Carpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet; many other clinical ...features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutations of RAB23, encoding a small GTPase that regulates vesicular transport, are present in the majority of cases. Here, we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning. We describe five affected individuals with similar dysmorphic facies, and three of them had either complete situs inversus, dextrocardia, or transposition of the great arteries; similar cardiac abnormalities were previously identified in a mouse mutant for the orthologous Megf8. The mutant alleles comprise one nonsense, three missense, and two splice-site mutations; we demonstrate in zebrafish that, in contrast to the wild-type protein, the proteins containing all three missense alterations provide only weak rescue of an early gastrulation phenotype induced by Megf8 knockdown. We conclude that mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. We did not observe any subject with biallelic loss-of function mutations, suggesting that some residual MEGF8 function might be necessary for survival and might influence the phenotypes observed.
Abstract
Background
Identification of patients at high risk of surgical-site infection may allow clinicians to target interventions and monitoring to minimize associated morbidity. The aim of this ...systematic review was to identify and evaluate prognostic tools for the prediction of surgical-site infection in gastrointestinal surgery.
Methods
This systematic review sought to identify original studies describing the development and validation of prognostic models for 30-day SSI after gastrointestinal surgery (PROSPERO: CRD42022311019). MEDLINE, Embase, Global Health, and IEEE Xplore were searched from 1 January 2000 to 24 February 2022. Studies were excluded if prognostic models included postoperative parameters or were procedure specific. A narrative synthesis was performed, with sample-size sufficiency, discriminative ability (area under the receiver operating characteristic curve), and prognostic accuracy compared.
Results
Of 2249 records reviewed, 23 eligible prognostic models were identified. A total of 13 (57 per cent) reported no internal validation and only 4 (17 per cent) had undergone external validation. Most identified operative contamination (57 per cent, 13 of 23) and duration (52 per cent, 12 of 23) as important predictors; however, there remained substantial heterogeneity in other predictors identified (range 2–28). All models demonstrated a high risk of bias due to the analytic approach, with overall low applicability to an undifferentiated gastrointestinal surgical population. Model discrimination was reported in most studies (83 per cent, 19 of 23); however, calibration (22 per cent, 5 of 23) and prognostic accuracy (17 per cent, 4 of 23) were infrequently assessed. Of externally validated models (of which there were four), none displayed ‘good’ discrimination (area under the receiver operating characteristic curve greater than or equal to 0.7).
Conclusion
The risk of surgical-site infection after gastrointestinal surgery is insufficiently described by existing risk-prediction tools, which are not suitable for routine use. Novel risk-stratification tools are required to target perioperative interventions and mitigate modifiable risk factors.
Lay Summary
This study is about finding ways to predict if someone will get an infection after having surgery on their stomach and intestines. If doctors know who is at high risk of getting an infection, they can take steps to prevent it and help the patient recover faster. The researchers looked at all the recent studies that have tried to predict who might get an infection after surgery. They found 23 studies that were good enough to look at in more detail. The researchers found that the studies they looked at were not very good at predicting who might get an infection. Most of the studies did not even check if their predictions were accurate. The few studies that did check were not very good at it. This means that doctors cannot use these predictions to help their patients. This means that doctors need to find better ways to predict who might get an infection after surgery on their stomach and intestines. If they can do this, they can help their patients recover faster and avoid problems like infections.
The aim of this systematic review was to identify original studies describing the development and validation of prognostic models for 30-day surgical-site infection after gastrointestinal surgery. The risk of surgical-site infection after gastrointestinal surgery is insufficiently described by existing risk-prediction tools, which are not suitable for routine use. Novel risk-stratification tools are required to target perioperative interventions and mitigate modifiable risk factors.
Acute kidney injury is associated with a poor prognosis in acute liver failure but little is known of outcomes in patients undergoing transplantation for acute liver failure who require renal ...replacement therapy.
A retrospective analysis of the United Kingdom Transplant Registry was performed (1 January 2001-31 December 2011) with patient and graft survival determined using Kaplan-Meier methods. Cox proportional hazards models were used together with propensity-score based full matching on renal replacement therapy use.
Three-year patient and graft survival for patients receiving renal replacement therapy were 77.7% and 72.6% compared with 85.1% and 79.4% for those not requiring renal replacement therapy (P<0.001 and P = 0.009 respectively, n = 725). In a Cox proportional hazards model, renal replacement therapy was a predictor of both patient death (hazard ratio (HR) 1.59, 95% CI 1.01-2.50, P = 0.044) but not graft loss (HR 1.39, 95% CI 0.92-2.10, P = 0.114). In groups fully matched on baseline covariates, those not receiving renal replacement therapy with a serum creatinine greater than 175 μmol/L had a significantly worse risk of graft failure than those receiving renal replacement therapy.
In patients being transplanted for acute liver failure, use of renal replacement therapy is a strong predictor of patient death and graft loss. Those not receiving renal replacement therapy with an elevated serum creatinine may be at greater risk of early graft failure than those receiving renal replacement therapy. A low threshold for instituting renal replacement therapy may therefore be beneficial.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups ...of patients who remain at high risk of dying in hospital.
In this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260.
Between March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8–32·7) in March 9 to April 26, 2020, to 16·4% (15·0–17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in the risk of mortality per 7-week period (odds ratio OR 0·68 95% CI 0·65–0·71). The higher proportions of patients with severe disease and comorbidities earlier in the first wave (March and April) than in June and July accounted for 10·2% of this reduction. The use of respiratory support changed during the first wave, with gradually increased use of non-invasive ventilation over the first wave. Changes in respiratory support and use of steroids accounted for 22·2%, OR 0·95 (0·94–0·95) of the reduction in in-hospital mortality.
The reduction in in-hospital mortality in patients with COVID-19 during the first wave in the UK was partly accounted for by changes in the case-mix and illness severity. A significant reduction in in-hospital mortality was associated with differences in respiratory support and critical care use, which could partly reflect accrual of clinical knowledge. The remaining improvement in in-hospital mortality is not explained by these factors, and could be associated with changes in community behaviour, inoculum dose, and hospital capacity strain.
National Institute for Health Research and the Medical Research Council.
To prospectively validate two risk scores to predict mortality (4C Mortality) and in-hospital deterioration (4C Deterioration) among adults hospitalised with COVID-19.
Prospective observational ...cohort study of adults (age ≥18 years) with confirmed or highly suspected COVID-19 recruited into the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study in 306 hospitals across England, Scotland and Wales. Patients were recruited between 27 August 2020 and 17 February 2021, with at least 4 weeks follow-up before final data extraction. The main outcome measures were discrimination and calibration of models for in-hospital deterioration (defined as any requirement of ventilatory support or critical care, or death) and mortality, incorporating predefined subgroups.
76 588 participants were included, of whom 27 352 (37.4%) deteriorated and 12 581 (17.4%) died. Both the 4C Mortality (0.78 (0.77 to 0.78)) and 4C Deterioration scores (pooled C-statistic 0.76 (95% CI 0.75 to 0.77)) demonstrated consistent discrimination across all nine National Health Service regions, with similar performance metrics to the original validation cohorts. Calibration remained stable (4C Mortality: pooled slope 1.09, pooled calibration-in-the-large 0.12; 4C Deterioration: 1.00, -0.04), with no need for temporal recalibration during the second UK pandemic wave of hospital admissions.
Both 4C risk stratification models demonstrate consistent performance to predict clinical deterioration and mortality in a large prospective second wave validation cohort of UK patients. Despite recent advances in the treatment and management of adults hospitalised with COVID-19, both scores can continue to inform clinical decision making.
ISRCTN66726260.
The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the ...D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure.
Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323.
These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.
Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have ...frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries-a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5' untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5' UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.
Malnutrition represents a key priority for global health policy, yet the impact of nutritional state on cancer surgery worldwide remains poorly described. We aimed to analyse the effect of ...malnutrition on early postoperative outcomes following elective surgery for colorectal or gastric cancer.
We did an international, multicentre, prospective cohort study of patients undergoing elective surgery for colorectal or gastric cancer between April 1, 2018, and Jan 31, 2019. Patients were excluded if the primary pathology was benign, they presented with cancer recurrence, or if they underwent emergency surgery (within 72 h of hospital admission). Malnutrition was defined with the Global Leadership Initiative on Malnutrition criteria. The primary outcome was death or a major complication within 30 days of surgery. Multilevel logistic regression and a three-way mediation analysis were done to establish the relationship between country income group, nutritional status, and 30-day postoperative outcomes.
This study included 5709 patients (4593 with colorectal cancer and 1116 with gastric cancer) from 381 hospitals in 75 countries. The mean age was 64·8 years (SD 13·5) and 2432 (42·6%) patients were female . Severe malnutrition was present in 1899 (33·3%) of 5709 patients, with a disproportionate burden in upper-middle-income countries (504 44·4% of 1135) and low-income and lower-middle-income countries (601 62·5% of 962). After adjustment for patient and hospital risk factors, severe malnutrition was associated with an increased risk of 30-day mortality across all country income groups (high income: adjusted odds ratio aOR 1·96 95% CI 1·14–3·37, p=0·015; upper-middle income: 3·05 1·45–6·42, p=0·003; low income and lower-middle income: 11·57 5·87–22·80, p<0·0001). Severe malnutrition mediated an estimated 32% of early deaths in low-income and lower-middle-income countries (aOR 1·41 95% CI 1·22–1·64) and an estimated 40% of early deaths in upper-middle-income countries (1·18 1·08–1·30).
Severe malnutrition is common in patients undergoing surgery for gastrointestinal cancers and is a risk factor for 30-day mortality following elective surgery for colorectal or gastric cancer. There is an urgent need to examine whether perioperative nutritional interventions can improve early outcomes following gastrointestinal cancer surgery worldwide.
National Institute for Health Research Global Health Research Unit.
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