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Abstract Single-cell multiomic analysis of the epigenome, transcriptome, and proteome allows for comprehensive characterization of the molecular circuitry that underpins cell identity and state. However, the holistic interpretation of such datasets presents a challenge given a paucity of approaches for systematic, joint evaluation of different modalities. Here, we present Panpipes, a set of computational workflows designed to automate multimodal single-cell and spatial transcriptomic analyses by incorporating widely-used Python-based tools to perform quality control, preprocessing, integration, clustering, and reference mapping at scale. Panpipes allows reliable and customizable analysis and evaluation of individual and integrated modalities, thereby empowering decision-making before downstream investigations.

Aim: This is an era of minimally invasive and least traumatic surgical interventions being focused on. The traditional scalpel frenectomy technique offers an increase in post-operative sequelae. To unravel this scenario a comparative evaluation is carried out to find out the clinical outcomes and quality of life after maxillary labial frenectomy using a conventional scalpel and diode laser frenectomy of 980 nm. Materials and Methods: Thirty-six subjects age ranging between 18 and 45 years reported to the Department of Oral and Maxillofacial Surgery, MES Dental College, Perinthalmanna with an aberrant frenal attachment of maxillary labial frenum were randomly assigned into two groups. Group A underwent the conventional scalpel technique and group B for the diode laser-assisted (980 nm) frenectomy technique. The post-operative parameters of ooze from the surgical site, pain, wound healing, and discomfort or acceptance of the procedure were assessed on day 1, day 7, and day 14, respectively. Results: The diode laser group exhibited statistically significant clinical and healing outcomes. Less pain, minimal or absent ooze, increased healing, and better acceptance of the procedure with diode laser at 1, 7, and 14 days recall visit. Conclusion: Surgical interventions involving needle puncture and the associated post-operative sequelae are the most dreaded experiences that make patients indifferent toward surgical treatments. Thus in terms of better clinical outcomes and improved quality of life diode laser frenectomy is an excellent alternative wherein a needleless anesthetic success followed by minimal surgical intervention and less post-operative sequelae with fast recovery is possible.

Abstract CD8+ T lymphocytes play vital roles in killing infected or deranged host cells, recruiting innate immune cells, and regulating other aspects of immune responses. Like any other cell, CD8+ T cells also produce extracellular particles. These include extracellular vesicles (EVs) and non‐vesicular extracellular particles (NVEPs). T cell‐derived EVs are proposed to mediate cell‐to‐cell signalling, especially in the context of inflammatory responses, autoimmunity, and infectious diseases. CD8+ T cells also produce supramolecular attack particles (SMAPs), which are in the same size range as EVs and mediate a component of T cell mediated killing. The isolation technique selected will have a profound effect on yield, purity, biochemical properties and function of T cell‐derived particles; making it important to directly compare different approaches. In this study, we compared commonly used techniques (membrane spin filtration, ultracentrifugation, or size exclusion liquid chromatography) to isolate particles from activated human CD8+ T cells and validated our results by single‐particle methods, including nanoparticle tracking analysis, flow cytometry, electron microscopy and super‐resolution microscopy of the purified sample as well as bulk proteomics and lipidomics analyses to evaluate the quality and nature of enriched T cell‐derived particles. Our results show that there is a trade‐off between the yield and the quality of T cell‐derived particles. Furthermore, the protein and lipid composition of the particles is dramatically impacted by the isolation technique applied. We conclude that from the techniques evaluated, size exclusion liquid chromatography offers the highest quality of T cell derived EVs and SMAPs with acceptable yields for compositional and functional studies.

The surgical repair of thoracoabdominal aortic aneurysm (TAAA) remains one of the most technically demanding surgical procedures in vascular surgery. High-volume centers still have significant morbidity and mortality rates of 12%–15%. Emergence of thoracic endovascular aneurysm repair (TEVAR) improved these figures but was limited by the availability of customized grafts and cost factors. An effective alternative approach hence is a hybrid procedure that involves the combination of open technique for debranching of viscerorenal aorta and use of standard TEVAR stent graft to cover aneurysmal segment. We report a case of an elderly male who underwent a successful staged Hybrid TEVAR procedure for Type 3 equivalent TAAA.

Abstract Reduction of car use is one of the most effective ways to tackle congestion‐related problems. Using positive incentives to stimulate bicycle use is one possibility to reduce car use. Cycling is a sustainable transport mode that uses little space and is healthy. There is evidence that positive incentives may be more effective than punishing travellers for undesirable behaviour, and the emergence of mobile applications for delivering interventions has opened up new opportunities for influencing travellers. So far, few studies have focused on exploring the effectiveness of positive incentives on long‐term behavioural change. We used the SMART app to deliver positive incentives to more than 6000 travellers in the Dutch region of Twente. The app automatically tracks users and provides incentives such as challenges with rewards, feedback, and messages. This study covers the period from March 2017 to June 2018, in which more than 1000 SMART users participated in monthly challenges. We evaluated the effects of the challenges and rewards and found that the challenges did encourage cycling and reduced car use in the short term. There is also some evidence for behavioural change over a longer time period.

Maxillofacial fractures are one of the common presentations in an emergency department. They are considered to be one of the significant and dominant conditions that requires treatment as the fractures can result in morbidity, mortality, psychological, functional disability, and facial mutilation. The incidence, patterns, and etiology of maxillofacial fractures vary from one country to another due to the geographical, cultural, social, and economic differences. The present study included 176 patients from January 2019 to September 2020 that aimed to evaluate the pattern of maxillofacial fractures and to learn the etiology for the same.

Objectives Ophthalmic conditions including anterior uveitis (AU), episcleritis and scleritis may occur in association with the inflammatory bowel diseases (IBD) as ophthalmic extraintestinal manifestations. The aim of this study was to assess the risk of a later IBD diagnosis in those presenting with IBD associated ocular inflammation (IAOI).Design Retrospective cohort study.Setting Primary care UK database.Participants 38 805 subjects with an IAOI were identified (median age 51 (38–65), 57% women) and matched to 153 018 subjects without IAOI.Measures The risk of a subsequent diagnosis of IBD in subjects with IAOIs compared with age/sex matched subjects without IAOI. HRs were adjusted for age, sex, body mass index, deprivation, comorbidity, smoking, baseline axial arthropathy, diarrhoea, loperamide prescription, anaemia, lower gastrointestinal bleeding and abdominal pain.Logistic regression was used to produce a prediction model for a diagnosis of IBD within 3 years of an AU diagnosis.Results 213 (0.6%) subsequent IBD diagnoses (102 ulcerative colitis (UC) and 111 Crohn’s disease (CD)) were recorded in those with IAOIs and 329 (0.2%) (215 UC and 114 CD) in those without. Median time to IBD diagnosis was 882 (IQR 365–2043) days in those with IAOI and 1403 (IQR 623–2516) in those without. The adjusted HR for a subsequent diagnosis of IBD was 2.25 (95% CI 1.89 to 2.68), p

Objectives To identify the association between periodontal diseases (gingivitis and periodontitis) and chronic diseases including cardiovascular disease, cardiometabolic disease, autoimmune disease and mental ill health.Design Retrospective cohort.Setting IQVIA Medical Research Data-UK between 1 January 1995 and 1 January 2019.Participants 64 379 adult patients with a general practitioner recorded diagnosis of periodontal disease (exposed patients) were matched to 251 161 unexposed patients by age, sex, deprivation and registration date.Main outcome measures Logistic regression models accounting for covariates of clinical importance were undertaken to estimate the adjusted OR (aOR) of having chronic diseases at baseline in the exposed compared with the unexposed group. Incidence rates for each outcome of interest were then provided followed by the calculation of adjusted HRs using cox regression modelling to describe the risk of outcome development in each group.Results The average age at cohort entry was 45 years and the median follow-up was 3.4 years. At study entry, the exposed cohort had an increased likelihood of having a diagnosis of cardiovascular disease (aOR 1.43; 95% CI 1.38 to 1.48), cardiometabolic disease (aOR 1.16; 95% CI 1.13 to 1.19), autoimmune disease (aOR 1.33; 95% CI 1.28 to 1.37) and mental ill health (aOR 1.79; 95% CI 1.75 to 1.83) compared with the unexposed group. During the follow-up of individuals without pre-existing outcomes of interest, the exposed group had an increased risk of developing cardiovascular disease (HR 1.18; 95% CI 1.13 to 1.23), cardiometabolic disease (HR 1.07; 95% CI 1.03 to 1.10), autoimmune disease (HR 1.33; 95% CI 1.26 to 1.40) and mental ill health (HR 1.37; 95% CI 1.33 to 1.42) compared with the unexposed group.Conclusions In this cohort, periodontal diseases appeared to be associated with an increased risk of developing cardiovascular, cardiometabolic, autoimmune diseases and mental ill health. Periodontal diseases are very common; therefore, an increased risk of other chronic diseases represent a substantial public health burden.

To promote sustainable urban development, transport policies need to change from a car-oriented mobility planning paradigm to an accessibility-based paradigm, integrating land-use and transport policies. This paper uses the concept of planning paradigms to describe the current status of municipal transport planning and problem framing. The dominant transport planning paradigm of 172 Dutch municipalities is determined, based on a conceptual framework with 24 mobility and accessibility planning criteria. Statistical analysis is then conducted to find linkages between the planning paradigm and transport, land-use, and institutional characteristics of the municipalities. We show that the mobility planning paradigm still dominates Dutch municipal transport planning, and the accessibility planning paradigm is mostly found in large cities and highly urban municipalities. However, we do find indications of slow change in the transport planning paradigms in Dutch municipalities, as older policy documents are more (car) mobility focused than newer policy documents. Further research is necessary to examine the evolution of the paradigm shift in municipal transport planning over time and what factors promote the realization of such a paradigm shift.

Acute suprarenal aortic occlusion, though rarely reported carries a high morbidity and mortality. Renal ischemia is one of the usual presenting features. Limb salvage and renal preservation depend on prompt diagnosis and management. A young patient with acute suprarenal aortic occlusion having renal failure and limb ischemia was managed with suprarenal thrombectomy and aortobifemoral bypass at our centre. Even though the presentation was delayed, renal functions were restored post procedure. This case highlights that renal revascularisation can be attempted in select cases with delayed presentation.

Notch signaling regulates squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is tumor suppressive. Here, we show that conditional activation of Notch in squamous cells activates a context-specific gene expression program through lineage-specific regulatory elements. Among direct Notch target genes are multiple DNA damage response genes, including IER5, which we show is required for Notch-induced differentiation of squamous carcinoma cells and TERT-immortalized keratinocytes. IER5 is epistatic to PPP2R2A, a gene that encodes the PP2A B55α subunit, which we show interacts with IER5 in cells and in purified systems. Thus, Notch and DNA-damage response pathways converge in squamous cells on common genes that promote differentiation, which may serve to eliminate damaged cells from the proliferative pool. We further propose that crosstalk involving Notch and PP2A enables tuning and integration of Notch signaling with other pathways that regulate squamous differentiation.

Background Domestic abuse (DA) against women is a global public health problem. Although the possible health burden could be substantial, the associations between DA and subsequent cardiometabolic disease (cardiovascular disease, hypertension, and type 2 diabetes mellitus) and all‐cause mortality are poorly understood. Methods and Results This retrospective cohort study consisted of UK‐based primary care patients between January 1, 1995, to December 1, 2017. Overall, 18 547 women exposed to DA were matched to 72 231 unexposed women by age and lifestyle factors. The main outcomes, presented as adjusted incidence rate ratios (IRRs), were the risk of developing cardiovascular disease, hypertension, type 2 diabetes mellitus, and all‐cause mortality. In total, 181 exposed women experienced a cardiovascular disease event compared with 644 of the unexposed control group, relating to an increased adjusted IRR of 1.31 (95% CI, 1.11–1.55; P=0.001). There was also an increased risk of subsequent type 2 diabetes mellitus (adjusted IRR: 1.51; 95% CI, 1.30–1.76; P

Background and Aims: Transversus abdominis plane (TAP) block is a technique proposed to minimise pain after anterior iliac crest bone harvesting. This study aims to evaluate the postoperative pain in patients who receive ultrasound-guided TAP block to supplement routine wound infiltration. Material and Methods: A total of 143 patients aged between 6 and 22 years were randomised into two groups. Patients in group A received supplemental TAP block on the same side. Patients in group B received local anesthetic wound infiltration alone. Pain scores were compared at the first and 24th postoperative hours. Results: TAP block significantly reduced pain and delirium in the immediate postoperative period. The mean FLACC (Face, Legs, Activity, Cry, Consolability) score after 10 min was 0.8 in group A versus 1.8 in group B (P = 0.001). The mean Watcha scale at 10 min was 1.0 in group A versus 1.2 in group B (P = 0.001). After 24 h, 81.7% of patients in group A had no pain versus 59.7% in group B (P = 0.004). The incidence of intolerable pain at 24 h was 5.6% in group B versus 0% in group A (P = 0.04). Cumulative ambulation scores were significantly better in group A (P < 0.05). There was a strong and positive correlation between the analgesia and ability to ambulate comfortably at 24 h postop (Pearson's coefficient 0.95). Conclusion: Supplemental ultrasound-guided TAP block given intraoperatively reduces the postoperative pain. The incidence of emergence delirium was low. These patients were also able to ambulate earlier.

Primary inferior vena cava (IVC) tumors are rare with the incidence of about 0.05% overall with leiomyosarcoma (LMS) being malignant and the most common. They are late to present and slow growing, seen predominantly in females in their fifth or sixth decades and have a poor prognosis with a 5-year survival rate touching about 35% even with complete surgical resection. We present our experience with two patients diagnosed to have IVC LMS and underwent complete surgical resection of the tumor with reconstruction of IVC using coated polyester graft. In one patient, only infrarenal IVC was reconstructed, whereas in second patient, bilateral renal veins were also reconstructed along with suprarenal IVC. There is no consensus regarding the optimal treatment of this aggressive tumor, but complete excision of the tumor with wide margins with or without IVC reconstruction have been widely accepted as primary modality of treatment. Neoadjuvant or adjuvant chemoradiotherapy have limited role in the management of this rare tumor.

Background: Fresh frozen plasma (FFP) should be thawed before transfusing to the patient. Prolonged or uncontrolled thawing can denature plasma proteins. The potential risk of contamination by wet thawing had always been a point of concern. Aims: Here, we compared and evaluated the effect of thawing on clotting factor activities by two different methods (wet and dry) and other factors such as risk of bacterial contamination, throughput, turnaround time, and efficacy of thawing. Subjects and Methods: All FFPs were prepared from Group O donors and stored at −40°C. Twenty-one FFPs were thawed in Plasmatherm II at 45°C for 15 min and another 21 were thawed in thawing bath at 37°C for 20–30 min randomly. Analysis of prothrombin time, activated partial thromboplastin time, fibrinogen, and factor VIII was done in ACL TOP 300 (IL) at the time of preparation and immediately after thawing of FFPs. Volume, duration of thawing, ease of use, accessibility, and equipment maintenance were also compared. Results: There was a statistically significant difference in coagulation parameters after thawing in both methods compared to the time of preparation (P < 0.05), but all values were within normal limits. There was no significant difference in coagulation parameters between the two methods (P > 0.05). Mixed bacterial growth was observed from swabs taken from the water bath. Conclusion: Plasmatherm II can be a good alternative to water bath to rapidly thaw FFPs by preserving coagulation factors and eliminating the risk of bacterial contamination.

BACKGROUND AND AIMS:The effect of smoking on the risk of developing inflammatory bowel diseases (IBD) may be heterogeneous across ethnicity and geography. Although trends in smoking for the general population are well described, it is unknown whether these can be extrapolated to the IBD cohort. Smoking prevalence trends specific to the global IBD cohort over time have not been previously reported. This is a systematic review of smoking prevalence specific to the IBD cohort across geography. METHODS:A systematic literature search was conducted on Medline and Embase from January 1st 1946 to April 5th 2018 to identify population-based studies assessing the prevalence of smoking at diagnosis in inception cohorts of Crohn's disease(CD) or ulcerative colitis(UC). Studies that did not report smoking data from time of diagnosis or the year of IBD diagnosis were excluded. Prevalence of smoking in IBD was stratified by geography and across time. RESULTS:We identified 56 studies that were eligible for inclusion. Smoking prevalence data at diagnosis of CD and UC was collected from twenty and twenty-five countries respectively. Never-smokers in the newly diagnosed CD population in the West has increased over the last two decades, especially in the United Kingdom and Sweden; +26.6% and +11.2% respectively. Never-smokers at CD diagnosis in newly industrialised nations have decreased over the 1990s and 2000s; China (-19.36%). Never-smokers at UC diagnosis also decreased in China; -15.4%. The former-smoker population at UC diagnosis in China is expanding; 11%(1990-2006) to 34%(2011-2013). CONCLUSION:There has been a reduction in the prevalence of smoking in the IBD cohort in the West. This is not consistent globally. Although, smoking prevalence has decreased in the general population of newly industrialised nations, this remains an important risk factor with longer term outcomes awaiting translation in both UC and CD.

Objective: To address the unmet medical need to better prognosticate patients with diffuse gliomas and to predict responses to chemotherapy regimens.Methods: ZEB1 alterations were retrospectively identified from a cohort of 1,160 diffuse glioma patients. Epigenome-wide association scans (EWAS) were performed on available data. We determined the utility of ZEB1 as a prognostic indicator of patient survival in diffuse gliomas and assessed the value of ZEB1 to predict the efficacy of treating diffuse glioma patients with procarbazine, CCNU, and vincristine along with radiation at diagnosis. Decision curve analysis (DCA) was used to determine if ZEB1 added benefit to clinical decision-making over and above conventional methods.Results: Fifteen percent of diffuse glioma patients had a ZEB1 deletion. ZEB1 deletion was associated with poor overall survival (OS) with and without adjustment for age and tumor grade (adjusted HR: 4.25; 95% CI: 2.35 to 7.66; P < 0.001). Decision curve analysis confirmed that ZEB1 status with or without IDH1 was more beneficial to clinical decision making than conventional information such as age and tumor grade. We showed that ZEB1 regulates TERT expression, and patients with ZEB1 deletions likely subsume patients with mutant TERT expression in diffuse gliomas. ZEB1 influenced clinical decision making to initiate procarbazine, CCNU, and vincristine treatment.Conclusion: We demonstrate the prognostic value of ZEB1 in diffuse glioma patients. We further determine ZEB1 to be a vital and influential molecular marker in clinical decisions that exceed conventional methods regarding whether to treat or not treat patients with diffuse glioma.

BackgroundIdentification of a microRNA (miRNA) pattern to be used as a biomarker for HNSCC is challenging given the heterogeneity of the disease and different methodologies used. To better define the field, we performed a prospective analysis of blood, tumor, and paired benign tissues in tongue squamous cell carcinoma (SCC) patients.MethodsPlasma samples were collected prior to surgery, and paired tumor and benign tissue blocks were collected from tongue cancer resections. Circulating free and exosomal miRNA, and paired tumor and benign tissues miRNA were analyzed. TaqMan-based miRNA arrays were used to quantitate the expression of 747 human miRNAs. The comparative Ct method assessed the miRNA profile results, and Student’s t-test determined statistical significance between tumor and benign samples.ResultsSixteen of 359 miRNAs detected were differentially expressed between paired tumor and benign tissue. Nine were upregulated, and seven downregulated in tumor tissue. All nine upregulated and six of seven downregulated tumor miRNAs were expressed in circulating exosomes. In contrast, eight of nine upregulated and four of seven downregulated tumor miRNAs were circulating free in the plasma.ConclusionAn aberrantly expressed pattern of miRNA was identified in both tumor and plasma of patients with tongue SCC, suggesting this may be a biomarker for SCC of the oral tongue. Circulating exosomes appear to be a more reliable method for evaluation of circulating tumor-miRNA expression. Further studies with a larger cohort of patients and serial blood samples are needed to validate our findings.

Bike-sharing programs, with initiatives to increase bike use and improve accessibility of urban transit, have received increasing attention in growing number of cities across the world. The latest generation of bike-sharing systems has employed smart card technology that produces station-based data or trip-level data. This facilitates the studies of the practical use of these systems. However, few studies have paid attention to the changes in users and system usage over the years, as well as the impact of system expansion on its usage. Monitoring the changes of system usage over years enables the identification of system performance and can serve as an input for improving the location-allocation of stations. The objective of this study is to explore the impact of the expansion of a bicycle-sharing system on the usage of the system. This was conducted for a bicycle-sharing system in Zhongshan (China), using operational usage data of different years following system expansion. To this end, we performed statistical and spatial analyses to examine the changes in both users and system usage between before and after the system expansion. The findings show that there is a big variation in users and aggregate usage following the system expansion. However, the trend in spatial distribution of demand shows no substantial difference over the years, i.e. the same high-demand and low-demand areas appear. There are decreases in demand for some old stations over the years, which can be attributed to either the negative performance of the system or the competition of nearby new stations. Expanding the system not only extends the original users' ability to reach new areas but also attracts new users to use bike-sharing systems. In the conclusions, we present and discuss the findings, and offer recommendations for the further expansion of system.

Edward Said was the quintessential intellectual of the last quarter of the twentieth century. Commonly celebrated as the founding figure of postcolonialism, his critical oeuvre spans varied terrain. The very strength of his critique lies in these diverse tributaries of thought. Crossing borders and boundaries incessantly, Said’s intellectual project celebrates the culture of resistance while opposing doctrinaire rhetoric. The paper tries to journey along the multifarious “margins” of discourses that crop up in Said. “In-between” spaces have to be investigated for their radical potential, while daring to “transgress” has its own dangers. Said unmasks the unholy nexus between knowledge and power in the mapping of the “Orient” that abetted the colonial enterprise. His contrapuntal readings of literary texts reveal the ubiquitous presence of imperial empire. Consequently, voices from the margins spur counter narratives and “writing back” in the postcolonial condition. Intellectuals in exile tend to be “marginal” and this location helps in looking at the two or even three sides of an issue. Questions of identity, selfhood, nationality, politics, memory, history, representation, geography, homeland, anxieties of influence are dealt with in the paper. The intertwining of the personal and the political occurs in Said. “Memory” is the only hope for resuscitating a “lost world” and battling the accompanying sense of “loss” and “despair” infused in both individuals and communities alike. The paper tries to address how “border crossing” and the “coalescing of margins” create an interdisciplinary breadth in Said, which resist categorization. The “centre/margin” binary is problematized by acknowledging the presence of “many voices,” “polyphony” being a favourite concept of Said. Music gave to him metaphors for human emancipation, while “transgression” was vital. His acknowledgement and assimilation of fellow critics is also mentioned. Beyond enunciating insider-outsider distinctions, Said tried to cultivate knowledge as a bridge between different interests and locations.

The paper looks at the Indian nation, which grows increasingly intolerant of heterogenity. The death of M.F. Husain, the Rushdie controversy and the censoring of A.K. Ramanujan’s essay attest this fact. The subaltern experience of two significant land struggles in the state of Kerala—the Muthanga agitation spearheaded by a tribal woman C.K. Janu and the Chengara land struggle under a dalit Laha Gopalan—testify to the presence of “orientalisms” within. Schisms within the subaltern movement, opposition from Marxist outfits and the geographical spaces of land “occupied”; autobiographies of Janu, Mukhtar Mai and Nalini Jameela, incidents of “honour killing,” slut walk, breast tax and “love jihad” are interrogated . The complexities of orientalisms, which work along the identities of religion, caste and gender are dealt with.

This paper describes the variation in traffic volumes in the Dutch city of Almelo. For this study, we used traffic counts which were collected at about 20 intersections from September 2004 until September 2005. The objective of this study is to provide insight in both periodic and random variation in urban traffic volumes. This insight is used by policy makers and traffic managers to determine a suitable set of traffic measures. It is also a basis for short term predictions of volumes. We conclude that we can distinguish the following types of variation with respect to the average daily volume profile. (1) Seasonal variations with time-scales of weeks and weekly variations that describe the variation from day to day. These variations can be as large as 10% for the city of Almelo. (2) Periodic variations at time-scales of typically 30 minutes. These variations are recurrent and are often larger than 10%. (3) Noise. This variation has a random character. We show that the noise can be approximated by a Poisson distribution.