral protein translation. The IRES includes a predicted pseudoknot interaction near the AUG start codon, but the results of previous studies of its structure have been conflicting. Using mutational analysis coupled with activity and functional assays, we verified the importance of pseudoknot base pairings for IRES-mediated translation and, using 35 mutants, conducted a comprehensive study of the structural tolerance and functional contributions of the pseudoknot. Ribosomal toeprinting experiments show that the entirety of the pseudoknot element positions the initiation codon in the mRNA binding cleft of the 40S ribosomal subunit. Optimal spacing between the pseudoknot and the start site AUG resembles that between the Shine-Dalgarno sequence and the initiation codon in bacterial mRNAs. Finally, we validated the HCV IRES pseudoknot as a potential drug target using antisense 2'-OMe oligonucleotides.

Embryonic stem cells (ESCs) can proliferate and self-renew, maintaining their pluripotency status in vitro for a long period of time. Pluripotent states of ESCs in vitro are supported by a network of signaling, transcriptional and epigenetic regulatory interactions known as the pluripotency gene regulatory network (PGRN). Despite extensive investigation of the network, the exact order of regulatory links and many structural features of the network are still missing. Analysis of published data and literature reveals numerous PGRN components regulating each other in a mutual fashion, thus creating multiple regulatory feedback control circuits. Here we consider possible organizational features of PGRN and describe examples representing known feedback control loops in the context of mouse ESCs. We discuss how the feedback control interactions can contribute to learning behavior and dynamic responses of pluripotency gene network to changing environments. Keywords: Embryonic stem cells, Gene networks, Feedback control, Cellular memory

Notch signaling plays a role in specifying a cardiac fate but the downstream effectors remain unknown. In this study we implicate the Notch downstream effector HES5 in cardiogenesis. We show transient Hes5 expression in early mesoderm of gastrulating embryos and demonstrate, by loss and gain-of-function experiments in mouse embryonic stem cells, that HES5 favors cardiac over primitive erythroid fate. Hes5 overexpression promotes upregulation of the cardiac gene Isl1, while the hematopoietic regulator Scl is downregulated. Moreover, whereas a pulse of Hes5 instructs cardiac commitment, sustained expression after lineage specification impairs progression of differentiation to contracting cardiomyocytes. These findings establish a role for HES5 in cardiogenesis and provide insights into the early cardiac molecular network.

Introduction: The science of dental implantology has evolved exponentially in the recent past but the intricacies in the selection of implant site, size and angulations has always been challenging to the clinician and it is very difficult to meet these challenges without dental imageology. Aims: To compare panoramic radiography with computed tomography (CT) and radiovisiography to analyze the relative advantages and disadvantages of these modalities. Materials and Methods: Total 27 sites in 20 patients of mandibular posterior molar edentulous areas were radiographed with four different radiographic methods. The implant sites were selected and the height of the available bone, the mean width of the available crestal bone and density were measured using all the three techniques (except density which was measured on CT alone). Comparison of all the values obtained with the three imaging modalities was done and data tabulated for statistical analysis. The one way analysis of variance (ANOVA) with post hoc analysis using least significance method (LSD) was used to test the differences between each group using the SPSS software version 16. Results: The mean value of vertical measurements using conventional OPG, panoramic CT, RVG, and paraxial CT was found to be 19.32, 18.43, 19.09, and 16.81 mm, respectively. The mean value of density of the bone using paraxial CT was found to be 631.23 HU with a standard deviation of 123.14. The mean value of width of the crestal bone below the height of the crest using paraxial CT was found to be a maximum of 14.03 mm and a minimum of 5.86 mm. Conclusion: The overall results suggested that the paraxial view of CT was better in assessing the parameters of implant site when compared to the other three modalities.

Loss-of-function approaches are fundamental for dissecting the roles played by genes but methods to simultaneously perturb several proteins in the same mammalian cell are scarce. Here the authors harness the plant auxin and jasmonate hormone-degradation pathways and RNAi technology, to control the levels of two proteins and validate its application in stem cells.

The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a human PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of POU5F1/OCT4 expression. Conversely, HNF1A overexpression increased PCSC marker expression and tumorsphere formation in pancreatic cancer cells and drove pancreatic ductal adenocarcinoma (PDA) cell growth. Importantly, depletion of HNF1A in xenografts impaired tumor growth and depleted PCSC marker-positive cells in vivo. Finally, we established an HNF1A-dependent gene signature in PDA cells that significantly correlated with reduced survivability in patients. These findings identify HNF1A as a central transcriptional regulator of PCSC properties and novel oncogene in PDA.

Human cytomegalovirus has hijacked and evolved a human G-protein-coupled receptor into US28, which functions as a promiscuous chemokine 'sink’ to facilitate evasion of host immune responses. To probe the molecular basis of US28’s unique ligand cross-reactivity, we deep-sequenced CX3CL1 chemokine libraries selected on ‘molecular casts’ of the US28 active-state and find that US28 can engage thousands of distinct chemokine sequences, many of which elicit diverse signaling outcomes. The structure of a G-protein-biased CX3CL1-variant in complex with US28 revealed an entirely unique chemokine amino terminal peptide conformation and remodeled constellation of receptor-ligand interactions. Receptor signaling, however, is remarkably robust to mutational disruption of these interactions. Thus, US28 accommodates and functionally discriminates amongst highly degenerate chemokine sequences by sensing the steric bulk of the ligands, which distort both receptor extracellular loops and the walls of the ligand binding pocket to varying degrees, rather than requiring sequence-specific bonding chemistries for recognition and signaling.

Analyses of gene expression in single mouse embryonic stem cells (mESCs) cultured in serum and LIF revealed the presence of two distinct cell subpopulations with individual gene expression signatures. Comparisons with published data revealed that cells in the first subpopulation are phenotypically similar to cells isolated from the inner cell mass (ICM). In contrast, cells in the second subpopulation appear to be more mature. Pluripotency Gene Regulatory Network (PGRN) reconstruction based on single-cell data and published data suggested antagonistic roles for Oct4 and Nanog in the maintenance of pluripotency states. Integrated analyses of published genomic binding (ChIP) data strongly supported this observation. Certain target genes alternatively regulated by OCT4 and NANOG, such as Sall4 and Zscan10, feed back into the top hierarchical regulator Oct4. Analyses of such incoherent feedforward loops with feedback (iFFL-FB) suggest a dynamic model for the maintenance of mESC pluripotency and self-renewal.

Tbx3, a member of the T-box family, plays important roles in development, stem cells, nuclear reprogramming, and cancer. Loss of Tbx3 induces differentiation in mouse embryonic stem cells (mESCs). However, we show that mESCs exist in an alternate stable pluripotent state in the absence of Tbx3. In-depth transcriptome analysis of this mESC state reveals Dppa3 as a direct downstream target of Tbx3. Also, Tbx3 facilitates the cell fate transition from pluripotent cells to mesoderm progenitors by directly repressing Wnt pathway members required for differentiation. Wnt signaling regulates differentiation of mESCs into mesoderm progenitors and helps to maintain a naive pluripotent state. We show that Tbx3, a downstream target of Wnt signaling, fine tunes these divergent roles of Wnt signaling in mESCs. In conclusion, we identify a signaling-TF axis that controls the exit of mESCs from a self-renewing pluripotent state toward mesoderm differentiation.

Regenerative endodontic procedures are biologically based procedures which deal with the regeneration of pulp-like tissue, more idealistically the pulp-dentin complex. The regeneration of this pulp-dentin complex in an infected necrotic tooth with an open apex is possible only when the canal is effectively disinfected. Though there are various procedures for treating open apex ranging from Ca(OH) 2 apexification, mineral trioxide aggregate apexification and surgical approach, regeneration of tissues has always taken superior hand over the repair of tissues. The mechanics behind the regenerative endodontic procedures is that despite the tooth being necrotic, some pulp tissue can survive apically which under favorable conditions proliferate to aid in the process of regeneration. In the past 2 decades, an increased understanding of the physiological roles of platelets in wound healing and after tissue injury has led to the idea of using platelets as therapeutic tools in the field regenerative endodontics. In the present case report with an open apex, high sterilization protocol is followed using triple antibiotic paste as intra-canal medicament, followed which platelet rich fibrin is used as the regenerative material of choice. Over an 18-month follow-up period, clinically patient is asymptomatic and radiographically there is complete regression of the periapical lesion and initiation of the root end closure.

Introduction: Osteoporosis is a metabolic bone disease characterized by microarchitectural deterioration in bone tissue leading to fractures, and is essentially a preventable disease when detected in the early stages. Novel methods for early identification of osteoporosis can have a great impact in combating this otherwise progressive disease. Aims: The present study was conducted with the objectives of evaluating the precision of a radiomorphometric index [mental index (MI)] measured on a panoramic radiograph in early diagnosis of osteoporosis and finding its correlation with bone mineral density (BMD) measured by digital X-ray radiogrammetry method. Materials and Methods: The study consisted of 71 women who were in natural menopause. The MI was calculated by two investigators, with each investigator recording two sets of measurements. The BMD was assessed and the T-score was obtained by digital X-ray radiogrammetry method. Based on the T-score obtained, the patients were divided into three study groups of normal (n = 24), osteopenic (n = 30), and osteoporotic (n = 17). The values obtained were tabulated for statistical analysis. Results: In the present study, it was found that there was a statistically significant difference in the mean scores of MI among normal, osteopenic, and osteoporotic subjects. Normal subjects had significantly higher MI (P < 0.001) than the osteopenic subjects and, similarly, the osteopenic subjects had significantly higher MI (P < 0.001) than the osteoporotic subjects. The inter- and intra-investigator variability was found to be low. Conclusion: Based on the results of the present study, it was concluded that a simple radiomorphometric index (MI) which is relatively easier to measure on a panoramic radiograph can be an indicator of osteoporosis and may aid in early detection and treatment planning of one of the most prevalent metabolic bone diseases.

Introduction. The progression of chronic liver disease to cirrhosis involves both innate and adaptive immune system dysfunction resulting in increased risk of infectious complications. Vaccinations against pneumococcus, hepatitis A virus (HAV), and hepatitis B virus (HBV) are well tolerated and effective in disease prevention and reduction in morbidity and mortality. Prior studies assessing vaccination rates in patients with cirrhosis have specific limitations and to date no study has provided a comprehensive evaluation of vaccination rates in patients with cirrhosis in the United States. Aim. This study assessed vaccination rates for pneumococcus, HAV, and HBV in patients with cirrhosis. Results. Overall 59.7% of patients with cirrhosis received at least 1 vaccination during the study period. Vaccination rates within the same or following year of cirrhosis diagnosis were 19.9%, 7.7%, and 11.0% against pneumococcus, HAV, and HBV, respectively. Trend analysis revealed significant increases in vaccination rates for pneumococcus in all patients with cirrhosis and within subgroups based on age, gender, and presence of concomitant diabetes. Conclusion. The study demonstrated that vaccination rates in patients with cirrhosis remain suboptimal. Ultimately, the use of electronic medical record (EMR) reminders improved communication between healthcare professionals and public health programs to increase awareness are fundamental to reducing morbidity, mortality, and health-care related costs of vaccine preventable diseases in patients with cirrhosis.

Hemangiomas are well-known benign neoplasms of the body most commonly occurring in the head and neck region and less commonly in the oral cavity. The predominant site of occurrence, in the oral cavity, is lips followed by gingiva, tongue and palate. Treatment is primarily dependent on correct diagnosis of the lesion and its anatomic location. Here, we report a case of hemangioma on posterior third of the tongue in 34-year-old male patient, who was treated by sclerotherapy with sodium tetradecylsulphate (setrol) sclerosing agent.

A new source of progenitor cells can now be used to study hidden aspects of human lung development and pediatric lung disease.

Behçet’s disease (BD) is a chronic, relapsing multisystemic vascular condition. Behçet’s disease was described by Hulusi Behçet in 1937. This rare multisystem relapsing-remitting inflammatory disease is poorly understood but is thought to be an autoimmune inflammatory vasculitic process in a genetically predisposed population. Diagnosis of Behçet’s disease is based on International Criteria of Behçet’s Disease (ICBD). The present paper describes a case report of Behçet’s syndrome where aphthous stomatitis was treated with low level laser therapy.

Introduction: Thyroid carcinoma represents less than 1% of all cancers. The first line of treatment for thyroid cancer is partial/ total thyroidectomy. High-dose Iodine131 therapy using Iodine radioisotopes is commonly used in patients with well differentiated thyroid carcinoma after total thyroidectomy. In this process, the non-thyroidal tissues, such as, salivary gland, stomach and breast tissues also take up radioactive iodine. Salivary gland scintigraphy is widely accepted as a sensitive and valid method for evaluation of salivary gland dysfunction after Radioactive Iodine131 Therapy (RIT). Aim: To assess and compare the salivary flow rates, relative uptake and ejection fractions in parotid and submandibular glands just before and one month after Iodine131 therapy. Materials and Methods: The study was conducted on 24 patients diagnosed with well differentiated thyroid carcinoma who underwent partial/total thyroidectomy and were due for radioactive iodine therapy. These patients were divided into two groups based on the lesion based dosimetry (Group A: 60-100Gy; Group B: 100- 150Gy). Salivary gland assessment was done by salivary gland scintigraphy before and after RIT. Statistical Analysis: The data collected was tabulated and statistically analysed using SPSS software version16 using paired t-test and individual sample t-test. Results: A statistically significant difference in the uptake percent and ejection fraction percent in the parotid and submandibular glands before RIT and one month after RIT was observed in the study. Conclusion: We inferred from the study that there was an overall decrease in uptake percent and ejection fraction percent one month post RIT in both parotid and submandibular glands. Also, a statistically significant difference was noted in the uptake and ejection fraction percent between Group A and Group B concluding the fact that the damage is dose related.

Adenoid cystic carcinoma (ACC) is a slow-growing tumor of the salivary gland with high malignant potential, most commonly involving the minor salivary glands of the head and neck region. It is known for its long clinical course, indolent growth, local recurrence, and late distant metastasis. We report an unusual case of ACC in an adult male patient which remained undiagnosed for more than 15 years.