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Mitochondria represent key organelles influencing cellular homeostasis and have been implicated in the signalling events regulating protein synthesis. We examined whether mitochondrial bioenergetics (oxidative phosphorylation and reactive oxygen species (H2O2) emission, ROS) measured in vitroin permeabilized muscle fibres represent regulatory factors for integrated daily muscle protein synthesis rates and skeletal muscle mass changes across the spectrum of physical activity, including free‐living and bed‐rest conditions: n= 19 healthy, young men (26 ± 4 years, 23.4 ± 3.3 kg/m2) and following 12 weeks of resistance‐type exercise training: n= 10 healthy older men (70 ± 3 years, 25.2 ± 2.1 kg/m2). Additionally, we evaluated the direct relationship between attenuated mitochondrial ROS emission and integrated daily myofibrillar and sarcoplasmic protein synthesis rates in genetically modified mice (mitochondrial‐targeted catalase, MCAT). Neither oxidative phosphorylation nor H2O2emission were associated with muscle protein synthesis rates in healthy young men under free‐living conditions or following 1 week of bed rest (both P> 0.05). Greater increases in GSSG concentration were associated with greater skeletal muscle mass loss following bed rest (r= −0.49, P< 0.05). In older men, only submaximal mitochondrial oxidative phosphorylation (corrected for mitochondrial content) was positively associated with myofibrillar protein synthesis rates during exercise training (r= 0.72, P< 0.05). However, changes in oxidative phosphorylation and H2O2emission were not associated with changes in skeletal muscle mass following training (both P> 0.05). Additionally, MCAT mice displayed no differences in myofibrillar (2.62 ± 0.22 vs. 2.75 ± 0.15%/day) and sarcoplasmic (3.68 ± 0.35 vs. 3.54 ± 0.35%/day) protein synthesis rates when compared with wild‐type mice (both P> 0.05). Mitochondrial oxidative phosphorylation and reactive oxygen emission do not seem to represent key factors regulating muscle protein synthesis or muscle mass regulation across the spectrum of physical activity.

Communicating emotional experiences effectively is critical for adaptive functioning and personal and interpersonal well-being. Here, we investigated whether variability in depression symptoms undermines people’s ability to express their emotions to others (“emotional expressive accuracy”) and how those communication dynamics influence other’s impressions. In Phase 1, 49 “targets” were videotaped describing significant autobiographical events; they then watched their videos and continuously rated how positive/negative they were feeling throughout the narrative. In Phase 2, 171 “perceivers” watched subsets of videos from targets and similarly rated each target’s affect. Results from 1,645 unique target–perceiver observations indicate a link between target’s depressive symptoms and impaired emotional expressive accuracy for positive events, B= -0.002, t(1,501) = -3.152, p= .002. Likewise, more depressive targets were rated less favorably by perceivers, again when sharing positive events, B= -0.012, t(1,511) = -10.145, p< .001. Given the beneficial effects of “capitalization”—sharing positive experiences with others—these findings may illustrate one link between depressive symptoms and impoverished relationships.

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell–cell interaction analyses predict substantial endothelial-to-perivascular cell ligand–receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

Background: Risk-based monitoring (RBM) and risk-based quality management (RBQM) offer a compelling approach to increase efficiency, speed and quality in clinical trials by prioritizing and mitigating risks related to essential safety and efficacy data. Since 2013, the FDA and EMA have encouraged the use of RBM/RBQM, however adoption has been slow with limited understanding of the barriers to adoption. Methods: The Tufts Center for the Study of Drug Development conducted an online survey among pharmaceutical, biotechnology, and contract research organizations and gathered 206 responses on 32 distinct RBQM practices. Results: On average, companies implemented RBQM in 57% of their clinical trials. Lower levels of adoption were observed among companies conducting fewer than 25 trials annually (48%) compared to those conducting more than 100 trials annually (63%). Primary barriers to adoption include lack of organizational knowledge and awareness, mixed perceptions of the value proposition of RBQM, and poor change management planning and execution. Insights into improving the level of adoption are discussed.

More children with inflammatory bowel disease are being diagnosed, and complications like acute severe colitis can be fatal. Current treatment works in most cases, but some may need urgent surgery to save their lives. Tofacitinib is a new drug used in adults with good results, and it is an attractive option for different reasons. It acts fast so it can be used in urgent cases when other therapies do not work. Also, the effects disappear rapidly after stopping it, making it safer. We present six patients treated with tofacitinib for a severe episode when tofacitinib was the last option to avoid surgery. They responded quickly, with some patients being free of symptoms after a couple of days. No patient needed surgery. Laboratories improved rapidly during the following months. Four patients had their disease fully controlled at the last follow-up.

This monograph analyzes online coverage and social media posts from five professional athletes—Simone Biles, Serena Williama, Naomi Osaka, Chloe Kim, and Gracie Gold—to sheds light on the journalistic and individual narratives around athletes, performance, goals as these intersect with mental health. Online news and entertainment media’s general representation of athletes frequently emphasizes victory with a focus on outcomes, often overshadowing the athletes’ well-being. Using social identity and framing theories, the study identifies narratives in social and online media, emphasizing the storytelling components related to mental health, as well as what athletes express as potential causes of the mental health issues they are experiencing, especially intense competition, physical condition, media pressure, and a general lack of mental health awareness in sports. The study’s examination of how athletes use their social media platforms to help journalists craft their stories offers a deeper understanding of their mental health stories beyond the basic win-or-lose narrative. We advocate for a paradigm shift, urging recognition of athletes as individuals with vulnerabilities who deserve supportive environments.

This paper presents an examination of the interrelationship between household vehicle ownership and ridehailing use frequency. Both variables constitute important mobility choices with significant implications for the future of transport. Although it is generally known that these two behavioral phenomena are inversely related to one another, the direction of causality is rather ambiguous. Do vehicle ownership levels affect ridehailing use frequency, or does the adoption and use of ridehailing services affect vehicle ownership? If ridehailing services affect vehicle ownership, then it is plausible that a future of mobility-as-a-service would be characterized by lower levels of vehicle ownership. To explore the degree to which these causal relationships are prevalent in the population, a joint latent segmentation model system was formulated and estimated on a survey data set collected in four automobile-oriented metropolitan areas of the United States. The latent segmentation model system recognized that the causal structures driving the mobility choices of individuals were not directly observable. Model estimation results showed that 58% of the survey sample followed the causal structure in which ridehailing use frequency affected vehicle ownership. This finding suggests that there is considerable structural heterogeneity in the population with respect to causal structures and that ridehailing use does indeed hold considerable promise to effect changes in private vehicle ownership in the future.

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein–protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitropotency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59with a balanced profile, which are suitable for future development toward therapeutic use.

Zusammenfassung: Die lebensrettenden Basismaßnahmen (Basic Life Support, BLS) umfassen die Aufrechterhaltung freier Atemwege sowie die Unterstützung von Atmung und Kreislauf ohne Hilfsmittel, abgesehen von Infektionsschutzmaßnahmen. Die neueste Handlungsempfehlung der American Heart Association (AHA) vom 31.03.2008 beinhaltet die Forderung, dass Notfallzeugen eines außerklinischen Herzstillstands vermutlich kardialer Genese bei Erwachsenen, die nicht oder nicht mehr ausreichend in der kardiopulmonalen Reanimation (CPR) geübt sind, ausschließlich eine Herzdruckmassage ohne Beatmung durchführen sollen („compression-only CPR“). Notfallzeugen, die mit der CPR vertraut sind, wird nunmehr die Wahl zwischen konventioneller CPR (Herzdruckmassage mit Beatmung im Verhältnis 30:2) oder alleiniger Herzdruckmassage überlassen. Auf der Grundlage evidenzbasierter Medizin und unter Hinzuziehen auch neuester wissenschaftlicher Erkenntnisse ist es derzeit nicht vorgesehen, die aktuellen Reanimationsleitlinien des European Resuscitation Council (ERC) für „Lebensrettende Basismaßnahmen für Erwachsene“ zu ändern oder zu ergänzen. Sowohl der German Resuscitation Council (GRC) wie auch der ERC sehen keinerlei Änderungs- oder Ergänzungsbedarf für Europa und bleiben dabei, dass allein Laienhelfer, die nicht gewillt oder unfähig sind, eine Mund-zu-Mund-Beatmung durchzuführen, die CPR ausschließlich mittels Thoraxkompressionen durchführen sollten. Es wird betont, dass die Ausbildung von jugendlichen Laienhelfern und die Etablierung von Schulungsprogrammen durch Hilfsorganisationen und in Schulen stärker gefördert werden müssen.

Chromosome substitution lines (CSLs) are tentatively supreme resources to investigate non-allelic genetic interactions. However, the difficulty of generating such lines in most species largely yielded imperfect CSL panels, prohibiting a systematic dissection of epistasis. Here, we present the development and use of a unique and complete panel of CSLs in Arabidopsis thaliana, allowing the full factorial analysis of epistatic interactions. A first comparison of reciprocal single chromosome substitutions revealed a dependency of QTL detection on different genetic backgrounds. The subsequent analysis of the complete panel of CSLs enabled the mapping of the genetic interactors and identified multiple two- and three-way interactions for different traits. Some of the detected epistatic effects were as large as any observed main effect, illustrating the impact of epistasis on quantitative trait variation. We, therefore, have demonstrated the high power of detection and mapping of genome-wide epistasis, confirming the assumed supremacy of comprehensive CSL sets.

Clinical trial conduct poses numerous challenges, many pertaining to patient recruitment. The primary objectives of this study were to update benchmarks on site activation and patient enrollment gathered in previous Tufts CSDD studies and examine current usage of recruitment and retention tactics. The data collection focused on site activation and patient enrollment metrics used for studies. Analyses were conducted comparing results from 2012, 2019 and 2023. The results indicate that actual enrollments exceeded planned enrollments for a majority of studies and timelines were shorter than expected. In addition, differences were found for enrollment achievement by global region and site type. Further investigation into studies conducted during a later time frame and post-pandemic could be compared with current benchmarks to examine differences.

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1–3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53and RB1alterations were exclusively part of the common ancestor, MYCfamily amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300alterations underwent genome duplications. Gene-damaging TP53alterations and co-alterations of TP53missense mutations with TP73, CREBBP/EP300or FMN2were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.

Background: Primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) represent the liver’s two most common malignant neoplasms. Liver-directed therapies such as ablation have become part of multidisciplinary therapies despite a paucity of data. Therefore, an expert panel was convened to develop evidence-based recommendations regarding the use of microwave ablation (MWA) and radiofrequency ablation (RFA) for HCC or CRLM less than 5 cm in diameter in patients ineligible for other therapies. Methods: A systematic review was conducted for six key questions (KQ) regarding MWA or RFA for solitary liver tumors in patients deemed poor candidates for first-line therapy. Subject experts used the GRADE methodology to formulate evidence-based recommendations and future research recommendations. Results: The panel addressed six KQs pertaining to MWA vs. RFA outcomes and laparoscopic vs. percutaneous MWA. The available evidence was poor quality and individual studies included both HCC and CRLM. Therefore, the six KQs were condensed into two, recognizing that these were two disparate tumor groups and this grouping was somewhat arbitrary. With this significant limitation, the panel suggested that in appropriately selected patients, either MWA or RFA can be safe and feasible. However, this recommendation must be implemented cautiously when simultaneously considering patients with two disparate tumor biologies. The limited data suggested that laparoscopic MWA of anatomically more difficult tumors has a compensatory higher morbidity profile compared to percutaneous MWA, while achieving similar overall 1-year survival. Thus, either approach can be appropriate depending on patient-specific factors (very low certainty of evidence). Conclusion: Given the weak evidence, these guidelines provide modest guidance regarding liver ablative therapies for HCC and CRLM. Liver ablation is just one component of a multimodal approach and its use is currently limited to a highly selected population. The quality of the existing data is very low and therefore limits the strength of the guidelines. Background: The multidisciplinary management of both primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) may include liver-directed therapies as part of treatment algorithms; these algorithms focus heavily on control of liver-specific disease as in many cases this serves as a proxy for long-term survival. Hepatectomy is the primary treatment option in patients who can tolerate resection for both HCC and CRLM. Liver-directed therapies include arterial embolization, stereotactic body radiation therapy, and liver ablation. Over the last several decades, microwave ablation (MWA) and radiofrequency ablation (RFA) of liver tumors have been used in high-risk patients unfit for surgical intervention or tumors not amenable to local control with other therapies. As ablation is an evolving technology, outcomes data are primarily reported in liver tumors less than 3 cm in diameter, while data for liver tumors greater than 3 cm are limited for both HCC and CRLM. The authors sought to perform a systematic review of the existing data to assess for meaningful conclusions. Therefore, a multidisciplinary expert panel was convened to develop evidence-based recommendations to support clinicians, patients, and others regarding the role of liver ablation in the treatment of HCC and CRLM up to 5 cm in diameter. Methods: A systematic review was conducted for six key questions (KQ) regarding the use of either MWA or RFA for solitary HCC or CRLM. Due to the paucity of evidence available, HCC and CRLM less than 5 cm in diameter were combined into two final KQs which were used to develop recommendations. Evidence-based recommendations were formulated using the GRADE methodology by subject matter experts. Additionally, the panel developed recommendations for future research. Interpretation of strong and conditional recommendations: All guideline recommendations were assigned “conditional” recommendations. These were based on the GRADE approach. The words “the guideline panel suggests” were used for conditional recommendations. Key questions addressed by these guidelines: Should MWA (laparoscopic or open) vs. RFA (laparoscopic or open) be used for HCC or CRLM less than 5 cm ineligible for other therapies? Should laparoscopic MWA vs. percutaneous MWA be used for HCC and/or CRLM less than 5 cm ineligible for other therapies? Recommendations: Should MWA (laparoscopic or open) vs. RFA (laparoscopic or open) be used for HCC or CRLM less than 5 cm ineligible for other therapies? The panel suggests MWA and RFA are both safe and feasible. There was insufficient evidence to recommend one modality over another in terms of oncologic outcomes (conditional recommendation, very low certainty of evidence). Should laparoscopic MWA vs. percutaneous MWA be used for HCC and/or CRLM less than 5 cm ineligible for other therapies? The panel suggests that either ablative approach achieves similar overall outcomes, albeit through distinct patterns. The laparoscopic approach obtained better local control and the percutaneous approach had fewer morbidities while obtaining similar overall 1-year survival (conditional recommendation, very low certainty of evidence). How to use these guidelines: The aim of these guidelines is to assist surgeons and physicians in making management decisions for patients with HCC or CRLM. Given that the evidence for this guideline was based on very low certainty evidence, these guidelines should be applied with caution. They are also intended to provide education, inform advocacy, and describe future areas for research. The guidelines are not meant to mandate a particular approach or strategy given the lack of evidence and intricacies of the healthcare environment, individual patient needs, comorbidities, and surgeon experience. Specific situations require adjustment of treatment plans to suit the needs and priorities of the individual patient. Finally, since the guidelines take a patient-centered approach, patients can use these guidelines as a source of information and for discussion with their physicians.

This paper informs nurse leaders about the innovative role of the dually prepared nurse practitioner and provides practical ways for nurse leaders to support role implementation. In keeping with national reports and calls for action, this paper illustrates how dually certified primary care/psychiatric nurse practitioners are prepared to lead care for patients across the lifespan and with varying levels of acuity and high needs/high-cost patients in institutional and community-based settings. Selected outcomes from the Future of Nursing Report are presented with suggestions for role implementation. Future directions highlight the need to develop an evidence base for cost effectiveness and patient outcomes. [ABSTRACT FROM AUTHOR]

The Covid-19 pandemic drastically changed the way people work. This was no exception in the drug development industry, which like other industries has been grappling with the challenge of how to manage the transition back to the office while ensuring that people feel included. To understand what strategies organizations in the drug development industry are adopting and examine their impact on the employee experience, Tufts Center for the Study of Drug Development launched a survey that quantified the different strategies and their effect on work outcomes, including burnout, inclusion, and turnover. We found evidence that employees’ level of support for their organization’s remote work strategy had a significant impact on turnover, and this relationship was mediated by burnout and feeling of inclusion. Implications of the results are discussed.

The decline in postabsorptive and postprandial muscle protein fractional synthesis rates (FSR) does not quantitatively account for muscle atrophy during uncomplicated, short‐term disuse, when atrophy rates are the highest. We sought to determine whether 2 days of unilateral knee immobilization affects mixed muscle protein fractional breakdown rates (FBR) during postabsorptive and simulated postprandial conditions. Twenty‐three healthy, male participants (age: 22 ± 1 year; height: 179 ± 1 cm; body mass: 73.4 ± 1.5 kg; body mass index 22.8 ± 0.5 kg·m−2) took part in this randomized, controlled study. After 48 h of unilateral knee immobilization, primed continuous intravenous l‐[15N]‐phenylalanine and l‐[ring‐2H5]‐phenylalanine infusions were used for parallel determinations of FBR and FSR, respectively, in a postabsorptive (saline infusion; FAST) or simulated postprandial state (67.5 mg·kg body mass−1·h−1amino acid infusion; FED). Bilateral m. vastus lateralisbiopsies from the control (CON) and immobilized (IMM) legs, and arterialized‐venous blood samples, were collected throughout. Amino acid infusion rapidly increased plasma phenylalanine (59 ± 9%), leucine (76 ± 5%), isoleucine (109 ± 7%) and valine (42 ± 4%) concentrations in FED only (all P< 0.001), which was sustained for the remainder of infusion. Serum insulin concentrations peaked at 21.8 ± 2.2 mU·L−1at 15 min in FED only (P< 0.001) and were 60% greater in FED than FAST (P< 0.01). Immobilization did not influence FBR in either FAST (CON: 0.150 ± 0.018; IMM: 0.143 ± 0.017%·h−1) or FED (CON: 0.134 ± 0.012; IMM: 0.160 ± 0.018%·h−1; all effects P> 0.05). However, immobilization decreased FSR (P< 0.05) in both FAST (0.071 ± 0.004 vs. 0.086 ± 0.007%·h−1; IMM vs CON, respectively) and FED (0.066 ± 0.016 vs. 0.119 ± 0.016%·h−1; IMM vs CON, respectively). Consequently, immobilization decreased net muscle protein balance (P< 0.05) and to a greater extent in FED (CON: −0.012 ± 0.025; IMM: −0.095 ± 0.023%·h−1; P< 0.05) than FAST (CON: −0.064 ± 0.020; IMM: −0.072 ± 0.017%·h−1). We conclude that merely 2 days of leg immobilization does not modulate postabsorptive and simulated postprandial muscle protein breakdown rates. Instead, under these conditions the muscle negative muscle protein balance associated with brief periods of experimental disuse is driven near exclusively by reduced basal muscle protein synthesis rates and anabolic resistance to amino acid administration.

Describes the need for neurosurgical capabilities in combat zone to best provide care for combat casualties with trauma brain injury.

It remains unclear whether non–animal-derived dietary protein sources (and therefore vegan diets) can support resistance training-induced skeletal muscle remodeling to the same extent as animal-derived protein sources.

In the 10‐week, phase 2 CLARITY study of patients with major depressive disorder, adjunctive therapy to antidepressants with pimavanserin 34 mg once daily statistically significantly improved the Hamilton Depression Rating Scale (HAMD‐17) total score (primary endpoint) and Sheehan Disability Scale (SDS) score (secondary endpoint) versus placebo. This analysis characterized the exposure–response (E–R) relationships of pimavanserin in this CLARITY patient population. Exposure measures were estimated for each patient based on population‐pharmacokinetic empirical Bayesian estimates. E–R models were developed to describe exposure–efficacy (HAMD‐17, SDS, and Clinical Global Impression‐Improvement [CGI‐I] scale) and exposure–safety relationships (Karolinska Sleepiness Scale [KSS], Massachusetts General Hospital Sexual Functioning Inventory [MGH‐SFI], and adverse events [AEs] of headache, sedation, and somnolence) relationships. For the primary efficacy endpoint (HAMD‐17 scores), a sigmoid maximum‐effect model described the time course of response, and a linear function of pimavanserin exposure was statistically significant. HAMD‐17 scores decreased steadily over time following placebo and pimavanserin treatment; separation from placebo increased as peak pimavanserin plasma concentration (Cmax) increased. At median pimavanserin Cmax(34‐mg dose), the reduction from baseline in HAMD‐17 scores was −11.1 and −13.5 at weeks 5 and 10, respectively. Relative to placebo, the model predicted comparable reductions in HAMD‐17 scores at weeks 5 and 10. Similar improvements in favor of pimavanserin were detected with SDS, CGI‐I, MGH‐SFI, and KSS scores. No E–R relationship was found for AEs. E–R modeling predicted a relationship between higher pimavanserin exposure and improvement in HAMD‐17 score and improvement across multiple secondary efficacy endpoints.

This nationwide analysis shows that patients undergoing surgery with perioperative COVID-19 had higher risks of 30-day mortality & morbidity, especially thromboembolic events, compared to matched patients undergoing surgeries of similar urgency & complexity.

Background: Colorectal liver metastases (CRLM) occur in roughly half of patients with colorectal cancer. Minimally invasive surgery (MIS) has become an increasingly acceptable and utilized technique for resection in these patients, but there is a lack of specific guidelines on the use of MIS hepatectomy in this setting. A multidisciplinary expert panel was convened to develop evidence-based recommendations regarding the decision between MIS and open techniques for the resection of CRLM. Methods: Systematic review was conducted for two key questions (KQ) regarding the use of MIS versus open surgery for the resection of isolated liver metastases from colon and rectal cancer. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. Additionally, the panel developed recommendations for future research. Results: The panel addressed two KQs, which pertained to staged or simultaneous resection of resectable colon or rectal metastases. The panel made conditional recommendations for the use of MIS hepatectomy for both staged and simultaneous resection when deemed safe, feasible, and oncologically effective by the surgeon based on the individual patient characteristics. These recommendations were based on low and very low certainty of evidence. Conclusions: These evidence-based recommendations should provide guidance regarding surgical decision-making in the treatment of CRLM and highlight the importance of individual considerations of each case. Pursuing the identified research needs may help further refine the evidence and improve future versions of guidelines for the use of MIS techniques in the treatment of CRLM.

Ensuring equity is considered in all types of decision making, including with respect to cycling provision, is important. Studies have investigated equity in relation to provision of cycling infrastructure and facilities. However, identifying other factors that need consideration in cycling equity is important. This study explored the impact of cycling infrastructure provision on individual perceptions of cycling infrastructure in relation to sociodemographic characteristics in Auckland, New Zealand. The results indicated that bicycle lane availability did not significantly influence perceptions of cycling infrastructure; however, ethnicity and whether a person was a regular cyclist did. Among noncyclists and potential cyclists, ethnicity was the only factor found to significantly influence perceptions of cycling infrastructure. Māori, the indigenous people of New Zealand, and Pacific Islanders rated the provision of cycling infrastructure higher than others for the same level of bicycle infrastructure in their community. Whereas Māori had the highest percentage of potential cyclists among all ethnicities, Pacific Islanders had the highest percentage of noncyclists (64.9%), the lowest percentage of potential cyclists, and one of the lowest percentages of regular cyclists. The study showed that cycling provision perceptions were more affected by factors like ethnicity, education, and bicycle user type than objective measures of bicycle infrastructure. Following the capabilities approach of justice, this study suggests that equitable provision of cycling infrastructure may not lead to an equitable cycling environment. To achieve this, interpersonal and intrapersonal indicators such as ethnicity and community-related factors must also be considered to encourage and empower all population groups to cycle.

This important Western Trauma multicenter study found minimal benefit from embolization of liver injuries following the finding of blush on CT. Embolization carried a higher rate of complications with more drain placements and longer LOS.

Background: Gastroesophageal reflux disease (GERD) is one of the most common diseases in North America and globally. The aim of this guideline is to provide evidence-based recommendations regarding the most utilized and available endoscopic and surgical treatments for GERD. Methods: Systematic literature reviews were conducted for 4 key questions regarding the surgical and endoscopic treatments for GERD in adults: preoperative evaluation, endoscopic vs surgical or medical treatment, complete vs partial fundoplication, and treatment for obesity (body mass index [BMI] ≥ 35 kg/m2) and concomitant GERD. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. Recommendations for future research were also proposed. Results: The consensus provided 13 recommendations. Through the development of these evidence-based recommendations, an algorithm was proposed for aid in the treatment of GERD. Patients with typical symptoms should undergo upper endoscopy, manometry, and pH-testing; additional testing may be required for patients with atypical or extra-esophageal symptoms. Patients with normal or abnormal findings on manometry should consider undergoing partial fundoplication. Magnetic sphincter augmentation or fundoplication are appropriate surgical procedures for adults with GERD. For patients who wish to avoid surgery, the Stretta procedure and transoral incisionless fundoplication (TIF 2.0) were found to have better outcomes than proton pump inhibitors alone. Patients with concomitant obesity were recommended to undergo either gastric bypass or fundoplication, although patients with severe comorbid disease or BMI > 50 should undergo Roux-en-Y gastric bypass for the additional benefits that follow weight loss. Conclusion: Using the recommendations an algorithm was developed by this panel, so that physicians may better counsel their patients with GERD. There are certain patient factors that have been excluded from included studies/trials, and so these recommendations should not replace surgeon–patient decision making. Engaging in the identified research areas may improve future care for GERD patients.

ABSTRACTGyromitrin (acetaldehyde N-methyl-N-formylhydrazone) and its homologs are deadly mycotoxins produced most infamously by the lorchel (also known as false morel) Gyromitra esculenta, which is paradoxically consumed as a delicacy in some parts of the world. There is much speculation about the presence of gyromitrin in other species of the lorchel family (Discinaceae), but no studies have broadly assessed its distribution. Given the history of poisonings associated with the consumption of G. esculentaand G. ambigua, we hypothesized that gyromitrin evolved in the last common ancestor of these taxa and would be present in their descendants with adaptive loss of function in the nested truffle clade, Hydnotrya. To test this hypothesis, we developed a sensitive analytical derivatization method for the detection of gyromitrin using 2,4-dinitrobenzaldehyde as the derivatization reagent. In total, we analyzed 66 specimens for the presence of gyromitrin over 105 tests. Moreover, we sequenced the nuc rDNA internal transcribed spacer region ITS1-5.8S-ITS2 (ITS barcode) and nuc 28S rDNA to assist in species identification and to infer a supporting phylogenetic tree. We detected gyromitrin in all tested specimens from the G. esculentagroup as well as G. leucoxantha. This distribution is consistent with a model of rapid evolution coupled with horizontal transfer, which is typical for secondary metabolites. We clarified that gyromitrin production in Discinaceae is both discontinuous and more limited than previously thought. Further research is required to elucidate the gyromitrin biosynthesis gene cluster and its evolutionary history in lorchels.