A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma.

Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68+ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8+ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68+ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.

Preschool children generate quantity inferences from both words and pictures.

As children learn to communicate with others, they must develop an understanding of the principles that underlie human communication. Recent evidence suggests that adults expect communicative principles to govern all forms of communication, not just language, but evidence about children's ability to do so is sparse. This study investigated whether preschool children expect both pictures and words to adhere to the communicative principle of quantity using a simple matched paradigm. Children (N = 293) aged of 3 to 5 years (52.5% male and 47.5% female; majority White with college-educated mothers) participated. Results show that children as young as 3.5 years can use the communicative principle of quantity to infer meaning across verbal and pictorial alternatives.

Acute respiratory distress syndrome driven by severe hypercalcemia and acute kidney injury: A case report and literature review of a rare, life-threatening complication.

Acute respiratory distress syndrome (ARDS) is a rare and under-reported complication of hypercalcemia, which often presents in conjunction with acute kidney injury (AKI). Unfamiliarity with the condition inevitably leads to management uncertainty, resulting in fatal outcomes. Early identification, however, confers a good prognosis. We report a case of a 40-year-old male who presented with severe hypercalcemia and AKI and rapidly deteriorated due to ARDS, with no evidence of cardiogenic pulmonary edema or fluid overload. Infection screens were negative. He died despite invasive ventilation and continuous venous-venous hemofiltration. His autopsy revealed extensive metastatic pulmonary calcifications and alveolar edema. We found only 10 other cases of hypercalcemia-induced ARDS in the literature, with only 2 patients surviving. We provide the first literature review on the subject to guide the management of this rare but fatal complication, which can be managed with good outcomes if considered early.

The Potential Role of Iceland in Northern Europe's Protein Self-Sufficiency: Feasibility Study of Large-Scale Production of Spirulina in a Novel Energy-Food System.

Europe is dependent on protein-rich crop imports to meet domestic food demand. This has moved the topic of sustainable protein self-sufficiency up the policy agenda. The current study assesses the feasibility of protein self-sufficiency in Iceland, and its capacity to meet Northern Europe's demand, based on industrial-scale cultivation of Spirulina in novel production units. Production units currently operating in Iceland, and laboratory-derived nutritional profile for the Spirulina cultivated, provide the basis for a theoretical protein self-sufficiency model. Integrating installed and potentially installed energy generation data, the model elaborates six production scale-up scenarios. Annual biomass produced is compared with recommended dietary allowance figures for protein and essential amino acids to determine whether Northern Europe's population demands can be met in 2030. Results show that Iceland could be protein self-sufficient under the most conservative scenario, with 20,925 tonnes of Spirulina produced using 15% of currently installed capacity. In a greater allocation of energy capacity used by heavy industry, Iceland could additionally meet the needs of Lithuania, or Latvia, Estonia, Jersey, Isle of Man, Guernsey, and Faroe Islands. Under the most ambitious scenario utilizing planned energy projects, Iceland could support itself plus Denmark, or Finland, or Norway, or Ireland with up to 242,366 tonnes of biomass. On a protein-per-protein basis, each kilogram of Spirulina consumed instead of beef could save 0.315 tonnes CO2-eq. Under the most ambitious scenario, this yields annual savings of 75.1 million tonnes CO2-eq or 7.3% of quarterly European greenhouse gas emissions. Finally, practicalities of production scale-up are discussed.

Commentary on ethical dilemmas in the management of infants with necrotizing enterocolitis totalis.

This is a commentary on the manuscript titled "Ethical Dilemmas in the Management of Infants with Necrotizing Enterocolitis Totalis".

Representing agents, patients, goals and instruments in causative events: A cross-linguistic investigation of early language and cognition.

Although it is widely assumed that the linguistic description of events is based on a structured representation of event components at the perceptual/conceptual level, little empirical work has tested this assumption directly. Here, we test the connection between language and perception/cognition cross-linguistically, focusing on the relative salience of causative event components in language and cognition. We draw on evidence from preschoolers speaking English or Turkish. In a picture description task, Turkish-speaking 3-5-year-olds mentioned Agents less than their English-speaking peers (Turkish allows subject drop); furthermore, both language groups mentioned Patients more frequently than Goals, and Instruments less frequently than either Patients or Goals. In a change blindness task, both language groups were equally accurate at detecting changes to Agents (despite surface differences in Agent mentions). The remaining components also behaved similarly: both language groups were less accurate in detecting changes to Instruments than either Patients or Goals (even though Turkish-speaking preschoolers were less accurate overall than their English-speaking peers). To our knowledge, this is the first study offering evidence for a strong-even though not strict-homology between linguistic and conceptual event roles in young learners cross-linguistically.

Future foods for risk-resilient diets.

Future foods, such as microalgae, mycoprotein and mealworm, have been suggested as nutritious and sustainable dietary options. Here we consider one of the most profound, yet neglected, benefits of future foods farming systems-their potential to provide essential nutrition in the face of systemic disturbances-and discuss major barriers to realizing this prospect.

Postfundoplication retching: Strategies for management.

BACKGROUND: Retching is a common symptom in children following antireflux surgery, particularly in those with neurodisability. There is now a strong body of evidence that implicates retching as a major cause of wrap breakdown. Retching is not a symptom of gastroesophageal reflux disease; it is a component of the emetic reflex. In addition to causing wrap breakdown, it is indicative of the presence of nausea. It is a highly aversive experience and warrants treatment in its own right. METHODS: A framework was constructed for the management of postoperative retching, with strategies targeting different components of the emetic reflex. The impact of differing antireflux procedures upon retching was also considered. CONCLUSIONS: Once treatable underlying causes have been excluded, the approach includes modifications to feeds and feeding regimens, antiemetics and motility agents. Neuromodulation and other, novel, therapies may prove beneficial in future. Children at risk of postoperative retching may be identified before any antireflux surgery is performed. Fundoplication is inappropriate in these children because it does not treat their symptoms, which are not because of gastroesophageal reflux, and may make them worse. They are also at risk of wrap disruption. Alternative strategies for symptom management should be employed, and fundoplication should be avoided. LEVEL OF EVIDENCE: II-V.

Motion verbs and memory for motion events.

Language is assumed to affect memory by offering an additional medium of encoding visual stimuli. Given that natural languages differ, cross-linguistic differences might impact memory processes. We investigate the role of motion verbs on memory for motion events in speakers of English, which preferentially encodes manner in motion verbs (e.g., driving), and Greek, which tends to encode path of motion in verbs (e.g., entering). Participants viewed a series of motion events and we later assessed their memory of the path and manner of the original events. There were no effects of language-specific biases on memory when participants watched events in silence; both English and Greek speakers remembered paths better than manners of motion. Moreover, even when motion verbs were available (either produced by or heard by the participants), they affected memory similarly regardless of the participants' language: path verbs attenuated memory for manners of motion, but the reverse did not occur. We conclude that overt language affects motion memory, but these effects interact with underlying, shared biases in how viewers represent motion events.

Temporal trends in treatment and survival of older adult diffuse large B-Cell lymphoma patients in the SEER-Medicare linked database.

To describe temporal trends in treatment among older adult (≥66 years) patients diagnosed with diffuse large B-cell lymphoma (DLBCL), we analyzed 18,058 DLBCL patients from the Surveillance, Epidemiology, and End Results linked Medicare (SEER-Medicare) database diagnosed between 2001 and 2013. Among 65% of patients receiving treatment after diagnosis, R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) was the most common frontline therapy, increasing with more recent treatment year: 51% (2001-2003) vs. 69% (2010-2014). Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) was uncommon in these Medicare patients. As the addition of rituximab increased over time, we also observed an improved survival rate over time. It is possible there is an association, but we cannot make this inference as effectiveness was not measured in this study. Overall survival estimates indicated that survival probabilities steadily improved in more recent years; however, 5-year survival was <40%, indicating the need for improved treatment options for older adult DLBCL patients.

Does retching matter? Reviewing the evidence-Physiology and forces.

Failure of antireflux surgery is common in children with neurodisability, with a high incidence of persistent or recurrent symptoms, including retching. Anatomical disruption of the wrap is a frequent finding, but what forces underlie this disruption? This article reviews the forces generated during potential wrap-stressing episodes, putting them into the clinical context of wrap failure. Historically, wrap failure has been attributed to pressures arising from a reduction in gastric capacity or compliance, with advocates for an additional, gastric emptying procedure, at the time of fundoplication. However, any postoperative pressure changes are small and insufficient to cause disruption, and evidence of benefit from gastric emptying procedures is lacking. Diaphragmatic stressor events are common in the presence of neurodisability, and there is now increasing recognition of an association between diaphragmatic stressors and wrap breakdown. The analysis in this review demonstrates that the greatest forces on the fundoplication wrap are those associated with retching and vomiting. The direction and magnitude of these forces are sufficient to cause wrap herniation into the thorax, and wrap separation. Clinical series confirm that retching is consistently and strongly associated with wrap breakdown. Retching needs to be addressed if we are to reduce the incidence of wrap failure. Level of Evidence V.

Certified Child Life Specialists Lessen Emotional Distress of Children Undergoing Laceration Repair in the Emergency Department.

OBJECTIVE: The objective of this study is to evaluate the impact of certified child life specialists (CCLSs) on the emotional responses of children undergoing laceration repair in the emergency department (ED). METHODS: Patients 4 to 12 years of age who required laceration repair by suturing were prospectively enrolled at an urban tertiary pediatric ED. Certified child life specialists are not available at all times in our institution, allowing for a priori categorization of subjects into 2 comparison groups, those with and those without CCLS involvement. Subjects requiring anxiolysis, pharmacologic sedation, narcotics, or physical restraint were excluded. The Children's Emotional Manifestation Scale, a previously validated Likert-like tool, was used to quantify the patients' distress, with a higher score reflecting a more emotional child. Just before placement of the first suture, subjects were scored by trained independent observers. Baseline data included age, sex, race, type of local anesthetic, length and location of laceration, and analgesics administered. The primary endpoint of emotional score was compared with a 2-tailed Mann-Whitney U test, with a P < 0.05 considered statistically significant. RESULTS: Two hundred one patients constituted the final study cohort, with 103 (51%) having CCLS involvement. Study groups did not differ in regards to any baseline demographic or clinical characteristics. The median emotional score for patients with child life services was 7 (interquartile range, 6-9) versus 9 (interquartile range, 7.5-12) for those without (P < 0.0005). CONCLUSIONS: Certified child life specialist involvement is associated with less emotional distress for children undergoing laceration repair in the ED.

Association Between Hospital Financial Distress and Immediate Breast Reconstruction Surgery After Mastectomy Among Women With Ductal Carcinoma In Situ.

Importance: Hospital financial distress (HFD) is a state in which a hospital is at risk of closure because of its financial condition. Hospital financial distress may reduce the services a hospital can offer, particularly unprofitable ones. Few studies have assessed the association of HFD with quality of care. Objective: To examine the association between HFD and receipt of immediate breast reconstruction surgery after mastectomy among women diagnosed with ductal carcinoma in situ (DCIS). Design, Setting, and Participants: This retrospective cohort study assessed data from the Nationwide Inpatient Sample of 5760 women older than 18 years (mean [SD] age: 57.5 [13.2]) with DCIS who underwent mastectomy in 2008-2012 at hospitals categorized by financial distress. Women treated at 1156 hospitals located in 538 different counties across Arkansas, Arizona, California, Colorado, Connecticut, Florida, Iowa, Kentucky, Massachusetts, Maryland, Missouri, North Carolina, New Hampshire, New Jersey, Nevada, New York, Oregon, Pennsylvania, Rhode Island, Utah, Virginia, Vermont, Washington, Wisconsin, West Virginia, and Wyoming were included. Of these, 2385 women (41.4%) underwent immediate breast reconstruction surgery. Women with invasive cancer were excluded. The database included unique hospital identification variables, and participants were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes. Data were analyzed from January 1, 2012, to February 28, 2014. Main Outcomes and Measures: The primary outcome was the adjusted association between HFD and receipt of immediate breast reconstruction surgery after mastectomy. Results: In this analysis of database information, 2385 of 5760 women (41.4%) received immediate breast reconstruction surgery. Of these, 693 (36.7%) were treated at a hospital under high HFD and received immediate breast reconstruction surgery compared with 863 (44.0%) treated at a hospital under low HFD (P < .001). Reconstruction surgery was associated with younger age, white race, private insurance, treatment at a teaching and cancer hospital, private hospital ownership, and the percentage of individuals in the county with insurance. After adjustment, women treated at hospitals under high HFD (OR, 0.79; 95% CI, 0.62-0.99) and medium HFD (OR, 0.76; 95% CI, 0.61-0.94) were significantly less likely to receive reconstruction than women treated at hospitals with low to no HFD. Conclusions and Relevance: The financial strength of the hospital where a patient receives treatment is associated with receipt of immediate breast reconstruction surgery. In addition to focusing on patient-related factors, efforts to improve quality should also focus on hospital-related factors.

An Ounce of Prevention: Deaths Averted From Primary Prevention Interventions.

INTRODUCTION: The U.S. lags in the nationwide implementation of primary prevention interventions that have been shown to be efficacious. However, the potential population health benefit of widespread implementation of these primary prevention interventions remains unclear. METHODS: The meta-analytic literature from October 2013 to March 2014 of primary prevention interventions published between January 2000 and March 2014 was reviewed. The authors then estimated the number of deaths that could have been averted in the U.S. in 2010 if all rigorously studied, efficacious primary prevention interventions for which population attributable risk proportions could be estimated were implemented nationwide. RESULTS: A total of 372,054 (15.1%) of all U.S. deaths in 2010 would have been averted if all rigorously studied, efficacious primary prevention interventions were implemented. Two in three averted deaths would have been from cardiovascular disease or malignancy. CONCLUSIONS: A substantial proportion of deaths in the U.S. in 2010 could have been averted if efficacious primary prevention interventions were implemented nationwide. Further investment in the implementation of efficacious interventions is warranted to maximize population health in the U.S.

The genetics of gastroesophageal adenocarcinoma and the use of circulating cell free DNA for disease detection and monitoring.

INTRODUCTION: Gastroesophageal adenocarcinoma (GOA) is a frequently occurring cancer worldwide with a poor clinical outcome. Adenocarcinomas of the esophagus and gastroesophageal junction have shown a recent increase in frequency, therefore there is need to increase our understanding of GOA in order to improve our ability to detect, monitor and treat the disease. Areas covered: The authors discuss the current classification of GOA in the context of recent changes in incidence. The authors also discuss developments in the understanding of disease biology and recent discoveries from whole genome and whole exome sequencing, and studies in immunotherapy. Finally, the authors discuss the recent developments in the use of circulating tumour DNA (ctDNA). PubMed search terms were in English including 'esophageal/gastric adenocarcinoma', 'gastroesophageal junctional tumour', 'whole genome/exome sequencing', 'immunotherapy' and 'circulating tumour DNA'. Expert commentary: Shared biological and genetic changes in GOA suggest it can be investigated as a single disease entity with different molecular subtypes. A number of genes are recurrently mutated including TP53, SMAD4, PIK3CA and there are frequent somatic copy number alterations and high levels of chromosomal instability. A subset of these genetic alterations have been detected in ctDNA and may provide an important avenue of research for detecting minimal residual disease and response to chemo- and immunotherapies.

Functional outcomes in Hirschsprung disease: A single institution's 12-year experience.

AIMS: Hirschsprung disease (HD) is a chronic condition associated with long-term morbidity. We assessed the short and long-term functional outcomes of operated patients in a single institution over a 12-year period. MATERIALS AND METHODS: We conducted a retrospective review of all children operated for HD between 2002 and 2014. Postoperative functional outcomes were assessed using the Rintala Bowel Function Score (BFS, 0-20, 20=best score). We assessed hospital admissions, complications including Hirschsprung associated enterocolitis (HAEC) and the need for further surgical procedures. RESULTS: 72 (52 male) patients were studied, of whom, 6 (8%) had a positive family history, 5 (7%) had Trisomy 21 and 5 (7%) had total colonic HD. The median age at diagnosis was 6.5days (2 days-6.7 years) and median follow-up was 6years (1-12years). All patients except two underwent a Duhamel pull-through procedure. The median age at surgery was 4months (6days-90months). 37 (51%) procedures were performed single-stage and 7 (10%) were laparoscopically assisted. Our early complication rate was 15%; 11 (15%) patients were treated for HAEC and 43 (60%) did not require any further surgery. 12 (17%) underwent injection of botulinum toxin, 7 (10%) needed residual spur division and 4 (5%) required an unplanned, post pull-through enterostomy for obstructive defecation symptoms and HAEC. Two (3%) patients underwent an Antegrade Colonic Enema (ACE) stoma. The median BFS was 17 (5-20). There were two deaths both out of hospital. CONCLUSIONS: Long-term functional outcomes following Duhamel Pull-Through surgery are satisfactory although 40% of patients needed some form of further surgical intervention. The management of anal sphincter achalasia has improved with the use of botulinum toxin and we advocate aggressive and early management of this condition for symptoms of obstructive defecation and HAEC. LEVEL OF EVIDENCE: III.

Steady Increase In Prices For Oral Anticancer Drugs After Market Launch Suggests A Lack Of Competitive Pressure.

The cost of treating cancer has risen to unprecedented heights, putting tremendous financial pressure on patients, payers, and society. Previous studies have documented the rising prices of cancer drugs at launch, but less critical attention has been paid to the cost of these drugs after launch. We used pharmacy claims for commercially insured individuals to examine trends in postlaunch prices over time for orally administered anticancer drugs recently approved by the Food and Drug Administration (FDA). In the period 2007-13, inflation-adjusted per patient monthly drug prices increased 5 percent each year. Certain market changes also played a role, with prices rising an additional 10 percent with each supplemental indication approved by the FDA and declining 2 percent with the FDA's approval of a competitor drug. Our findings suggest that there is currently little competitive pressure in the oral anticancer drug market. Policy makers who wish to reduce the costs of anticancer drugs should consider implementing policies that affect prices not only at launch but also later.