Synergies of THESEUS with the large facilities of the 2030s and guest observer opportunities.

The proposed THESEUS mission will vastly expand the capabilities to monitor the high-energy sky. It will specifically exploit large samples of gamma-ray bursts to probe the early universe back to the first generation of stars, and to advance multi-messenger astrophysics by detecting and localizing the counterparts of gravitational waves and cosmic neutrino sources. The combination and coordination of these activities with multi-wavelength, multi-messenger facilities expected to be operating in the 2030s will open new avenues of exploration in many areas of astrophysics, cosmology and fundamental physics, thus adding considerable strength to the overall scientific impact of THESEUS and these facilities. We discuss here a number of these powerful synergies and guest observer opportunities.

Systematic review of cognitive deficits in adult mitochondrial disease.

The profile and trajectory of cognitive impairment in mitochondrial disease are poorly defined. This systematic review sought to evaluate the current literature on cognition in mitochondrial disease, and to determine future research directions. A systematic review was conducted, employing PubMed, Medline, Psycinfo, Embase and Web of Science, and 360-degree citation methods. English language papers on adult patients were included. The literature search yielded 2421 articles, of which 167 met inclusion criteria. Case reports and reviews of medical reports of patients yielded broad diagnoses of dementia, cognitive impairment and cognitive decline. In contrast, systematic investigations of cognitive functioning using detailed cognitive batteries identified focal cognitive rather than global deficits. Results were variable, but included visuospatial functioning, memory, attention, processing speed and executive functions. Conclusions from studies have been hampered by small sample sizes, variation in genotype and the breadth and depth of assessments undertaken. Comprehensive cognitive research with concurrent functional neuroimaging and physical correlates of mitochondrial disease in larger samples of well-characterized patients may discern the aetiology and progression of cognitive deficits. These data provide insights into the pattern and trajectory of cognitive impairments, which are invaluable for clinical monitoring, health planning and clinical trial readiness.

A case-comparison study of pregnant women with mitochondrial disease - what to expect?

OBJECTIVE: Mitochondrial disease is a disorder of energy metabolism that affects 1 in 4300 adults in the UK. Pregnancy is associated with physiological demands that have implications for energy metabolism. We were interested to know how pregnancy was affected in women with mitochondrial disease, particularly those with the most common pathogenic mutation m.3243A>G. DESIGN: Retrospective case-comparison study. POPULATION/SETTING: Sixty-seven women with genetically confirmed mitochondrial disease from the UK Mitochondrial Diseases Cohort and 69 unaffected women participated. METHODS: Participants answered questionnaires regarding each of their pregnancies. Patients were divided into two groups according to genetic mutation, with those harbouring m.3243A>G comprising a single group. MAIN OUTCOME MEASURES: Pregnancy-related complications, mode of delivery, gestational age and birthweight of newborns. RESULTS: Of 139 live births in the comparison group, 62 were in the m.3243A>G group and 87 were in the 'all other mutations' group. Pregnancies of women with the m.3243A>G mutation had significantly more gestational diabetes (odds ratio [OR] = 8.2, 95% CI 1.3-50.1), breathing difficulties (OR = 7.8, 95% CI 1.0-59.1) and hypertension (OR = 8.2, 95% CI 3.1-21.5) than the comparison group. Only half of the pregnancies in the m.3243A>G group had normal vaginal delivery, with emergency caesarean section accounting for 24.2% of deliveries. Babies were born significantly earlier to mothers harbouring m.3243A>G with 53.3% of them preterm (<37 weeks). These babies were also more likely to require resuscitation and admission. CONCLUSION: Women who carried the m.3243A>G mutation appeared to be at higher risk of complications during pregnancies, caesarean section and preterm delivery than the unaffected women or those with other forms of mitochondrial disease. TWEETABLE ABSTRACT: Pregnant women with mitochondrial disease - m.3243A>G mutation - are at greatly increased risk of complications and preterm delivery.

K-homology splicing regulatory protein (KSRP) promotes post-transcriptional destabilization of Spry4 transcripts in non-small cell lung cancer.

AU-rich element-binding proteins (ARE-BPs) offer post-transcriptional regulation of gene expression via physical interaction and recruitment of RNA decay machinery to the AU-rich elements within the 3'-UTR of the target transcripts. However, the role of ARE-BPs in lung cancer remains poorly understood. In this study, we have identified that K-homology splicing regulatory protein (KSRP), an ARE-BP, is robustly up-regulated in human lung cancer. Importantly, Kaplan-Meier survival analysis indicated that elevated KSRP expression was correlated with poor overall survival of lung cancer patients. Furthermore, cigarette smoke, a leading risk factor for lung cancer, was also identified to be an important contributor to increased KSRP expression. Remarkably, silencing of KSRP decreased cell proliferation, reversed anchorage-independent growth, and reduced migration/invasion, suggesting an oncogenic role for KSRP in lung cancer. Finally, we provide mechanistic evidence that KSRP promotes the down-regulation of Spry4 by a previously unidentified mechanism, i.e. post-transcriptional mRNA regulation.

The suppression of star formation by powerful active galactic nuclei.

The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight correlation between the mass of the black hole and the mass of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming galaxies are usually dust-obscured and are brightest at infrared and submillimetre wavelengths. Here we report submillimetre and X-ray observations that show that rapid star formation was common in the host galaxies of AGN when the Universe was 2-6 billion years old, but that the most vigorous star formation is not observed around black holes above an X-ray luminosity of 10(44) ergs per second. This suppression of star formation in the host galaxy of a powerful AGN is a key prediction of models in which the AGN drives an outflow, expelling the interstellar medium of its host and transforming the galaxy's properties in a brief period of cosmic time.

Submillimetre galaxies reside in dark matter haloes with masses greater than 3 × 10(11) solar masses.

The extragalactic background light at far-infrared wavelengths comes from optically faint, dusty, star-forming galaxies in the Universe with star formation rates of a few hundred solar masses per year. These faint, submillimetre galaxies are challenging to study individually because of the relatively poor spatial resolution of far-infrared telescopes. Instead, their average properties can be studied using statistics such as the angular power spectrum of the background intensity variations. A previous attempt at measuring this power spectrum resulted in the suggestion that the clustering amplitude is below the level computed with a simple ansatz based on a halo model. Here we report excess clustering over the linear prediction at arcminute angular scales in the power spectrum of brightness fluctuations at 250, 350 and 500 µm. From this excess, we find that submillimetre galaxies are located in dark matter haloes with a minimum mass, M(min), such that log(10)[M(min)/M(⊙)] = 11.5(+0.7)(-0.2) at 350 µm, where M(⊙) is the solar mass. This minimum dark matter halo mass corresponds to the most efficient mass scale for star formation in the Universe, and is lower than that predicted by semi-analytical models for galaxy formation.

Isolated popliteus tendon injury does not lead to abnormal laxity in posterior-stabilised total knee arthroplasty.

PURPOSE: The popliteus tendon is crucial to postero-lateral stability and prone to iatrogenic injury intra-operatively. Its role in the stability of the replaced knee remains contentious. The aim of this study was to use computer navigation to quantify the effect of popliteus sectioning on the 'envelope of laxity' (EoL) offered by a posterior-stabilised (PS) total knee arthroplasty (TKA) and compare with that of the native knee. METHODS: Loaded cadaveric legs were mounted on a purpose built rig. EoL was measured in 3 degrees of freedom using computer navigation. Knees were subjectively stressed in varus/valgus, internal/external rotation and anterior draw. This was performed preoperatively, during TKA and after sectioning of the popliteus tendon. Real-time data were recorded at 0°, 30°, 60° and 90° of flexion as the operating surgeon stressed the knee in 3 degrees of freedom to its subjective endpoint. Mixed-effect modelling was used to quantify the effects of intervention on degree of laxity. RESULTS: In all conditions, there was an increase in laxity with knee flexion. Insertion of a PS TKA resulted in increased constraint, particularly in rotation. Sectioning of the popliteus did not result in a significant increase in knee laxity to 90º of knee flexion. However, at deeper flexion angles, tendon sectioning overcame the constraints of the implant resulting in a significant increase in rotatory and varus/valgus laxity towards the native condition. CONCLUSION: These findings support the view that certain current designs of PS knee replacement can constrain the knee in flexion in the absence of postero-lateral deficiency. For this implant, isolated sectioning of the popliteus tendon did not substantially generate abnormal knee laxity.

Spatial variation in the risk of hospitalization with childhood pneumonia and empyema in the North of England.

The aim of this study was to investigate spatial variation in risk of hospitalization in childhood pneumonia and empyema in the North of England and associated risk factors. Data on childhood (0-14 years) hospital admissions with a diagnosis pneumonia or empyema were linked to postcode districts. Bayesian conditional autoregressive models were used to evaluate spatial variation and the relevance of specific spatial covariates in an area-based study using postcode as the areal unit. There was a sixfold variation in the risk of hospitalization due to pneumonia across the study region. Variation in risk was associated with material deprivation, Child Well-being Index (CWI) health domain score, number of children requiring local authority support, and distance to hospital. No significant spatial variation in risk for empyema was found.

Can we define envelope of laxity during navigated knee arthroplasty?

PURPOSE: Functional outcomes after knee arthroplasty (TKA) remain poor. The ability to restore the soft tissue envelope intraoperatively may improve such outcomes. The aim of this study was to extend the scope of computer navigation as a tool to quantifying the envelope of laxity during subjective stress testing preoperatively and to quantify the effects of knee replacement and how it changes as a result of ligamentous failure. METHODS: Loaded cadaveric legs were mounted on a purpose-built rig. Envelope of laxity was measured in 3 degrees of freedom using computer navigation. Knees were subjectively stressed in varus/valgus, internal/external rotation and anterior draw. This was performed preoperatively, during TKA and after sequential sectioning of ligaments. Real-time data were recorded at 0°, 30°, 60° and 90° of flexion. Mixed effect modelling was used to quantify the effects of intervention on degree of laxity. RESULTS: In all cases, there was an increase in laxity with increasing flexion or ligament sectioning. Operator and movement cycle had no effect. Insertion of a TKA showed increased stability within the joint, especially in internal/external rotation and anterior drawer. Once the PCL and popliteus were cut, the implant only maintained some rotatory stability; thereafter, the soft tissue envelope failed. CONCLUSIONS: This work has shown a novel way by which computer navigation can be used to analyse soft tissue behaviour during TKA beyond the coronal plane and throughout range of motion. Despite subjective stress testing, our results show reproducible patterns of soft tissue behaviour-in particular a wide range of mid-flexion excursion. It also quantifies the limits within which a cruciate-retaining TKR can maintain knee stability. This functionality may guide the surgeon in identifying and/or preventing soft tissue imbalances intra-operatively, improving functional results.

Rapid growth of black holes in massive star-forming galaxies.

The tight relationship between the masses of black holes and galaxy spheroids in nearby galaxies implies a causal connection between the growth of these two components. Optically luminous quasars host the most prodigious accreting black holes in the Universe, and can account for greater than or approximately equal to 30 per cent of the total cosmological black-hole growth. As typical quasars are not, however, undergoing intense star formation and already host massive black holes (> 10(8)M(o), where M(o) is the solar mass), there must have been an earlier pre-quasar phase when these black holes grew (mass range approximately (10(6)-10(8))M(o)). The likely signature of this earlier stage is simultaneous black-hole growth and star formation in distant (redshift z > 1; >8 billion light years away) luminous galaxies. Here we report ultra-deep X-ray observations of distant star-forming galaxies that are bright at submillimetre wavelengths. We find that the black holes in these galaxies are growing almost continuously throughout periods of intense star formation. This activity appears to be more tightly associated with these galaxies than any other coeval galaxy populations. We show that the black-hole growth from these galaxies is consistent with that expected for the pre-quasar phase.

Results of laparoscopic intragastric surgery.

BACKGROUND: Technological and operative advancements have allowed laparoscopic intragastric surgery (LIGS) to be applied in the treatment of superficial gastric or submucosal lesions. The aim of this study was to evaluate short- and long-term outcomes following LIGS. METHODS: From 2000 to 2013, 25 LIGSs were performed for superficial gastric lesions. Clinical records were reviewed retrospectively for peri-operative course and long-term outcomes with particular attention to the oncological follow-up for patients with malignant lesions. RESULTS: Nineteen (76%) lesions were located close to the EGJ, three (12%) in the lesser curvature, two (8%) in the posterior wall and one (4%) in the prepyloric-antral region. A multiport technique was used in 15 (60%) patients and a single-access approach in 10 (40%) patients. The median operative time was 140 (50-210) minutes. No conversion to open or conventional laparoscopic surgery was needed. Mortality was nil, and severe morbidity occurred in one (4%) patient. The median length of stay was 6 (3-10) days. Indications of LIGS were adenocarcinoma in 11 (44%) patients, gastrointestinal stromal tumors (GISTs) in 6 (24%) patients and benign lesions in eight (32%) patients. En bloc resection was obtained in 24 (96%) patients with R0 margins in 23 (92%) patients. After a median follow-up of 76 (26-171) months, recurrence was detected in 4 (36%) patients with advanced malignant adenocarcinoma. CONCLUSION: LIGS provides an interesting alternative to major gastric and EGJ resection when endoscopic resection is not suitable for highly selected patients with superficial gastric lesions.

Defining and Assessing the Reproducibility of Crohn's Disease Endoscopic Lesions: A Delphi-like Method from the GETAID.

BACKGROUND AND AIMS: Defining and assessing the reproducibility of Crohn's disease [CD] endoscopic lesions is essential in assessing endoscopic healing. METHODS: Twelve endoscopic CD experts from the GETAID defined aphthoid erosions [AE], superficial ulcerations [SU], deep ulcerations [DU], stenosis, and fistulas according to a Delphi-like method. Thirty different GETAID physicians declared if they found acceptable each definition. Intra- and inter-observer agreements were investigated using 100 videos with one tagged specific lesion [AE, SU, DU, or sham lesion] read by 15 independent endoscopists at baseline and 1 month later in a randomised order. Video quality was determined by an external reader. According to kappa estimate [κ ±standard error], intra or inter-observer agreement was qualified as 'moderate' [0.4-0.6], 'substantial' [0.6-0.8], or 'almost perfect' [0.8-1.0]. RESULTS: Among 30 different experts, 83% to 97% found acceptable the definitions retrieved from the Delphi-like method. Intra-observer κ was 0.717 [±0.019] for SU, 0.681 [±0.027] for AE, 0.856 [±0.014] for DU, showing 'substantial' agreement. It was 0.801 [±0.016] for any ulceration [DU or SU]. There was a high variability across readers from 'moderate' to 'almost perfect' agreement. Inter-observer κ was 0.548 [±0.042] for SU, 0.554 [±0.028] for AE 0.694 [±0.041] for DU, and 0.705 [±0.042] for any ulceration. Inter-observer agreement increased when reading the 53 high-quality videos: 0.787 [±0.064] [p = 0.001], 0.607 [±0.043] [p = 0.001], and 0.782 [±0.064][p = 0.001] for DU, AE, and any ulceration, respectively. CONCLUSIONS: Despite variable intra-agreement level across readers, the GETAID definitions for CD endoscopic lesions provided 'substantial' inter-observer agreements, especially in case of high-quality videos.

Steroid treatment causes deterioration of myocardial function in the {delta}-sarcoglycan-deficient mouse model for dilated cardiomyopathy.

AIMS: As oral corticosteroids have a beneficial effect on muscle strength in Duchenne muscular dystrophy, it has been suggested that they may also be a useful treatment in the pathologically related sarcoglycanopathies. The delta-sarcoglycan-deficient mouse (Sgcd-null) is a model for both limb girdle muscular dystrophy 2F (LGMD2F) and dilated cardiomyopathy. METHODS AND RESULTS: To study the effect of oral corticosteroids on cardiac function, we treated 8-week-old Sgcd-null mice with prednisolone (1.5 mg/kg body weight/day orally) for 8 weeks. In vivo cardiac function was assessed by pressure-volume loops using a conductance catheter. We found a well-compensated cardiomyopathy at baseline in Sgcd-null mice with decreased myocardial contractility, increased preload, and decreased afterload, maintaining a high cardiac output. Cardiac haemodynamics, surprisingly, did not improve in prednisolone-treated mice, but instead deteriorated with evidence of ventricular stiffening. On histology, after steroid treatment there was increased myocardial cell damage and increased myocardial fibrosis. CONCLUSION: Prednisolone led to a decompensation of cardiac haemodynamics in Sgcd-null mice and induced additional cardiac damage. On the basis of these findings, although mouse models may not completely replicate the human situation for LGMD2F, we conclude that careful cardiac monitoring is clearly indicated in patients on long-term corticosteroids.

The multiple merger assembly of a hyperluminous obscured quasar at redshift 4.6.

Galaxy mergers and gas accretion from the cosmic web drove the growth of galaxies and their central black holes at early epochs. We report spectroscopic imaging of a multiple merger event in the most luminous known galaxy, WISE J224607.56-052634.9 (W2246-0526), a dust-obscured quasar at redshift 4.6, 1.3 billion years after the Big Bang. Far-infrared dust continuum observations show three galaxy companions around W2246-0526 with disturbed morphologies, connected by streams of dust likely produced by the dynamical interaction. The detection of tidal dusty bridges shows that W2246-0526 is accreting its neighbors, suggesting that merger activity may be a dominant mechanism through which the most luminous galaxies simultaneously obscure and feed their central supermassive black holes.

Endoscopic Detection of Small Bowel Dysplasia and Adenocarcinoma in Crohn's Disease: A Prospective Cohort-Study in High-Risk Patients.

BACKGROUND AND AIMS: Crohn's disease [CD] is associated with an increased risk of small bowel adenocarcinoma [SBA]. There are no recommendations on endoscopic screening of SBA in CD patients. The aim of this study was to evaluate the feasibility and value of endoscopic screening for SBA in CD patients at high-risk of SBA. METHODS: We performed an exploratory multi-centre study in a prospective cohort of CD patients at high-risk of SBA defined as long-term small bowel disease without bowel resection for the past 10 years. Depending on the location of the disease, baseline upper and/or lower enteroscopies were performed. Random and targeted biopsies using chromoendoscopy were taken. Patients were followed-up for at least 1 year after inclusion. RESULTS: In total, 101 patients [62 men; median age: 48 years; median duration of disease: 19 years] were recruited in ten centres. The endoscopic procedure was incomplete in 47 cases because of impassable strictures and dilation was performed in four patients. Indeterminate small bowel dysplasia was identified in two patients at endoscopic screening; SBA was confirmed in one after surgical resection. With an at least 1-year follow-up duration, two additional cases of SBA were identified in patients who underwent surgery for obstruction, resulting in a 33% sensitivity rate for SBA endoscopic screening. CONCLUSION: In a cohort of high-risk patients, the prevalence of dysplasia and SBA on CD was 4%. Because of its low sensitivity, endoscopic screening cannot be recommended for surveillance in CD patients at high-risk of SBA.

No statistically significant kinematic difference found between a cruciate-retaining and posterior-stabilised Triathlon knee arthroplasty: a laboratory study involving eight cadavers examining soft-tissue laxity.

The aim of this study was to compare the maximum laxity conferred by the cruciate-retaining (CR) and posterior-stabilised (PS) Triathlon single-radius total knee arthroplasty (TKA) for anterior drawer, varus-valgus opening and rotation in eight cadaver knees through a defined arc of flexion (0º to 110º). The null hypothesis was that the limits of laxity of CR- and PS-TKAs are not significantly different. The investigation was undertaken in eight loaded cadaver knees undergoing subjective stress testing using a measurement rig. Firstly the native knee was tested prior to preparation for CR-TKA and subsequently for PS-TKA implantation. Surgical navigation was used to track maximal displacements/rotations at 0º, 30º, 60º, 90º and 110° of flexion. Mixed-effects modelling was used to define the behaviour of the TKAs. The laxity measured for the CR- and PS-TKAs revealed no statistically significant differences over the studied flexion arc for the two versions of TKA. Compared with the native knee both TKAs exhibited slightly increased anterior drawer and decreased varus-valgus and internal-external roational laxities. We believe further study is required to define the clinical states for which the additional constraint offered by a PS-TKA implant may be beneficial.

[Appropriate medication prescribing in older people]. / Bon usage des médicaments chez le sujet âgé.

Drug-induced adverse effects are one of the main avoidable causes of hospitalization in older people. Numerous lists of potentially inappropriate medications for older people have been published, as national and international guidelines for appropriate prescribing in numerous diseases and for different age categories. The present review describes the general rules for an appropriate prescribing in older people and summarizes, for the main conditions encountered in older people, medications that are too often under-prescribed, the precautions of use of the main drugs that induce adverse effects, and drugs for which the benefit to risk ratio is unfavourable in older people. All these data are assembled in educational tables designed to be printed in a practical pocket format and used in daily practice by prescribers, whether physicians, surgeons or pharmacists.

Crohn's disease clinical course and severity in obese patients.

BACKGROUND AND AIMS: Obesity is unusual in Crohn's disease and the particularities of the disease in obese patients have not been studied. METHODS: 2065 patients were studied retrospectively. Obesity was defined by a BMI value >25.0 at disease onset and >30.0 at any time during the course of the disease. Disease characteristics, therapeutic needs, and year-by-year disease activity were determined in patients with and without obesity. RESULTS: 62 patients (3%) were obese. When compared with non-obese patients, obese patients did not show differences regarding sex, intestinal disease location, and disease behavior, but at diagnosis they were older (32 vs 28 years, P = 0.01) and a larger proportion had anoperineal disease (35 vs 24%, P = 0.03). When the 62 obese patients were paired for sex, location of disease at onset, date of birth, and date of diagnosis with 124 non-obese patients, the disease severity assessed by the importance of medical therapy and excisional surgery did not differ in the two groups but time to development of anoperineal abscess or fistula was shorter in obese patients, and obese patients were more prone to develop an active disease (OR 1.50, 95% CI 1.07-2.11) and to require hospitalization (OR 2.35, 95% CI 1.56-3.52) CONCLUSION: Obesity in Crohn's disease is associated with more frequent anoperineal complications and a more marked year-by-year disease activity, but does not alter significantly the long-term course of the disease.

[Treatment of a hemorrhagic duodenal varice by endoscopic sclerotherapy]. / Traitement par sclérothérapie endoscopique d'une varice duodénale hémorragique.

We report the case of a duodenal varix rupture in a 37-year-old man revealing an alcoholic cirrhosis. Endoscopic diagnosis of this duodenal varix was difficult because of its atypical and changing appearance. Endoscopic sclerotherapy was completely successful and there was no recurrent bleeding. Although duodenal varix is rare, this case and the literature emphasize the importance of considering this diagnosis in all patients with duodenal tumoral lesions and suspected portal hypertension. In this context, duodenal biopsy can be dangerous and should be avoided. In case of duodenal varix rupture, endoscopic sclerotherapy appears to be a safe and efficient first-choice therapy.

[The preventive effects of physical activity in the elderly]. / Les effets préventifs de l'activité physique chez les personnes âgées.

PHYSICAL ACTIVITY AND AGING: Physical activity prevents some age-related impairment. Physical activity reduces the decline of physical capacity which remains limited by maximal heart rate, and reduces the incidence of cardiovascular diseases by decreasing and preventing associated risk factors. Physical activity reduces age-related bone loss, its effect being potentialized by hormonal replacement therapy, and improves balance function, leading to a lower incidence of falls and fractures in older subjects. Physical activity helps to preserve nutritional balance and lean mass/fat mass ratio and reduces age-related insulin resistance. Moreover, physical activity has a beneficial influence on psychological function by improving cognitive performances and decreasing incidence of depression. Lastly, physical activity seems to reduce the incidence of several cancers, colic and mammary cancers particularly. PHYSICAL ACTIVITY, QUANTITY AND QUALITY OF LIFE: These multiple actions explain that physical activity, if it's adapted to subject's specificities increases longevity, delay entry in dependence and improves quality of life in older subjects. WHAT ARE THE RECOMMENDED ACTIVITIES: There is a superiority of individualized programs giving greater place to warm-up and associated endurance and resistive exercises intended to improve simultaneously cardiovascular and muscular functions. SPECIAL INTERESTS OF PHYSICAL ACTIVITY IN FRAIL AND VERY OLD SUBJECTS: Throughout its beneficial effects on aerobic capacity, muscular function, social integration, cognitive function and autonomy, physical activity may have a particular interest in frail subjects, when programs are adapted to physical capacities of these subjects and associated with nutritional supplements.