A Hybrid Method for Density Power Divergence Minimization with Application to Robust Univariate Location and Scale Estimation.

We develop a new globally convergent optimization method for solving a constrained minimization problem underlying the minimum density power divergence estimator for univariate Gaussian data in the presence of outliers. Our hybrid procedure combines classical Newton's method with a gradient descent iteration equipped with a step control mechanism based on Armijo's rule to ensure global convergence. Extensive simulations comparing the resulting estimation procedure with the more prominent robust competitor, Minimum Covariance Determinant (MCD) estimator, across a wide range of breakdown point values suggest improved efficiency of our method. Application to estimation and inference for a real-world dataset is also given.

A TNIP1-driven systemic autoimmune disorder with elevated IgG4.

Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88. The variant increased interferon-ß without altering nuclear factor kappa-light-chain-enhancer of activated B cells signaling, and impaired MyD88 and IRAK1 recruitment to autophagosomes. Additionally, the Q333P variant impaired TNIP1 localization to damaged mitochondria and mitophagosome formation. Damaged mitochondria were abundant in the salivary epithelial cells of Tnip1Q346P mice. These findings suggest that TNIP1-mediated autoimmunity may be a consequence of increased TLR7 signaling due to impaired recruitment of downstream signaling molecules and damaged mitochondria to autophagosomes and may thus respond to TLR7-targeted therapeutics.

The Opioid Analgesic Reduction Study (OARS) Pilot: A Double-Blind Randomized Multicenter Trial.

BACKGROUND: With addiction rates and opioid deaths increasing, health care providers are obligated to help stem the opioid crisis. As limited studies examine the comparative effectiveness of fixed-dose combination nonopioid analgesia to opioid-containing analgesia, a comparative effectiveness study was planned and refined by conducting a pilot study. METHODS: The Opioid Analgesic Reduction Study (OARS) pilot, a stratified, randomized, multisite, double-blind clinical trial, was designed to test technology and procedures to be used in the full OARS trial. Participants engaged in the full protocol, enabling the collection of OARS outcome data. Eligible participants reporting to 1 of 5 sites for partial or full bony impacted mandibular third molar extraction were stratified by biologic sex and randomized to 1 of 2 treatment groups, OPIOID or NONOPIOID. OPIOID participants were provided 20 doses of hydrocodone 5 mg/acetaminophen 300 mg. NONOPIOID participants were provided 20 doses of ibuprofen 400 mg/acetaminophen 500 mg. OARS outcomes data, including pain experience, adverse effects, sleep quality, pain interference, overall satisfaction, and remaining opioid tablets available for diversion, were collected via surveys, electronic medication bottles, eDiary, and activity/sleep monitor. RESULTS: Fifty-three participants were randomized with 50 completing the OARS pilot protocol. Across all outcome pain domains, in all but 1 time period, NONOPIOID was better in managing pain than OPIOID (P < 0.05 level). Other outcomes suggest less pain interference, less adverse events, better sleep quality, better overall satisfaction, and fewer opioid-containing tablets available for diversion. DISCUSSION: Results suggest patients requiring impacted mandibular third molar extraction would benefit from fixed-dose combination nonopioid analgesia. KNOWLEDGE TRANSFER STATEMENT: Study results suggest fixed-dose nonopioid combination ibuprofen 400 mg/acetaminophen 500 mg is superior to opioid-containing analgesic (hydrocodone 5 mg/acetaminophen 500 mg). This knowledge should inform surgeons and patients in the selection of postsurgical analgesia.

Internal and external workload in national and international netball competition.

Differences in workload exist between netball playing positions and competition levels, but no research has compared workloads experienced by the same elite players during national and international competitions. This study collected internal (heart rate) and external (PlayerLoad·min-1) workload data per match quarter from 44 players during a national competition and 12 players during an international competition. Nine players played in both competitions. Linear mixed models compared percentage of match quarter in each heart rate zone and PlayerLoad·min-1 between competitions for each playing position. Workloads against low- and high-ranked international opponents were also compared. Internal workloads were greater in national compared to international competition for GD and WD positions. PlayerLoad·min-1 was significantly higher by 8-13% in the national competition for positions WD and C, and by 5-8% in the international competition for GD and GA. Positional differences may indicate a role of the team's tactical style of play. Workloads were generally greater against higher- rather than lower-ranked international opponents. These results indicate that tactical factors in combination with playing position and opposition characteristics should be considered when preparing physically for matches.

Influence of preovulatory estradiol treatment on the maintenance of pregnancy in beef cattle receiving in vivo produced embryos.

This experiment was designed to determine the role of preovulatory estradiol in pregnancy retention after embryo transfer (ET). Cows were synchronized with the 7-d CO-Synch + CIDR® protocol. On d0 (d-2 =CIDR® removal), cows were grouped by estrual status (estrual [Positive Control] and nonestrual), and nonestrual cows were administered Gonadotropin Releasing Hormone (GnRH) and randomly assigned to either no treatment (Negative Control) or Estradiol (0.1 mg estradiol 17-ß IM). All cows received an embryo on d7. Pregnancy status was retrospectively classified on d56, 30, 24, and 19 by either ultrasonography, plasma pregnancy-associated glycoproteins analysis (PAGs), expression of interferon-stimulated genes, plasma progesterone (P4) concentrations, or a combination of the factors. There was no difference in estradiol concentrations on day 0 h 0 (P > 0.16). At day 0 h 2, Estradiol cows (15.7 ± 0.25 pg/mL) had elevated (P < 0.001) estradiol compared with Positive Controls (3.4 ± 0.26 pg/mL) or Negative Controls (4.3 ± 0.25 pg/mL). On d19, pregnancy rates did not differ (P = 0.14) among treatments. On d24, Positive Controls (47%) had greater (P < 0.01) pregnancy rates than Negative Controls (32%); Estradiol cows were intermediate (40%). There was no difference (P = 0.38) in pregnancy rates between Positive Control (41%) and Estradiol (36%) cows on d30, but Negative Control (27%) cows had (P = 0.01) or tended (P = 0.08) to have decreased pregnancy rates, respectively. Thus, preovulatory estradiol may elicit an effect on early uterine attachment or alter histotroph components, consequently improving pregnancy maintenance through d30.

TLR7 gain-of-function genetic variation causes human lupus.

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1-7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10-12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.

Machine Learning Improves Upon Clinicians' Prediction of End Stage Kidney Disease.

Background and Objectives: Chronic kidney disease progression to ESKD is associated with a marked increase in mortality and morbidity. Its progression is highly variable and difficult to predict. Methods: This is an observational, retrospective, single-centre study. The cohort was patients attending hospital and nephrology clinic at The Canberra Hospital from September 1996 to March 2018. Demographic data, vital signs, kidney function test, proteinuria, and serum glucose were extracted. The model was trained on the featurised time series data with XGBoost. Its performance was compared against six nephrologists and the Kidney Failure Risk Equation (KFRE). Results: A total of 12,371 patients were included, with 2,388 were found to have an adequate density (three eGFR data points in the first 2 years) for subsequent analysis. Patients were divided into 80%/20% ratio for training and testing datasets.ML model had superior performance than nephrologist in predicting ESKD within 2 years with 93.9% accuracy, 60% sensitivity, 97.7% specificity, 75% positive predictive value. The ML model was superior in all performance metrics to the KFRE 4- and 8-variable models.eGFR and glucose were found to be highly contributing to the ESKD prediction performance. Conclusions: The computational predictions had higher accuracy, specificity and positive predictive value, which indicates the potential integration into clinical workflows for decision support.

Reconciling communication repertoires: navigating interactions involving persons with severe/profound intellectual disability, a classic grounded theory study.

BACKGROUND: A rights-based agenda, informed by the UNCRPD, that advocates person-centredness, inclusion, empowerment and self-determination is shaping service provision to people with intellectual disability (ID). Listening to their perspectives is fundamental to meeting these goals. However, communication with people with severe/profound ID is challenging and difficult. Therefore, this study aims to generate a theory that explains how people communicate with and understand each other in these interactions. METHODS: Classic grounded theory (CGT) methodology was used as it recognises that knowledge can be captured rather than interpreted. According to CGT, capturing rather than interpreting experiences strengthens findings, particularly in relation to participants with severe/profound ID. Concurrent theoretical sampling, data collection and analysis were undertaken. Twenty-two individuals participated in the study: 3 people with severe/profound ID and 19 people with whom they interact. Data were collected over a 9-month period and involved video recordings, field notes, individual and group interviews. Data were analysed using CGT methods of coding, constant comparison and memoing. RESULTS: The Theory of Reconciling Communication Repertoires was generated. Nurturing a sense of belonging emerged as the main concern and core category that is resolved by reconciling communication repertoires. A communication repertoire refers to the cache of communication skills a person has available to them. To reconcile repertoires is to harmonise or make them compatible with each other in order to communicate. Interactions are navigated through five stages: motivation to interact, connection establishment, reciprocally engaging, navigating understanding and confusion resolution. CONCLUSIONS: The Theory of Reconciling Communication Repertoires explains how interactions involving people with severe/profound ID are navigated. While this is a substantive rather than formal theory, it has the potential to inform practice, policy, management, education and research as it outlines how communication with people with severe/profound ID can take place to design, inform and plan person-centred care.

Efficacy of computational predictions of the functional effect of idiosyncratic pharmacogenetic variants.

BACKGROUND: Pharmacogenetic variation is important to drug responses through diverse and complex mechanisms. Predictions of the functional impact of missense pharmacogenetic variants primarily rely on the degree of sequence conservation between species as a primary discriminator. However, idiosyncratic or off-target drug-variant interactions sometimes involve effects that are peripheral or accessory to the central systems in which a gene functions. Given the importance of sequence conservation to functional prediction tools-these idiosyncratic pharmacogenetic variants may violate the assumptions of predictive software commonly used to infer their effect. METHODS: Here we exhaustively assess the effectiveness of eleven missense mutation functional inference tools on all known pharmacogenetic missense variants contained in the Pharmacogenomics Knowledgebase (PharmGKB) repository. We categorize PharmGKB entries into sub-classes to catalog likely off-target interactions, such that we may compare predictions across different variant annotations. RESULTS: As previously demonstrated, functional inference tools perform variably across the complete set of PharmGKB variants, with large numbers of variants incorrectly classified as 'benign'. However, we find substantial differences amongst PharmGKB variant sub-classes, particularly in variants known to cause off-target, type B adverse drug reactions, that are largely unrelated to the main pharmacological action of the drug. Specifically, variants associated with off-target effects (hence referred to as off-target variants) were most often incorrectly classified as 'benign'. These results highlight the importance of understanding the underlying mechanism of pharmacogenetic variants and how variants associated with off-target effects will ultimately require new predictive algorithms. CONCLUSION: In this work we demonstrate that functional inference tools perform poorly on pharmacogenetic variants, particularly on subsets enriched for variants causing off-target, type B adverse drug reactions. We describe how to identify variants associated with off-target effects within PharmGKB in order to generate a training set of variants that is needed to develop new algorithms specifically for this class of variant. Development of such tools will lead to more accurate functional predictions and pave the way for the increased wide-spread adoption of pharmacogenetics in clinical practice.

A Point Mutation in IKAROS ZF1 Causes a B Cell Deficiency in Mice.

IKZF1 (IKAROS) is essential for normal lymphopoiesis in both humans and mice. Previous Ikzf1 mouse models have demonstrated the dual role for IKZF1 in both B and T cell development and have indicated differential requirements of each zinc finger. Furthermore, mutations in IKZF1 are known to cause common variable immunodeficiency in patients characterized by a loss of B cells and reduced Ab production. Through N-ethyl-N-nitrosourea mutagenesis, we have discovered a novel Ikzf1 mutant mouse with a missense mutation (L132P) in zinc finger 1 (ZF1) located in the DNA binding domain. Unlike other previously reported murine Ikzf1 mutations, this L132P point mutation (Ikzf1L132P ) conserves overall protein expression and has a B cell-specific phenotype with no effect on T cell development, indicating that ZF1 is not required for T cells. Mice have reduced Ab responses to immunization and show a progressive loss of serum Igs compared with wild-type littermates. IKZF1L132P overexpressed in NIH3T3 or HEK293T cells failed to localize to pericentromeric heterochromatin and bind target DNA sequences. Coexpression of wild-type and mutant IKZF1, however, allows for localization to pericentromeric heterochromatin and binding to DNA indicating a haploinsufficient mechanism of action for IKZF1L132P Furthermore, Ikzf1+/L132P mice have late onset defective Ig production, similar to what is observed in common variable immunodeficiency patients. RNA sequencing revealed a total loss of Hsf1 expression in follicular B cells, suggesting a possible functional link for the humoral immune response defects observed in Ikzf1L132P/L132P mice.

Detecting Causal Variants in Mendelian Disorders Using Whole-Genome Sequencing.

Increasingly affordable sequencing technologies are revolutionizing the field of genomic medicine. It is now feasible to interrogate all major classes of variation in an individual across the entire genome for less than $1000 USD. While the generation of patient sequence information using these technologies has become routine, the analysis and interpretation of this data remains the greatest obstacle to widespread clinical implementation. This chapter summarizes the steps to identify, annotate, and prioritize variant information required for clinical report generation. We discuss methods to detect each variant class and describe strategies to increase the likelihood of detecting causal variant(s) in Mendelian disease. Lastly, we describe a sample workflow for synthesizing large amount of genetic information into concise clinical reports.

Atypical B cells are part of an alternative lineage of B cells that participates in responses to vaccination and infection in humans.

The diversity of circulating human B cells is unknown. We use single-cell RNA sequencing (RNA-seq) to examine the diversity of both antigen-specific and total B cells in healthy subjects and malaria-exposed individuals. This reveals two B cell lineages: a classical lineage of activated and resting memory B cells and an alternative lineage, which includes previously described atypical B cells. Although atypical B cells have previously been associated with disease states, the alternative lineage is common in healthy controls, as well as malaria-exposed individuals. We further track Plasmodium-specific B cells after malaria vaccination in naive volunteers. We find that alternative lineage cells are primed after the initial immunization and respond to booster doses. However, alternative lineage cells develop an atypical phenotype with repeated boosts. The data highlight that atypical cells are part of a wider alternative lineage of B cells that are a normal component of healthy immune responses.

NINJ1 mediates plasma membrane rupture during lytic cell death.

Plasma membrane rupture (PMR) is the final cataclysmic event in lytic cell death. PMR releases intracellular molecules known as damage-associated molecular patterns (DAMPs) that propagate the inflammatory response1-3. The underlying mechanism of PMR, however, is unknown. Here we show that the cell-surface NINJ1 protein4-8, which contains two transmembrane regions, has an essential role in the induction of PMR. A forward-genetic screen of randomly mutagenized mice linked NINJ1 to PMR. Ninj1-/- macrophages exhibited impaired PMR in response to diverse inducers of pyroptotic, necrotic and apoptotic cell death, and were unable to release numerous intracellular proteins including HMGB1 (a known DAMP) and LDH (a standard measure of PMR). Ninj1-/- macrophages died, but with a distinctive and persistent ballooned morphology, attributable to defective disintegration of bubble-like herniations. Ninj1-/- mice were more susceptible than wild-type mice to infection with Citrobacter rodentium, which suggests a role for PMR in anti-bacterial host defence. Mechanistically, NINJ1 used an evolutionarily conserved extracellular domain for oligomerization and subsequent PMR. The discovery of NINJ1 as a mediator of PMR overturns the long-held idea that cell death-related PMR is a passive event.

An Assessment of Earth's Climate Sensitivity Using Multiple Lines of Evidence.

We assess evidence relevant to Earth's equilibrium climate sensitivity per doubling of atmospheric CO2, characterized by an effective sensitivity S. This evidence includes feedback process understanding, the historical climate record, and the paleoclimate record. An S value lower than 2 K is difficult to reconcile with any of the three lines of evidence. The amount of cooling during the Last Glacial Maximum provides strong evidence against values of S greater than 4.5 K. Other lines of evidence in combination also show that this is relatively unlikely. We use a Bayesian approach to produce a probability density function (PDF) for S given all the evidence, including tests of robustness to difficult-to-quantify uncertainties and different priors. The 66% range is 2.6-3.9 K for our Baseline calculation and remains within 2.3-4.5 K under the robustness tests; corresponding 5-95% ranges are 2.3-4.7 K, bounded by 2.0-5.7 K (although such high-confidence ranges should be regarded more cautiously). This indicates a stronger constraint on S than reported in past assessments, by lifting the low end of the range. This narrowing occurs because the three lines of evidence agree and are judged to be largely independent and because of greater confidence in understanding feedback processes and in combining evidence. We identify promising avenues for further narrowing the range in S, in particular using comprehensive models and process understanding to address limitations in the traditional forcing-feedback paradigm for interpreting past changes.

Prospective Evaluation of Cognitive Health and Related Factors in Elderly at Risk for Developing Alzheimer's Dementia: A Longitudinal Cohort Study.

BACKGROUND: The CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer's disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD). OBJECTIVES: The study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to APOE ε4 subgroup. DESIGN: This single-site study was conducted at the Imperial College London (ICL) in the United Kingdom. Participants 60 to 85 years of age were classified as high, medium (amnestic or non-amnestic) or low risk for developing MCI-AD based on RBANS z-scores. A series of clinical outcome assessments (COAs) on factors influencing baseline cognitive changes were collected in each of the instrument categories of cognition, lifestyle exposure, mood, and sleep. Data collection was planned to occur every 6 months for 48 months, however the median follow-up time was 18.1 months due to early termination of study by the sponsor. RESULTS: 987 participants were screened, among them 690 participants were actively followed-up post baseline, of whom 165 (23.9%) were APOE ε4 carriers; with at least one copy of the allele. The mean age was 68.73 years, 94.6% were white, 57.4% were female, and 34.8% had a Family History of Dementia with a somewhat larger percentage in the APOE ε4 carrier group (42.4%) compared to the non-carrier group (32.4%). Over half of the participants were married and 53% had a Bachelor's or higher degree. Most frequently, safety events typical for this population consisted of upper respiratory tract infection (10.4%), falls (5.2%), hypertension (3.5%) and back pain (3.0%). Conclusion (clinical relevance): AD-related measures collected during the CHARIOT PRO Main study will allow identification and evaluation of AD risk factors and markers associated with cognitive performance from the pre-clinical stage. Evaluating the psycho-biological characteristics of these pre-symptomatic individuals in relation to their natural neurocognitive trajectories will enhance current understanding on determinants of the initial signs of cognitive changes linked to AD.

Strong Dependence of Atmospheric Feedbacks on Mixed-Phase Microphysics and Aerosol-Cloud Interactions in HadGEM3.

We analyze the atmospheric processes that explain the large changes in radiative feedbacks between the two latest climate configurations of the Hadley Centre Global Environmental model. We use a large set of atmosphere-only climate change simulations (amip and amip-p4K) to separate the contributions to the differences in feedback parameter from all the atmospheric model developments between the two latest model configurations. We show that the differences are mostly driven by changes in the shortwave cloud radiative feedback in the midlatitudes, mainly over the Southern Ocean. Two new schemes explain most of the differences: the introduction of a new aerosol scheme and the development of a new mixed-phase cloud scheme. Both schemes reduce the strength of the preexisting shortwave negative cloud feedback in the midlatitudes. The new aerosol scheme dampens a strong aerosol-cloud interaction, and it also suppresses a negative clear-sky shortwave feedback. The mixed-phase scheme increases the amount of cloud liquid water path (LWP) in the present day and reduces the increase in LWP with warming. Both changes contribute to reducing the negative radiative feedback of the increase of LWP in the warmer climate. The mixed-phase scheme also enhances a strong, preexisting, positive cloud fraction feedback. We assess the realism of the changes by comparing present-day simulations against observations and discuss avenues that could help constrain the relevant processes.

Recurrent miscalling of missense variation from short-read genome sequence data.

BACKGROUND: Short-read resequencing of genomes produces abundant information of the genetic variation of individuals. Due to their numerous nature, these variants are rarely exhaustively validated. Furthermore, low levels of undetected variant miscalling will have a systematic and disproportionate impact on the interpretation of individual genome sequence information, especially should these also be carried through into in reference databases of genomic variation. RESULTS: We find that sequence variation from short-read sequence data is subject to recurrent-yet-intermittent miscalling that occurs in a sequence intrinsic manner and is very sensitive to sequence read length. The miscalls arise from difficulties aligning short reads to redundant genomic regions, where the rate of sequencing error approaches the sequence diversity between redundant regions. We find the resultant miscalled variants to be sensitive to small sequence variations between genomes, and thereby are often intrinsic to an individual, pedigree, strain or human ethnic group. In human exome sequences, we identify 2-300 recurrent false positive variants per individual, almost all of which are present in public databases of human genomic variation. From the exomes of non-reference strains of inbred mice, we identify 3-5000 recurrent false positive variants per mouse - the number of which increasing with greater distance between an individual mouse strain and the reference C57BL6 mouse genome. We show that recurrently miscalled variants may be reproduced for a given genome from repeated simulation rounds of read resampling, realignment and recalling. As such, it is possible to identify more than two-thirds of false positive variation from only ten rounds of simulation. CONCLUSION: Identification and removal of recurrent false positive variants from specific individual variant sets will improve overall data quality. Variant miscalls arising are highly sequence intrinsic and are often specific to an individual, pedigree or ethnicity. Further, read length is a strong determinant of whether given false variants will be called for any given genome - which has profound significance for cohort studies that pool datasets collected and sequenced at different points in time.

Transanal endoscopic microsurgery for rectal lesions in a specialist regional early rectal cancer centre: the Mersey experience.

AIM: Organ-preserving local excision by transanal endoscopic microsurgery (TEM) for early rectal cancer offers significantly lower morbidity as compared to formal rectal cancer resection with acceptable outcomes. This study presents our 6-year experience of TEM for rectal lesions referred to a specialist early rectal cancer centre in the UK. METHOD: Data were collected for all patients referred for TEM of suspected early rectal cancer to a regional specialist early rectal cancer multidisciplinary team (MDT) over a 6-year period. RESULTS: One hundred and forty-one patients who underwent full-thickness TEM for suspected or confirmed early rectal cancer were included. Thirty patients were referred for TEM following incomplete endoscopic polypectomy. Final pathology was benign in 77 (54.6%) cases and malignant in 64 (45.4%). Of the 61 confirmed adenocarcinomas, TEM resections were pT0 in 17 (27.9%), pT1 in 32 (51.7%), pT2 in 11 (18.0%) and pT3 in 1 (1.6%). Thirty-eight of 61 patients (62.3%) had one or more poor histological prognostic features and these patients were offered further treatment. Twenty-three of 61 (37.7%) patients with rectal adenocarcinoma required no further treatment following TEM. Forty-three cases of rectal adenocarcinoma were available for establishing recurrence rates. Two of 43 patients (4.7%) developed a recurrence at a median follow-up of 28.7 months (12.1-66.5 months). The overall estimated 5-year overall survival rate was 87.9% and the disease-free survival rate was 82.9%. CONCLUSION: Acceptable outcomes are possible for TEM surgery with appropriate patient selection, effective technique, expert histopathology, appropriate referral for adjuvant treatment and meticulous follow-up. This can be achieved through an early rectal cancer MDT in a dedicated specialist regional centre.

IL-1 receptor antagonist, anakinra, prevents myocardial dysfunction in a mouse model of Kawasaki disease vasculitis and myocarditis.

Kawasaki disease (KD) vasculitis is an acute febrile illness of childhood characterized by systemic vasculitis of unknown origin, and is the most common cause of acquired heart disease among children in the United States. While  histological evidence of myocarditis can be found in all patients with acute KD, only a minority of patients are clinically symptomatic and a subset demonstrate echocardiographic evidence of impaired myocardial function, as well as increased left ventricular mass, presumed to be due to myocardial edema and inflammation. Up to a third of KD patients fail to respond to first-line therapy with intravenous immunoglobulin (IVIG), and the use of interleukin (IL)-1 receptor antagonist (IL-1Ra, anakinra) is currently being investigated as an alternative therapeutic approach to treat IVIG-resistant patients. In this study, we sought to investigate the effect of IL-1Ra on myocardial dysfunction and its relation to myocarditis development during KD vasculitis. We used the Lactobacillus casei cell-wall extract (LCWE)-induced murine model of KD vasculitis and investigated the effect of IL-1Ra pretreatment on myocardial dysfunction during KD vasculitis by performing histological, magnetic resonance imaging (MRI) and echocardiographic evaluations. IL-1Ra pretreatment significantly reduced KD-induced myocardial inflammation and N-terminal pro B-type natriuretic peptide (NT-proBNP) release. Both MRI and echocardiographic studies on LCWE-injected KD mice demonstrated that IL-1Ra pretreatment results in an improved ejection fraction and a normalized left ventricular function. These findings further support the potential beneficial effects of IL-1Ra therapy in preventing the cardiovascular complications in acute KD patients, including the myocarditis and myocardial dysfunction associated with acute KD.

IRF2 transcriptionally induces GSDMD expression for pyroptosis.

Gasdermin-D (GSDMD) is cleaved by caspase-1, caspase-4, and caspase-11 in response to canonical and noncanonical inflammasome activation. Upon cleavage, GSDMD oligomerizes and forms plasma membrane pores, resulting in interleukin-1ß (IL-1ß) secretion, pyroptotic cell death, and inflammatory pathologies, including periodic fever syndromes and septic shock-a plague on modern medicine. Here, we showed that IRF2, a member of the interferon regulatory factor (IRF) family of transcription factors, was essential for the transcriptional activation of GSDMD. A forward genetic screen with N-ethyl-N-nitrosourea (ENU)-mutagenized mice linked IRF2 to inflammasome signaling. GSDMD expression was substantially attenuated in IRF2-deficient macrophages, endothelial cells, and multiple tissues, which corresponded with reduced IL-1ß secretion and inhibited pyroptosis. Mechanistically, IRF2 bound to a previously uncharacterized but unique site within the GSDMD promoter to directly drive GSDMD transcription for the execution of pyroptosis. Disruption of this single IRF2-binding site abolished signaling by both the canonical and noncanonical inflammasomes. Together, our data illuminate a key transcriptional mechanism for expression of the gene encoding GSDMD, a critical mediator of inflammatory pathologies.