An allelic series at the EDNRB2 locus controls diverse piebalding patterns in the domestic pigeon.

Variation in pigment patterns within and among vertebrate species reflects underlying changes in cell migration and function that can impact health, reproductive success, and survival. The domestic pigeon (Columba livia) is an exceptional model for understanding the genetic changes that give rise to diverse pigment patterns, as selective breeding has given rise to hundreds of breeds with extensive variation in plumage color and pattern. Here, we map the genetic architecture of a suite of pigmentation phenotypes known as piebalding. Piebalding is characterized by patches of pigmented and non-pigmented feathers, and these plumage patterns are often breed-specific and stable across generations. Using a combination of quantitative trait locus mapping in F2 laboratory crosses and genome-wide association analysis, we identify a locus associated with piebalding across many pigeon breeds. This shared locus harbors a candidate gene, EDNRB2, that is a known regulator of pigment cell migration, proliferation, and survival. We discover multiple distinct haplotypes at the EDNRB2 locus in piebald pigeons, which include a mix of protein-coding, noncoding, and structural variants that are associated with depigmentation in specific plumage regions. These results identify a role for EDNRB2 in pigment patterning in the domestic pigeon, and highlight how repeated selection at a single locus can generate a diverse array of stable and heritable pigment patterns.

Impact of a pharmacist-led oral chemotherapy monitoring clinic at the South Texas Veterans Health Care System.

As cancer treatments shift from traditional intravenous chemotherapy to inclusion of oral oncolytics, there is a critical need for structured oral chemotherapy monitoring and follow-up programs. To provide continuous care and minimize clinical gaps to Veterans receiving oral chemotherapy, the hematology/oncology clinical pharmacy practitioners designed and initiated a pilot, pharmacist-driven, Oral Chemotherapy Monitoring Clinic at the South Texas Veterans Health Care System supported by an oral chemotherapy certified pharmacy technician. A retrospective evaluation of patients receiving oral chemotherapy at the South Texas Veterans Health Care System was performed before (Phase I) and after (Phase II) pilot implementation to assess the impact of an Oral Chemotherapy Monitoring Clinic on compliance with drug-specific lab and symptom monitoring. Complete monitoring was defined as 100% of recommended labs and symptoms assessed per cycle, partial monitoring was <100%, but >0%, and incomplete monitoring was defined as 0%. The primary outcome assessed the proportion of patients receiving complete monitoring in Phase II compared to Phase I. Most patients were male (94%), with a median age of 72 years. The most common oncolytic was abiraterone acetate. Overall, drug-specific baseline and follow-up laboratory and symptom monitoring was complete at a statistically significantly higher rate in Phase II compared with Phase I (p-value < 0.01). A significantly higher portion of patients in the Phase II cohort had a clinical pharmacy practitioner intervention (44% vs. 90%; p < 0.01). Monitoring for Veterans receiving oral chemotherapy was optimized with clinical pharmacy practitioner and certified pharmacy technician involvement while simultaneously alleviating Oncologist and nurse oral chemotherapy workload.

Virtual psychoeducation for improvement of pain catastrophizing in pediatric presurgical patients and caregivers: a proof-of-concept study.

PURPOSE: Pain catastrophizing (PC) is the tendency to magnify the threat value of pain sensations and is associated with greater postsurgical pain intensity, functional disability, and pain chronicity. Higher parental PC predicts higher chronic postsurgical pain in youth. Treating PC in caregivers and youth prior to surgery may improve recovery and surgical outcomes. We developed and evaluated a psychoeducational workshop addressing PC for presurgical youth and their parents/caregivers. We hypothesized that parent/caregiver and youth PC scores would decrease over time. We also explored preintervention levels of youth anxiety and depression as moderators of outcome. METHODS: Youth (n = 43) and caregivers (n = 41) attended a virtual, group-based single-session intervention (SSI). Single-session intervention content addressed pain neuroscience, PC, and adaptive coping strategies for managing pain and PC drawn from cognitive-behavioural, acceptance and commitment, and dialectical behaviour therapy approaches. Participants completed questionnaires assessing PC at preintervention, postintervention, and two weeks postsurgery. Youth mood and anxiety were assessed at preintervention. RESULTS: Caregiver PC scores decreased from pre- to postintervention (P = 0.006), and this was maintained at postsurgery (P = 0.002). Youth PC scores decreased from preintervention to postsurgery, but only for those with higher preintervention anxiety (P = 0.01). CONCLUSION: Our results provide proof-of-concept support for a virtual SSI targeting caregivers and youth PC during the perioperative period. The present findings highlight the possible need to screen presurgical candidates for symptoms of anxiety. Replication with larger and more diverse samples, and a more robust design are warranted.

RéSUMé: OBJECTIF: Le terme de dramatisation de la douleur décrit la tendance à amplifier la valeur de menace des sensations de douleur et est associée à une plus grande intensité de la douleur postopératoire, à une incapacité fonctionnelle et à une chronicité de la douleur. Une dramatisation parentale plus élevée de la douleur prédit une douleur postopératoire chronique plus élevée chez les jeunes. Le traitement de la dramatisation de la douleur chez les soignant·es et les jeunes avant la chirurgie peut améliorer le rétablissement et les devenirs chirurgicaux. Nous avons mis au point et évalué un atelier psychoéducatif sur la dramatisation de la douleur destiné aux jeunes en période préchirurgicale et à leurs parents/soignant·es. Nous avons émis l'hypothèse que les scores de dramatisation de la douleur des parents/soignant·es et des jeunes diminueraient avec le temps. Nous avons également exploré les niveaux d'anxiété et de dépression des jeunes avant l'intervention en tant qu'éléments modérateurs des résultats. MéTHODE: Des jeunes (n = 43) et les personnes en prenant soin (n = 41) ont participé à une seule intervention virtuelle en groupe. Le contenu de l'intervention unique portait sur les neurosciences de la douleur, la dramatisation de la douleur et les stratégies d'adaptation pour la prise en charge de la douleur et la dramatisation de la douleur tirées des approches cognitivo-comportementales, d'acceptation et d'engagement, et de thérapie comportementale dialectique. Les participant·es ont rempli des questionnaires évaluant la dramatisation de la douleur avant l'intervention, après l'intervention et deux semaines après la chirurgie. L'humeur et l'anxiété des jeunes ont été évaluées avant l'intervention. RéSULTATS: Les scores de dramatisation de la douleur des soignant·es ont diminué de la période précédant à la période suivant l'intervention (P = 0,006), et cela s'est maintenu après la chirurgie (P = 0,002). Les scores de dramatisation de la douleur des jeunes ont diminué de la période précédant l'intervention à la période postchirurgie, mais seulement chez les jeunes présentant une anxiété pré-intervention plus élevée (P = 0,01). CONCLUSION: Nos résultats appuient la preuve de concept pour une intervention virtuelle unique ciblant la dramatisation de la douleur chez les soignant·es et les jeunes en période périopératoire. Ces résultats soulignent la nécessité potentielle de dépister les symptômes d'anxiété chez les candidat·es avant la chirurgie. La réplication avec des échantillons plus grands et plus diversifiés et une conception plus robuste est justifiée.

Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: a pilot study.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) carry significant morbidity and mortality. AECOPD treatment remains limited. High molecular weight hyaluronan (HMW-HA) is a glycosaminoglycan sugar, which is a physiological constituent of the lung extracellular matrix and has notable anti-inflammatory and hydrating properties. RESEARCH QUESTION: We hypothesized that inhaled HMW-HA will improve outcomes in AECOPD. METHODS: We conducted a single center, randomized, placebo-controlled, double-blind study to investigate the effect of inhaled HMW-HA in patients with severe AECOPD necessitating non-invasive positive-pressure ventilation (NIPPV). Primary endpoint was time until liberation from NIPPV. RESULTS: Out of 44 screened patients, 41 were included in the study (21 for placebo and 20 for HMW-HA). Patients treated with HMW-HA had significantly shorter duration of NIPPV. HMW-HA treated patients also had lower measured peak airway pressures on the ventilator and lower systemic inflammation markers after liberation from NIPPV. In vitro testing showed that HMW-HA significantly improved mucociliary transport in air-liquid interface cultures of primary bronchial cells from COPD patients and healthy primary cells exposed to cigarette smoke extract. INTERPRETATION: Inhaled HMW-HA shortens the duration of respiratory failure and need for non-invasive ventilation in patients with AECOPD. Beneficial effects of HMW-HA on mucociliary clearance and inflammation may account for some of the effects (NCT02674880, www.clinicaltrials.gov ).

Mapping DNA methylation with high-throughput nanopore sequencing.

DNA chemical modifications regulate genomic function. We present a framework for mapping cytosine and adenosine methylation with the Oxford Nanopore Technologies MinION using this nanopore sequencer's ionic current signal. We map three cytosine variants and two adenine variants. The results show that our model is sensitive enough to detect changes in genomic DNA methylation levels as a function of growth phase in Escherichia coli.

Integration of a CD19 CAR into the TCR Alpha Chain Locus Streamlines Production of Allogeneic Gene-Edited CAR T Cells.

Adoptive cellular therapy using chimeric antigen receptor (CAR) T cell therapies have produced significant objective responses in patients with CD19+ hematological malignancies, including durable complete responses. Although the majority of clinical trials to date have used autologous patient cells as the starting material to generate CAR T cells, this strategy poses significant manufacturing challenges and, for some patients, may not be feasible because of their advanced disease state or difficulty with manufacturing suitable numbers of CAR T cells. Alternatively, T cells from a healthy donor can be used to produce an allogeneic CAR T therapy, provided the cells are rendered incapable of eliciting graft versus host disease (GvHD). One approach to the production of these cells is gene editing to eliminate expression of the endogenous T cell receptor (TCR). Here we report a streamlined strategy for generating allogeneic CAR T cells by targeting the insertion of a CAR transgene directly into the native TCR locus using an engineered homing endonuclease and an AAV donor template. We demonstrate that anti-CD19 CAR T cells produced in this manner do not express the endogenous TCR, exhibit potent effector functions in vitro, and mediate clearance of CD19+ tumors in an in vivo mouse model.

Effect of the Adoption of a Comprehensive Electronic Health Record on Graduate Medical Education: Perceptions of Faculty and Trainees.

OBJECTIVES: Health systems are adopting electronic health records (EHRs). There are few studies on the effects of EHR implementation on graduate medical education. The authors sought to longitudinally assess perceptions of the impact of EHRs on graduate medical education during implementation and 2 years after implementation. METHODS: A survey was distributed to faculty and trainees during the first year (2013) of adoption of the EHR system. A follow-up survey was distributed 2 years later (2015). The χ2 test was used to compare the quantitative responses, and factor analysis was conducted to identify correlations between items. Free text responses were analyzed qualitatively. RESULTS: The initial survey (in 2013) included 290 faculty and 106 trainees; the follow-up survey (in 2015) included 353 faculty and 226 trainees. In 2013, respondents had a positive impression of EHRs. During the implementation phase, participants believed that face-to-face teaching was negatively affected (P = 0.001). Faculty believed EHRs had a negative effect on trainees' ability to take a history/conduct physical examinations (P = 0.002) and to formulate a differential diagnosis/plan independently (P = 0.003). In 2015, faculty opinions of the impact of the EHR remained unchanged; trainee responses were more positive than in 2013 in some areas. Qualitative analysis showed that the most frequent strategies to enhance the educational process were the development of EHR skills and improved chart access and note assistance. CONCLUSIONS: Respondents remain positive about the EHR 2 years after implementation. Faculty remain concerned about its effect on the educational process, whereas residents appear more positive regarding the potential for EHRs to enhance their education.

In-vivo regulation of Krüppel-like factor 9 by corticosteroids and their receptors across tissues in tadpoles of Xenopus tropicalis.

Corticosteroids are critical for normal development and for mediating effects of stress during development in all vertebrates. Even though gene knockout studies in mouse and zebrafish have identified a number of developmental roles of corticosteroids and their receptors, the numerous pleiotropic actions of these hormones affecting various aspects of development are understudied. For the most part, neither the endogenous hormone(s) nor their receptor(s) regulating developmental processes during natural development have been determined. Here, we address this issue by elucidating the endogenous regulation of the transcription factor Krüppel-like factor 9 (klf9) across tissues during development by corticosteroid hormones (aldosterone and corticosterone) and their nuclear receptors (type-I and type-II receptors). First, we measured the developmental expression profiles of klf9 and type-I and type-II corticosteroid receptors in key target tissues, brain, lungs, and tail, during larval and metamorphic stages in Xenopus tropicalis. We also studied the corticosteroid regulation of klf9 in these tissues in-vivo using exogenous hormone treatments and receptor antagonists. Klf9 and the corticosteroid receptors were expressed in each tissue and significantly increased in expression reaching a peak at metamorphic climax, except for the type-II receptor in brain and tail whose expression did not change significantly across stages. Both corticosteroid hormones induced klf9 in each tissue, although aldosterone required a five times higher dose than corticosterone to cause a significant induction. The upregulation of klf9 by both corticosteroids was completely blocked by the use of the type-II receptor antagonist RU486 and not the type-I receptor antagonist spironolactone. These results are consistent with previous in-vitro studies and indicate for the first time in-vivo that corticosteroid regulation of klf9 occurs exclusively via corticosterone and type-II receptor interaction across tissues.

Women's embodied experiences of second trimester medical abortion.

Abortions in general, and second trimester abortions in particular, are experiences which in many contexts have limited sociocultural visibility. Research on second trimester abortion worldwide has focused on a range of associated factors including risks and acceptability of abortion methods, and characteristics and decision-making of women seeking the procedure. Scholarship to date has not adequately addressed the embodied physicality of second trimester abortion, from the perspective of women's lived experiences, nor how these experiences might inform future framings of abortion. To progress understandings of women's embodied experiences of second trimester abortion, we draw on the accounts of 18 women who had recently sought second trimester abortion in Scotland. We address four aspects of their experiences: later recognition of pregnancy; experiences of a second trimester pregnancy which ended in abortion; the "labour" of second trimester abortion; and the subsequent bodily transition. The paper has two key aims: Firstly, to make visible these experiences, and to consider how they relate to dominant sociocultural narratives of pregnancy; and secondly, to explore the concept of "liminality" as one means for interpreting them. Our findings contribute to informing future research, policy and practice around second trimester abortion. They highlight the need to maintain efforts to reduce silences around abortion and improve equity of access.

Genetics of Insulin Resistance and the Metabolic Syndrome.

Insulin resistance and the metabolic syndrome are complex metabolic traits and key risk factors for the development of cardiovascular disease. They result from the interplay of environmental and genetic factors but the full extent of the genetic background to these conditions remains incomplete. Large-scale genome-wide association studies have helped advance the identification of common genetic variation associated with insulin resistance and the metabolic syndrome, and more recently, exome sequencing has allowed the identification of rare variants associated with the pathogenesis of these conditions. Many variants associated with insulin resistance are directly involved in glucose metabolism; however, functional studies are required to assess the contribution of other variants to the development of insulin resistance. Many genetic variants involved in the pathogenesis of the metabolic syndrome are associated with lipid metabolism.

Characteristics of women who present for abortion towards the end of the mid-trimester in Scotland: national audit 2013-2014.

OBJECTIVES: Women in Scotland who request an abortion (for non-medical reasons) within the legal gestational limit (up to 24 weeks) but beyond the gestational limit of all abortion facilities in Scotland (only up to 20 weeks) must travel to England if they wish to terminate the pregnancy. We wished to determine the number and characteristics of women presenting at ≥16 weeks' gestation for abortion, and compare the characteristics of those proceeding to abortion with those continuing the pregnancy. METHODS: Over a period of 12 months we conducted a prospective audit of women presenting at ≥16 weeks' gestation to abortion services throughout Scotland. The characteristics of women proceeding to abortion and those continuing the pregnancy were compared. RESULTS: A total of 267 women presented for abortion at ≥16 weeks' gestation. Their median age was 22 years (range 14 to 47 years); 231 were from deprived areas (86.5%), 128 (47.9%) already had a child and 73 (27.3%) had previously undergone abortion. A total of 175 women (65.5%) proceeded to abortion, locally (n = 125; 46.8%) or in England (50; 18.7%). Those at ≥20 weeks' gestation were statistically more likely to continue the pregnancy than those at earlier gestations (p < 0.001). CONCLUSIONS: Relatively few women present for abortion in Scotland at ≥16 weeks' gestation. Those who are over 20 weeks' gestation and would need to travel to England for abortion are more likely to continue the pregnancy, suggesting that travel is a barrier to accessing legal abortion for this group of women. Provision of abortion services up to 24 weeks' gestation should be considered within Scotland.

p38 MAPK activation upregulates proinflammatory pathways in skeletal muscle cells from insulin-resistant type 2 diabetic patients.

Skeletal muscle is the key site of peripheral insulin resistance in type 2 diabetes. Insulin-stimulated glucose uptake is decreased in differentiated diabetic cultured myotubes, which is in keeping with a retained genetic/epigenetic defect of insulin action. We investigated differences in gene expression during differentiation between diabetic and control muscle cell cultures. Microarray analysis was performed using skeletal muscle cell cultures established from type 2 diabetic patients with a family history of type 2 diabetes and clinical evidence of marked insulin resistance and nondiabetic control subjects with no family history of diabetes. Genes and pathways upregulated with differentiation in the diabetic cultures, compared with controls, were identified using Gene Spring and Gene Set Enrichment Analysis. Gene sets upregulated in diabetic myotubes were associated predominantly with inflammation. p38 MAPK was identified as a key regulator of the expression of these proinflammatory gene sets, and p38 MAPK activation was found to be increased in the diabetic vs. control myotubes. Although inhibition of p38 MAPK activity decreased cytokine gene expression from the cultured diabetic myotubes significantly, it did not improve insulin-stimulated glucose uptake. Increased cytokine expression driven by increased p38 MAPK activation is a key feature of cultured myotubes derived from insulin-resistant type 2 diabetic patients. p38 MAPK inhibition decreased cytokine expression but did not affect the retained defect of impaired insulin action in the diabetic muscle cells.

Characterization of the Pristionchus pacificus "epigenetic toolkit" reveals the evolutionary loss of the histone methyltransferase complex PRC2.

Comparative approaches have revealed both divergent and convergent paths to achieving shared developmental outcomes. Thus, only through assembling multiple case studies can we understand biological principles. Yet, despite appreciating the conservation-or lack thereof-of developmental networks, the conservation of epigenetic mechanisms regulating these networks is poorly understood. The nematode Pristionchus pacificus has emerged as a model system of plasticity and epigenetic regulation as it exhibits a bacterivorous or omnivorous morph depending on its environment. Here, we determined the "epigenetic toolkit" available to P. pacificus as a resource for future functional work on plasticity, and as a comparison with Caenorhabditis elegans to investigate the conservation of epigenetic mechanisms. Broadly, we observed a similar cast of genes with putative epigenetic function between C. elegans and P. pacificus. However, we also found striking differences. Most notably, the histone methyltransferase complex PRC2 appears to be missing in P. pacificus. We described the deletion/pseudogenization of the PRC2 genes mes-2 and mes-6 and concluded that both were lost in the last common ancestor of P. pacificus and a related species P. arcanus. Interestingly, we observed the enzymatic product of PRC2 (H3K27me3) by mass spectrometry and immunofluorescence, suggesting that a currently unknown methyltransferase has been co-opted for heterochromatin silencing. Altogether, we have provided an inventory of epigenetic genes in P. pacificus to compare with C. elegans. This inventory will enable reverse-genetic experiments related to plasticity and has revealed the first loss of PRC2 in a multicellular organism.

National practice patterns in the use of endoscopic ultrasound biopsy for resectable Pancreatic Neuroendocrine Tumors: Insights into the role of DOTATATE PET/CT in diagnosis.

INTRODUCTION: Pancreatic neuroendocrine tumors (PNETs) are typically diagnosed using endoscopic ultrasound-guided (EUS) biopsy, which can be associated with complications. Since 2016, DOTATATE PET/CT has emerged as an effective tool to localize and stage PNETs. METHODS: Patients with PNETs who underwent R0 resections were identified from the 2004-2019 National Cancer Database PUF. Joinpoint regression and multivariable logistic regression were used to analyze trends in the use of biopsy. RESULTS: Of 16,746 R0 resected PNET patients, 44 â€‹% underwent diagnostic biopsy. Joinpoint regression showed a significant increase in the use of biopsy from 2004 to 2019 (APC 1.80, p â€‹< â€‹0.001). A higher percentage of patients diagnosed after DOTATATE approval underwent biopsy compared to those diagnosed before (48 â€‹% vs. 42 â€‹%, p â€‹< â€‹0.001). Adjusted analysis showed diagnosis after 2016 was associated with increased odds of biopsy (OR â€‹= â€‹1.67, p â€‹< â€‹0.001). CONCLUSIONS: Despite technologic advancement with DOTATATE PET/CT, there has been a significant increase in the proportion of resectable PNETs undergoing preoperative biopsy.

Nutrient Limitation Mimics Artemisinin Tolerance in Malaria.

Mounting evidence demonstrates that nutritional environment can alter pathogen drug sensitivity. While the rich media used for in vitro culture contains supraphysiological nutrient concentrations, pathogens encounter a relatively restrictive environment in vivo. We assessed the effect of nutrient limitation on the protozoan parasite that causes malaria and demonstrated that short-term growth under physiologically relevant mild nutrient stress (or "metabolic priming") triggers increased tolerance of a potent antimalarial drug. We observed beneficial effects using both short-term survival assays and longer-term proliferation studies, where metabolic priming increases parasite survival to a level previously defined as resistant (>1% survival). We performed these assessments by either decreasing single nutrients that have distinct roles in metabolism or using a media formulation that simulates the human plasma environment. We determined that priming-induced tolerance was restricted to parasites that had newly invaded the host red blood cell, but the effect was not dependent on genetic background. The molecular mechanisms of this intrinsic effect mimic aspects of genetic tolerance, including translational repression and protein export. This finding suggests that regardless of the impact on survival rates, environmental stress could stimulate changes that ultimately directly contribute to drug tolerance. Because metabolic stress is likely to occur more frequently in vivo compared to the stable in vitro environment, priming-induced drug tolerance has ramifications for how in vitro results translate to in vivo studies. Improving our understanding of how pathogens adjust their metabolism to impact survival of current and future drugs is an important avenue of research to slow the evolution of resistance. IMPORTANCE There is a dire need for effective treatments against microbial pathogens. Yet, the continuing emergence of drug resistance necessitates a deeper knowledge of how pathogens respond to treatments. We have long appreciated the contribution of genetic evolution to drug resistance, but transient metabolic changes that arise in response to environmental factors are less recognized. Here, we demonstrate that short-term growth of malaria parasites in a nutrient-limiting environment triggers cellular changes that lead to better survival of drug treatment. We found that these strategies are similar to those employed by drug-tolerant parasites, which suggests that starvation "primes" parasites to survive and potentially evolve resistance. Since the environment of the human host is relatively nutrient restrictive compared to growth conditions in standard laboratory culture, this discovery highlights the important connections among nutrient levels, protective cellular pathways, and resistance evolution.

Survival and quality-of-life outcomes in early-stage NSCLC patients: a literature review of real-world evidence.

Aim: Assess the long-term survival and quality-of-life outcomes in early-stage NSCLC (eNSCLC) patients. Methods: Review of long-term survival and quality-of-life after curative treatment in eNSCLC patients in observational studies. Results: Disease-free proportion decreased in stage III vs stage I patients. Recurrence-free proportion decreased with age and disease stage. Advanced stage and vascular invasion increased risk of late recurrence. Conditional 5-year relative survival rates did not exceed 87%, indicating higher mortality in eNSCLC survivors. Lower conditional survival rates and relative survival rates were associated with older age and advanced disease. Survivors of eNSCLC had poorer physical quality-of-life. Conclusion: Despite curative-intent therapy, survivors of eNSCLC still face significant risks of recurrence, excess mortality, and diminished quality-of-life.

Early-stage NSCLC (eNSCLC) encompassing stage I and II, and resectable stage III disease is initially managed with curative-intent surgery and adjuvant chemotherapy to reduce the risk of recurrence. However, understanding the true curative potential and long-term outcomes is crucial for optimal clinical management. A literature review was conducted to identify observational studies describing long-term survival and quality-of-life outcomes following curative intent therapy in patients with eNSCLC. The proportion of patients who remained disease-free over time (without recurrence or death) statistically significantly decreased in patients with stage III disease compared with stage I disease. Similarly, the proportion of patients who remained recurrence-free over time decreased with increasing age and disease stage. A considerable risk of late recurrence (recurrence five or more years following resection) remained, increasing with advanced stage and tumor characteristics such as vascular invasion. Conditional 5-year relative survival rates did not exceed 87% in any study, indicating higher rates of all-cause mortality in long-term survivors of eNSCLC compared with members of the general population of the same age. Lower conditional 5-year relative survival rates, and 5 and 10-year relative survival rates were associated with older age and higher pathologic stage. Compared with the general population, survivors of eNSCLC reported significantly poorer physical quality-of-life, suggesting that symptoms persist after treatment. Overall, real-world evidence suggests that after standard curative-intent therapy, survivors of eNSCLC may not be considered fully cured, indicating a need for more effective adjuvant treatment in addition to the current standard of care.

Number of Local Regional Therapies for Hepatocellular Carcinoma and Peri-Operative Outcomes after Liver Transplantation.

The wait times for patients with hepatocellular carcinoma (HCC) listed for liver transplant are longer than ever, which has led to an increased reliance on the use of pre-operative LRTs. The impact that multiple rounds of LRTs have on peri-operative outcomes following transplant is unknown. This was a retrospective single center analysis of 298 consecutive patients with HCC who underwent liver transplant (January 2017 to May 2021). The data was obtained from two institution-specific databases and the TransQIP database. Of the 298 patients, 27 (9.1%) underwent no LRTs, 156 (52.4%) underwent 1-2 LRTs, and 115 (38.6%) underwent ≥3 LRTs prior to LT. The patients with ≥3 LRTs had a significantly higher rate of bile leak compared to patients who received 1-2 LRTs (7.0 vs. 1.3%, p = 0.014). Unadjusted and adjusted regression analyses demonstrated a significant association between the total number of LRTs administered and bile leak, but not rates of overall biliary complications. The total number of LRTs was not significantly associated with any other peri-operative or post-operative outcome measure. These findings support the aggressive use of LRTs to control HCC in patients awaiting liver transplant, with further evaluation needed to confirm the biliary leak findings.

An allelic series at the EDNRB2 locus controls diverse piebalding patterns in the domestic pigeon.

Variation in pigment patterns within and among vertebrate species reflects underlying changes in cell migration and function that can impact health, reproductive success, and survival. The domestic pigeon (Columba livia) is an exceptional model for understanding the genetic changes that give rise to diverse pigment patterns, as selective breeding has given rise to hundreds of breeds with extensive variation in plumage color and pattern. Here, we map the genetic architecture of a suite of pigmentation phenotypes known as piebalding. Piebalding is characterized by patches of pigmented and non-pigmented feathers, and these plumage patterns are often breed-specific and stable across generations. Using a combination of quantitative trait locus mapping in F2 laboratory crosses and genome-wide association analysis, we identify a locus associated with piebalding across many pigeon breeds. This shared locus harbors a candidate gene, EDNRB2, that is a known regulator of pigment cell migration, proliferation, and survival. We discover multiple distinct haplotypes at the EDNRB2 locus in piebald pigeons, which include a mix of protein-coding, noncoding, and structural variants that are associated with depigmentation in specific plumage regions. These results identify a role for EDNRB2 in pigment patterning in the domestic pigeon, and highlight how repeated selection at a single locus can generate a diverse array of stable and heritable pigment patterns.

Treatment patterns and survival of patients with locoregional recurrence in early-stage NSCLC: a literature review of real-world evidence.

Approximately 10-50% of patients treated for early-stage (I-III), resectable non-small cell lung cancer (eNSCLC) will develop locoregional recurrence. There is a lack of prospective trials evaluating optimal post-surgery follow-up for this patient population, and treatment guidelines recommend salvage therapies such as surgery, local ablative therapy, and (chemo)radiotherapy. A literature review was conducted according to pre-defined criteria to identify observational studies describing treatment patterns and survival outcomes in patients with eNSCLC who experienced locoregional recurrence. Results showed that, in real-world clinical practice, around 80% of patients with locoregional recurrence underwent any form of active treatment. The most frequently administered treatments were chemotherapy (35.7%), chemoradiotherapy (31.2%), radiotherapy (20.3%), and surgery alone (12.8%). Chemoradiotherapy was associated with improved PFS and OS compared with radiotherapy, while no statistically significant survival benefits were observed for patients receiving surgery in addition to these treatments. The overall survival of patients following treatment for locoregional recurrence was generally poor, and the proportion of patients who experienced any form of post-treatment re-recurrence ranged from 35 to 72%. These findings highlight the need to develop more effective treatment strategies for locoregional recurrence, including preventative treatments, and strategies to improve the survival outcomes of those who do develop locoregional recurrence.