Care of the patient with cleft lip and/or palate remains complex. Prior attempts at aggregating data to study the effectiveness of specific interventions or overall treatment protocols have been ...hindered by a lack of data standards. There exists a critical need to better define the outcomes- particularly those that matter most to patients and their families-and to standardize the methods by which these outcomes will be measured. This report summarizes the recommendations of an international, multidisciplinary working group with regard to which outcomes a typical cleft team could track, how those outcomes could be measured and recorded, and what strategies may be employed to sustainably implement a system for prospective data collection. It is only by agreeing on a common, standard set of outcome measures for the comprehensive appraisal of cleft care that intercenter comparisons can become possible. This is important for quality-improvement endeavors, comparative effectiveness research, and value-based health-care reform.
Extracellular histones in neutrophil extracellular traps (NETs) or in chromatin from injured tissues are highly pathological, particularly when liberated by DNases. We report the development of small ...polyanions (SPAs) (~0.9-1.4 kDa) that interact electrostatically with histones, neutralizing their pathological effects. In vitro, SPAs inhibited the cytotoxic, platelet-activating and erythrocyte-damaging effects of histones, mechanistic studies revealing that SPAs block disruption of lipid-bilayers by histones. In vivo, SPAs significantly inhibited sepsis, deep-vein thrombosis, and cardiac and tissue-flap models of ischemia-reperfusion injury (IRI), but appeared to differ in their capacity to neutralize NET-bound versus free histones. Analysis of sera from sepsis and cardiac IRI patients supported these differential findings. Further investigations revealed this effect was likely due to the ability of certain SPAs to displace histones from NETs, thus destabilising the structure. Finally, based on our work, a non-toxic SPA that inhibits both NET-bound and free histone mediated pathologies was identified for clinical development.
Apert syndrome is characterized by eyelid dysmorphology, V-pattern strabismus, extraocular muscle excyclorotation, and elevated intracranial pressure (ICP). We compare eyelid characteristics, ...severity of V-pattern strabismus, rectus muscle excyclorotation, and ICP control in Apert syndrome patients initially treated by endoscopic strip craniectomy (ESC) at about 4 months of age versus fronto-orbital advancement (FOA) performed about 1 year of age.
Twenty-five patients treated at Boston Children's Hospital met inclusion criteria for this retrospective cohort study. Primary outcomes were magnitude of palpebral fissure downslanting at 1, 3, and 5 years of age, severity of V-pattern strabismus, rectus muscle excyclorotation, and interventions to control ICP.
Before craniofacial repair and through 1 year of age, none of the studied parameters differed for FOA versus ESC treated patients. Palpebral fissure downslanting became statistically greater for those treated by FOA by 3 (
< 0.001) and 5 years of age (
= 0.001). Likewise, severity of palpebral fissure downslanting correlated with severity of V-pattern strabismus at 3 (
= 0.004) and 5 (
= 0.002) years of age. Palpebral fissure downslanting and rectus muscle excyclorotation were typically coexistent (
= 0.053). Secondary interventions to control ICP were required in four of 14 patients treated by ESC (primarily FOA) and in two of 11 patients initially treated by FOA (primarily third ventriculostomy) (
= 0.661).
Apert patients initially treated by ESC had less severe palpebral fissure downslanting and V-pattern strabismus, normalizing their appearance. Thirty percent initially treated by ESC required secondary FOA to control ICP.
In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. ...More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.
In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.
Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval CI, 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.
Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.).
Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics ...to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.
Immediate tracheal extubation of selected adult patients after orthotopic liver transplant (OLT) is common practice. We hypothesized that selected children may be safely extubated immediately after ...OLT and avoid potentially deleterious effects of artificial ventilation and sedation.
After June 2002, we chose immediate extubation unless a specific contraindication was identified. Charts of all children undergoing OLT between June 2002 and February 2005 were reviewed to audit safety and outcome of this approach. Comparative data were obtained for children undergoing first elective OLT at other UK centers.
Forty-six cadaveric liver transplants were performed in 40 patients: 26 of 34 (76%) elective transplants and 4 of 12 (33%) urgent transplants were extubated immediately after surgery. Eight of 14 (57%) children weighing less than 10 kg were successfully extubated. One child required reintubation after developing transfusion-related acute lung injury. There were no other events compromising patient or graft. Small recipient size, split/reduced grafts, preexisting respiratory disease, retransplantation, and acute liver failure did not individually preclude successful immediate extubation. After elective OLT, the mean duration of intensive care stay was significantly shorter in the extubated group than in those who were ventilated (2.5 vs. 6.1 days, P<0.01). All children receiving a liver transplant at other UK centers in 2003 were ventilated postoperatively. However, the median duration of intensive care stay (2 days) was the same as in our series.
Immediate extubation of selected children after OLT is safe. It may enhance patient recovery, benefit graft physiology, and reduce intensive care requirement.
Building chronological frameworks for proxy sequences spanning 130–60 ka b2k is plagued by difficulties and uncertainties. Recent developments in the North Atlantic region, however, affirm the ...potential offered by tephrochronology and specifically the search for cryptotephra. Here we review the potential offered by tephrostratigraphy for sequences spanning 130–60 ka b2k. We combine newly identified cryptotephra deposits from the NGRIP ice-core and a marine core from the Iceland Basin with previously published data from the ice and marine realms to construct the first tephrostratigraphical framework for this time-interval. Forty-three tephra or cryptotephra deposits are incorporated into this framework; twenty three tephra deposits are found in the Greenland ice-cores, including nine new NGRIP tephras, and twenty separate deposits are preserved in various North Atlantic marine sequences. Major, minor and trace element results are presented for the new NGRIP horizons together with age estimates based on their position within the ice-core record. Basaltic tephras of Icelandic origin dominate the framework with only eight tephras of rhyolitic composition found. New results from marine core MD99-2253 also illustrate some of the complexities and challenges of assessing the depositional integrity of marine cryptotephra deposits. Tephra-based correlations in the marine environment provide independent tie-points for this time-interval and highlight the potential of widening the application of tephrochronology. Further investigations, however, are required, that combine robust geochemical fingerprinting and a rigorous assessment of tephra depositional processes, in order to trace coeval events between the two depositional realms.
•A record of Icelandic tephra deposits in ice and marine cores between 60 and 130 ka.•New, previously unknown tephra deposits are identified as cryptotephras.•Marine-based cryptotephras require assessment of depositional processes.•Three tephras used to independently correlate North Atlantic marine cores.•New insights into potential of tephrochronology beyond 60 ka.
•Benzoic acid limited lactic acid bacteria growth in liquid feed for finisher pigs•The pH of liquid feed was stabilised with benzoic acid inclusion•Benzoic acid limited spontaneous fermentation in ...liquid feed for finisher pigs•Benzoic acid supplementation did not impact grow-finisher pig growth•Supplementation of benzoic acid to grow-finisher pigs did not impact carcass traits
Benzoic acid has long been used as a food preservative due to its antibacterial and antifungal effects. Supplementation to pig diets has also been shown to inhibit microbial free amino acid degradation and to control yeast growth in fermented liquid feed. However, the effect of dietary inclusion of benzoic acid (BA) in fresh liquid feed for grow-finisher pigs on feed quality and the resultant effects on pig growth remain unclear. The objective of the current study was to compare four inclusion levels of BA (VevoVitall®) on feed microbial quality and on the growth performance of grow-finisher pigs. Two-hundred and sixteen pigs with a starting weight of 30.0kg (± 7.43 SD) were used in the experiment. The four dietary treatments were as follows: (1) Basal diet + 0kg/t BA (0kg/t BA), (2) Basal diet + 2.5kg/t BA (2.5kg/t BA), (3) Basal diet + 5kg/t BA (5kg/t BA), (4) Basal diet + 10kg/t BA (10kg/t BA). Lactic acid bacteria (LAB) counts in the mixing tank were similar across treatments (P>0.05) but were lower in the troughs for the feed supplemented with 10kg/t BA than for all other treatments (P<0.01). The pH of the 10kg/t BA treatment was also lower than that of the other three treatments. However, this only occurred in the mixing tank (P<0.01), as in the trough, the basal diet had the lowest pH (lower than the other three treatments; P<0.01). Dietary BA inclusion did not affect average daily gain, average daily feed intake, feed conversion efficiency, final live-weight, carcass weight or carcass quality during the experimental period (P>0.05). In conclusion, while BA may limit the growth of LAB in liquid feed and stabilise feed pH, its inclusion in the diet did not improve the growth performance or carcass quality of grow-finisher pigs.
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