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Given the progression of laparoscopic surgery, questions continue to arise as to the ideal technique for a laparoscopic colectomy. The most debated of these questions is whether it is best to complete an intracorporeal (ICA) or extracorporeal (ECA) intestinal anastomosis. Here, we review the literature to date and report the equivalent safety and efficacy of ICA and ECA for laparoscopic right colectomy. However, these studies also indicate that when completed, ICA may prove beneficial with respect to earlier return of bowel function, less postoperative pain, shorter incision length, and reduced risk of wound infections. For this, we present the tips and tricks for completing all forms of laparoscopic ICAs during laparoscopic colectomy.

Substitution of a labile Cl− for an NHC ligand in DNA-intercalating [Pt(terpyridine)]+ complexes improved the cytotoxicity and cellular accumulation, while in vivo studies indicated good tolerability in zebrafish.

Unhealthy alcohol consumption is a global health problem. Adverse individual, public health, and socioeconomic consequences are attributable to harmful alcohol use. Epidemiological studies have shown that alcohol use disorder (AUD) and alcohol-associated liver disease (ALD) are the top two pathologies among alcohol-related diseases. Consistent with the major role that the liver plays in alcohol metabolism, uncontrolled drinking may cause significant damage to the liver. This damage is initiated by excessive fat accumulation in the liver, which can further progress to advanced liver disease. The only effective therapeutic strategies currently available for ALD are alcohol abstinence or liver transplantation. Any molecule with dual-pronged effects at the central and peripheral organs controlling addictive behaviors and associated metabolic pathways are a potentially important therapeutic target for treating AUD and ALD. Ghrelin, a hormone primarily derived from the stomach, has such properties, and regulates both behavioral and metabolic functions. In this review, we highlight recent advances in understanding the peripheral and central functions of the ghrelin system and its role in AUD and ALD pathogenesis. We first discuss the correlation between blood ghrelin concentrations and alcohol use or abstinence. Next, we discuss the role of ghrelin in alcohol-seeking behaviors and finally its role in the development of fatty liver by metabolic regulations and organ crosstalk. We propose that a better understanding of the ghrelin system could open an innovative avenue for improved treatments for AUD and associated medical consequences, including ALD.

Background This article presents evaluation findings of the India English Language Programme, an innovative programme aimed at providing Indian nurses with an opportunity to participate in an ethical and mutually beneficial learning programme aimed at supporting migration into the United Kingdom’s National Health Service (NHS). The programme provided 249 Indian nurses wishing to migrate to the NHS on an ‘earn, learn, and return’ basis with funding to support English language learning and accreditation sufficient to apply for Nursing and Midwifery Council (NMC) registration. The Programme provided English language training and pastoral support to candidates, in addition to the availability of remedial training and examination entry for those not meeting NMC proficiency requirements on their first attempt. Methods Descriptive statistical analysis of programme examination results and cost-effectiveness analysis is presented to demonstrate programme outputs and outcomes. Descriptive economic analysis of programme costings is presented alongside programme results to investigate the value-for-money provided by this programme. Results A total of 89 nurses were successful in meeting NMC proficiency requirements, representing a pass rate of 40%. Those undertaking OET training and examination(s) were more successful, compared to those undertaking British Council provision, with over half of candidates passing at the required level. This equates to an overall programme cost-per-pass of £4139 and represents a model to support health worker migration, in line with WHO guidelines, delivering individual learning and development, mutual health system gain, and value-for-money. Conclusions Taking place during the coronavirus pandemic, the programme evidences the effective delivery of online English language training to support health worker migration during a highly disruptive period for global health. This programme demonstrates an ethical and mutually beneficial pathway for English language improvement amongst internationally educated nurses to facilitate migration to and global health learning in the NHS. It provides a template through which healthcare leaders and nurse educators, working in policy and practice environments in the NHS and other English-speaking countries, can design future ethical health worker migration and training programmes to strengthen the global healthcare workforce.

Background The novel liver-gut hormone LEAP2 is a centrally acting inverse agonist, and competitive antagonist of orexigenic acyl ghrelin (AG), at the growth hormone secretagogue receptor, reducing food intake in rodents. In humans, the effects of LEAP2 on eating behaviour and mechanisms behind the post-prandial increase in LEAP2 are unclear, though this is reciprocal to the post-prandial decrease in plasma AG. Methods Plasma LEAP2 was measured in a secondary analysis of a previous study. Twenty-two adults without obesity attended after an overnight fast (Fasted-saline), consuming a 730kcal meal without (Fed-saline) or with (Fed-ghrelin) subcutaneous AG administration. Post-prandial changes in plasma LEAP2 were correlated with post-prandial changes in appetite, high-energy (HE) or low-energy (LE) food cue reactivity using functional MRI, ad libitum food intake, and plasma/serum AG, glucose, insulin and triglycerides. Results Post-prandial plasma LEAP2 increased by 24.5-52.2% at 70-150 min, but was unchanged by exogenous AG administration. Post-prandial increases in LEAP2 correlated positively with post-prandial decreases in appetite, and cue reactivity to HE/LE and HE food in anterior/posterior cingulate cortex, paracingulate cortex, frontal pole, middle frontal gyrus, with similar trend for food intake. Post-prandial increases in LEAP2 correlated negatively with body mass index, but did not correlate positively with increases in glucose, insulin or triglycerides, nor decreases in AG. Conclusions These correlational findings are consistent with a role for post-prandial increases in plasma LEAP2 in suppressing human eating behaviour in adults without obesity. Post-prandial increases in plasma LEAP2 are unrelated to changes in plasma AG and the mediator(s) remain uncertain.

SUMMARYIntracellular pathogens and other endosymbionts reprogram host cell transcription to suppress immune responses and recalibrate biosynthetic pathways. This reprogramming is critical in determining the outcome of infection or colonisation. Here, we combine pooled CRISPR knockout screening with dual host–microbe single-cell RNA-sequencing to identify the molecular mediators of these transcriptional interactions, a method we term dual perturb-seq. Applying dual perturb-seq to the intracellular pathogenToxoplasma gondii, we are able to identify previously uncharacterised effector proteins and directly infer their function from the transcriptomic data. We show thatTgGRA59 contributes to the export of other effector proteins from the parasite into the host cell and identify a novel effector,TgSOS1, that is necessary for sustained host STAT6 signalling and thereby contributes to parasite immune evasion and persistence. Together, this work demonstrates a novel tool that can be broadly adapted to interrogate host-microbe transcriptional interactions and reveal mechanisms of infection and immune evasion.

Figure S1. Study Protocol Figure S2. Correlation of post-prandial plasma LEAP2 with meal size consumed across different studies Figure S3. Plasma LEAP2 at study visits Figure S4. Food appeal ratings between visits for high-energy and low-energy foods Table S1. Whole brain analysis for correlations of post-prandial changes in BOLD signal to high-energy foods with plasma hormones Table S2. Whole brain analysis for correlations of post-prandial changes in BOLD signal to low-energy foods with plasma hormones Table S3. Whole brain analysis for correlations of post-prandial changes in BOLD signal to high- or low-energy foods with plasma hormones Supplementary References

Oncogenic KRAS impairs anti-tumour immune responses, but effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identifies mechanisms by which oncogenic KRAS promotes immune evasion, most notably expression of immunosuppressive cyclooxygenase-2 (COX-2) in cancer cells. Oncogenic KRAS was a potent inducer of COX-2 in both mouse and human lung cancer which was suppressed using KRAS inhibitors. COX-2 acting via prostaglandin E2 (PGE2) promotes resistance to immune checkpoint blockade (ICB) in both mouse and human lung adenocarcinoma. Targeting COX-2/PGE2 remodelled the tumour microenvironment by inducing pro-inflammatory polarisation of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX-2 expression contributed to tumour relapse after prolonged KRAS inhibition. We propose testing COX-2/PGE2 pathway inhibitors in combination with KRAS G12C inhibition or ICB in patients with KRAS-mutant lung cancer.SIGNIFICANCEHere we identify cyclooxygenase 2 signalling via prostaglandin E2 as a major mediator of immune evasion that is driven by oncogenic KRAS in both mouse and human lung cancer. COX2/PGE2signalling contributes to immunotherapy and KRAS-targeted therapy resistance which can be overcome by COX2/PGE2pathway inhibitors. This work suggests novel combination therapies for the treatment of KRAS-mutant lung cancer.

Study Objectives Adolescence is characterized by significant brain development, accompanied by changes in sleep timing and architecture. It also is a period of profound psychosocial changes, including the initiation of alcohol use; however, it is unknown how alcohol use affects sleep architecture in the context of adolescent development. We tracked developmental changes in polysomnographic (PSG) and electroencephalographic (EEG) sleep measures and their relationship with emergent alcohol use in adolescents considering confounding effects (e.g. cannabis use). Methods Adolescents (n = 94, 43% female, age: 12–21 years) in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study had annual laboratory PSG recordings across 4-years. Participants were no/low drinkers at baseline. Results Linear mixed effect models showed developmental changes in sleep macrostructure and EEG, including a decrease in slow wave sleep and slow wave (delta) EEG activity with advancing age. Emergent moderate/heavy alcohol use across three follow-up years was associated with a decline in percentage rapid eye movement (REM) sleep over time, a longer sleep onset latency (SOL) and shorter total sleep time (TST) in older adolescents, and lower non-REM delta and theta power in males. Conclusions These longitudinal data show substantial developmental changes in sleep architecture. Emergent alcohol use during this period was associated with altered sleep continuity, architecture, and EEG measures, with some effects dependent on age and sex. These effects, in part, could be attributed to the effects of alcohol on underlying brain maturation processes involved in sleep–wake regulation.

After neoadjuvant therapy, pathologic analysis of rectal cancer resected specimens may show a complete response in the primary tissue cancer with residual tumor in the lymph nodes (ypT0N+).The aim of this study was to describe the 5-year overall survival and factors associated with survival of ypT0N+ patients with rectal cancer who had neoadjuvant therapy followed by surgery and to compare these patients' survival with patients in other pathologic categories.We conducted a retrospective analysis.We used the National Cancer Database.We identified patients with rectal adenocarcinoma who underwent total neoadjuvant therapy or neoadjuvant chemoradiation followed by surgery between 2006 and 2016. Besides ypT0N+, 5 pathologic categories were identified: ypT0N0, ypT1-2N0, ypT3-4N0, ypT1-2N+, and ypT3-4N+.The primary outcome measure was 5-year overall survival.We included 30,751 patients with rectal adenocarcinoma. A total of 342 patients developed ypT0N+, of whom 181 (52.9%) received total neoadjuvant therapy. Among patients who received total neoadjuvant therapy, developing ypT0N+ was associated with a lower 5-year overall survival than ypT0N0 and ypT1-2N0. However, ypT0N+ disease was associated with a higher 5-year overall survival than ypT3-4N+. There were no differences in 5-year overall survival between ypT0N+ and ypT3-4N0 or ypT1-2N+. Similar findings were noticed among patients who received neoadjuvant chemoradiation and adjuvant chemotherapy. For patients with ypT0N+, older age, male gender, and higher number of positive lymph nodes were all associated with a decrease in the overall survival.Limitations include the retrospective nature of this study, lack of variables describing the chemotherapy and radiation regimens used, and paucity of data on disease-specific survival or recurrence.Developing ypT0N+ was associated with a lower 5-year overall survival than ypT0N0 and ypT1-2N0. However, it was associated with a higher 5-year overall survival than ypT3-4N+. See Video Abstract at http://links.lww.com/DCR/B863 .ANTECEDENTES:Después del tratamiento neoadyuvante en el cáncer de recto bajo, el análisis patológico de la pieza operatoria resecada, puede mostrar una respuesta patológica completa del tumor primario pero con tumor residual en los ganglios linfáticos (ypT0N+).OBJETIVOS:Describir la sobrevida general a 5 años y los factores asociados con la sobrevida de los pacientes ypT0N+ con cáncer de recto, que recibieron terapia neoadyuvante seguida de cirugía y comparar la sobrevida de estos pacientes con la de pacientes con otros estadios patológicos.DISEÑO:Realizamos un análisis retrospectivo.AJUSTES:Utilizamos la base de datos nacional del cáncer.PACIENTES:Identificamos pacientes con adenocarcinoma de recto que se sometieron a terapia neoadyuvante total, seguida de cirugía entre 2006 y 2016. Además de ypT0N +, se identificaron 5 categorías patológicas: ypT0N0, ypT1-2N0, ypT3-4N0, ypT1-2N+, e ypT3-4N+.PRINCIPAL MEDIDA DE RESULTADO:La medida de resultado principal fue la supervivencia general a 5 años.RESULTADOS:Se incluyeron 30.751 pacientes con adenocarcinoma de recto. Un total de 342 pacientes desarrollaron ypT0N+, de los cuales 181 (52,9%) recibieron terapia neoadyuvante total. Entre los pacientes que recibieron terapia neoadyuvante total, el desarrollo de ypT0N+ se asoció con una supervivencia general a 5 años más baja que ypT0N0 e ypT1-2N0. Sin embargo, la enfermedad ypT0N+ se asoció con una supervivencia general a 5 años más alta que ypT3-4N+. No hubo diferencias en la supervivencia global a 5 años entre ypT0N+ y ypT3-4N0 o ypT1-2N+. Se observaron hallazgos similares entre los pacientes que recibieron terapia neoadyuvante y quimioterapia adyuvante. Para los pacientes con ypT0N+, la edad avanzada, el sexo masculino y un mayor número de ganglios linfáticos positivos se asociaron con una disminución en la supervivencia general.LIMITACIONES:Las limitaciones incluyen la naturaleza retrospectiva del estudio, la falta de variables que describan los regímenes de quimioterapia y radiación utilizados y la escasez de datos sobre la supervivencia o la recurrencia específicas de la enfermedad.CONCLUSIONES:El desarrollo de ypT0N+ se asoció con una supervivencia general a 5 años más baja que ypT0N0 e ypT1-2N0. Sin embargo, se asoció con una supervivencia global a 5 años más alta que ypT3-4N+. Consulte Video Resumen en http://links.lww.com/DCR/B863 . (Traducción-Dr. Rodrigo Azolas ).

Background As the US healthcare system moves towards value-based care, hospitals have increased efforts to improve quality and reduce unnecessary resource use. Surgery is one of the most resource-intensive areas of healthcare and we aim to compare health resource utilization between open and minimally invasive cancer procedures. Methods We retrospectively analyzed cancer patients who underwent colon resection, rectal resection, lobectomy, or radical nephrectomy within the Premier hospital database between 2014 and 2019. Study outcomes included length of stay (LOS), discharge status, reoperation, and 30-day readmission. The open surgical approach was compared to minimally invasive approach (MIS), with subgroup analysis of laparoscopic/video-assisted thoracoscopic surgery (LAP/VATS) and robotic (RS) approaches, using inverse probability of treatment weighting. Results MIS patients had shorter LOS compared to open approach: − 1.87 days for lobectomy, − 1.34 days for colon resection, − 0.47 days for rectal resection, and − 1.21 days for radical nephrectomy (all p p Conclusion Our data demonstrate a significant shorter LOS, higher discharge to home rate, and lower rates of reoperation and readmission for MIS as compared to open procedures in patients with lung, kidney, and colorectal cancer. Patients who underwent robotic procedures had further reductions in LOS compare to laparoscopic/video-assisted thoracoscopic approach, while the reductions in LOS did not lead to increased rates of readmission.

BACKGROUND: Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia.METHODS: This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m2 on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617.FINDINGS: Between April 19, 2012, and July 10, 2017, 586 patients were randomly assigned to standard of care (n=292) or standard of care plus rituximab (n=294). Nine patients were excluded from the final analysis due to misdiagnosis (standard of care n=4, standard of care plus rituximab n=5). In the standard-of-care group, median age was 45 years (IQR 22-65), 159 (55%) of 292 participants were male, 128 (44%) were female, one (INTERPRETATION: Standard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient.

Patients with comorbid mental health and substance use disorders are at greater risk for mortality and have higher cancer care costs. At JADPRO Live Virtual 2021, Lisa W. Goldstone, MS, PharmD, BCPS, BCPP, talked through general considerations in the oncology setting for persons with comorbid mental health or substance use disorders, strategies for recognizing when patients with new or preexisting mental health symptoms or disorders may benefit from treatment and/or referral, and first and second-line pharmacotherapy options.

Summary Background The quadrivalent human papillomavirus (HPV) vaccine was shown to prevent infections and lesions related to HPV6, 11, 16, and 18 in a randomised, placebo-controlled study in men aged 16–26 years. We assessed the incidences of external genital warts related to HPV6 or 11, and external genital lesions and anal dysplasia related to HPV6, 11, 16, or 18, over 10 years of follow-up. Methods The 3-year base study was an international, multicentre, double-blind, randomised, placebo-controlled trial done at 71 sites in 18 countries. Eligible participants were heterosexual men (aged 16–23 years) or men who have sex with men (MSM; aged 16–26 years). Men who had clinically detectable anogenital warts or genital lesions at screening that were suggestive of infection with non-HPV sexually transmitted diseases, or who had a history of such findings, were excluded. Eligible participants were randomly assigned (1:1) to receive three doses of either quadrivalent HPV vaccine or placebo on day 1, month 2, and month 6, administered as a 0·5-mL injection into the deltoid muscle. The 7-year, open-label, long-term follow-up extension study was done at 46 centres in 16 countries. Participants who received one or more doses of the quadrivalent HPV vaccine in the base study were eligible for enrolment into the long-term follow-up study (early vaccination group). Placebo recipients were offered the three-dose quadrivalent HPV vaccine at the end of the base study; those who received one or more quadrivalent HPV vaccine doses were eligible for enrolment into the long-term follow-up study (catch-up vaccination group). The primary efficacy endpoints were the incidence of external genital warts related to HPV6 or 11 and the incidence of external genital lesions related to HPV6, 11, 16, or 18 in all participants and the incidence of anal intraepithelial neoplasia (including anal warts and flat lesions) or anal cancer related to HPV6, 11, 16, or 18 in MSM only. The primary efficacy analysis was done in the per-protocol population for the early vaccination group, which included participants who received all three vaccine doses, were seronegative at day 1 and PCR-negative from day 1 through month 7 of the base study for the HPV type being analysed, had no protocol violations that could affect evaluation of vaccine efficacy, and had attended at least one visit during the long-term follow-up study. For the catch-up vaccination group, efficacy was assessed in the modified intention-to-treat population, which included participants who had received at least one vaccine dose, were seronegative and PCR-negative for HPV types analysed from day 1 of the base study to the final follow-up visit before receiving the quadrivalent HPV vaccine, and had at least one long-term follow-up visit. Safety was assessed in all randomised participants who received at least one vaccine dose. This study is registered with ClinicalTrials.gov , NCT00090285 . Findings Between Aug 10, 2010, and April 3, 2017, 1803 participants were enrolled in the long-term follow-up study, of whom 936 (827 heterosexual men and 109 MSM) were included in the early vaccination group and 867 (739 heterosexual men and 128 MSM) were included in the catch-up vaccination group. Participants in the early vaccination group were followed up for a median of 9·5 years (range 0·1–11·5) after receiving the third dose of the quadrivalent HPV vaccine, and participants in the catch-up vaccination group were followed up for a median of 4·7 years (0·0–6·6) after receiving the third dose. In early vaccine group participants during long-term follow-up compared with the placebo group in the base study, the incidence per 10 000 person-years of external genital warts related to HPV6 or 11 was 0·0 (95% CI 0·0–8·7) versus 137·3 (83·9–212·1), of external genital lesions related to HPV6, 11, 16, or 18 was 0·0 (0·0–7·7) versus 140·4 (89·0–210·7), and of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 in MSM only was 20·5 (0·5–114·4) versus 906·2 (553·5–1399·5). Compared with during the base study (ie, before quadrivalent HPV vaccine administration), during the long-term follow-up period, participants in the catch-up vaccination group had no new reported cases of external genital warts related to HPV6 or 11 (149·6 cases per 10 000 person-years [95% CI 101·6–212·3] vs 0 cases per 10 000 person-years [0·0–13·5]) or external genital lesions related to HPV6, 11, 16, or 18 (155·1 cases per 10 000 person-years [108·0–215·7] vs 0 cases per 10 000 person-years [0·0–10·2]), and a lower incidence of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 (886·0 cases per 10 000 person-years [583·9–1289·1] vs 101·3 cases per 10 000 person-years [32·9–236·3]). No vaccine-related serious adverse events were reported. Interpretation The quadrivalent HPV vaccine provides durable protection against anogenital disease related to HPV6, 11, 16, and 18. The results support quadrivalent HPV vaccination in men, including catch-up vaccination. Funding Merck Sharp & Dohme.

We sought to identify genetic differences between right- and left-sided colon cancers and using these differences explain lower survival in right-sided cancers.A retrospective review of patients diagnosed with colon cancer was performed using The Cancer Genome Atlas, a cancer genetics registry with patient and tumour data from 20 North American institutions. The primary outcome was 5-year overall survival. Predictors for survival were identified using directed acyclic graphs and Cox proportional hazards models.A total of 206 right- and 214 left-sided colon cancer patients with 84 recorded deaths were identified. The frequency of mutated alleles differed significantly in 12 of 25 genes between right- and left-sided tumours. Right-sided tumours had worse survival with a hazard ratio of 1.71 (95% confidence interval 1.10-2.64, P = 0.017). The total effect of the genetic loci on survival showed five genes had a sizeable effect on survival: DNAH5, MUC16, NEB, SMAD4, and USH2A. Lasso-penalized Cox regression selected 13 variables for the highest-performing model, which included cancer stage, positive resection margin, and mutated alleles at nine genes: MUC16, USH2A, SMAD4, SYNE1, FLG, NEB, TTN, OBSCN, and DNAH5. Post-selection inference demonstrated that mutations in MUC16 (P = 0.01) and DNAH5 (P = 0.02) were particularly predictive of 5-year overall survival.Our study showed that genetic mutations may explain survival differences between tumour sites. Further studies on larger patient populations may identify other genes, which could form the foundation for more precise prognostication and treatment decisions beyond current rudimentary TNM staging.

Our lives are being measured in rapidly increasing ways and frequency. These measurements have beneficial and deleterious effects at both individual and social levels. Behavioral measurement technologies offer the promise of helping us to know ourselves better and to improve our well-being by using personalized feedback and gamification. At the same time, they present threats to our privacy, self-esteem, and motivation. At the societal level, the potential benefits of reducing bias and decision variability by using objective and transparent assessments are offset by threats of systematic, algorithmic bias from invalid or flawed measurements. Considerable technological progress, careful foresight, and continuous scrutiny will be needed so that the positive impacts of behavioral measurement technologies far outweigh the negative ones.

Статья предлагает предварительное описание трех революционных волн XXI в., их ключевых характеристик и причин. Одна из целей данной статьи – развить аналитические инструменты, в частности углубить понимание самого понятия революции и революционных событий, а также типологию революционных событий. В целом настоящая статья предлагает теоретический и отчасти количественный анализ революционного процесса ХХI в. Предложен новый подход к выделению волн революций, который включает следующие критерии: 1) реальную связанность событий в рамках Мир-Системы общими факторами; 2) количество революций не должно быть меньше 4-5; 3) временной интервал революционных событий – не более 10 лет между началом первого и началом последнего события; 4) в один хронологический период может произойти одна волна. На этой основе в XXI в. нами было выделено три волны. Первая волна – цветные революции 2000-2009 гг. Вторая волна – Арабская весна и ее глобальное эхо, 2010/2011-2013 гг. Третья волна – с 2018 г., незавершенная. Предложенный анализ позволяет дать оценку революционного процесса ХХI в. как (а) весьма активного, в котором интенсивность революций нарастает, (б) довольно разнообразного по типам революционных событий, (в) революционные события характерны для стран не только мир-системной периферии, но и мир-системного ядра.

The ideal aortic valve substitute in young adults remains unknown. Prosthetic valves are associated with a suboptimal survival and carry a significant risk of valve-related complications in young patients, mainly reinterventions with tissue valves and, thromboembolic events and major bleeding with mechanical prostheses. The Ross procedure is the only substitute that restores a survival curve similar to that of a matched general population, and permits a normal life without functional limitations. Though the risk of reintervention is the Achilles' heel of this procedure, it is very low in patients with aortic stenosis and can be mitigated in patients with aortic regurgitation by tailored surgical techniques. Finally, the Ozaki procedure and the transcatheter aortic valve implantation are seen by many as future alternatives but lack evidence and long-term follow-up in this specific patient population.

We are living in what some have described as an “age of protest.” Nevertheless, protesting has been around for thousands of years, and some core features of contemporary discourse are already prominent in antiquity. In this article I explore three key dimensions of protest and rebuke within early rabbinic (tannaitic) literature: power, violence, and responsibility. Although protest and rebuke overlap in many respects, tannaitic discussion of these actions diverge in significant ways that grant us greater clarity into the dynamics the early rabbis perceived to be at play when attempting to effectively confront others on the individual level. I argue that the differences between rabbinic discourse about these two types of confrontation in the three aforementioned areas stem from crucial differences in the ways these acts are perceived and received. The notable nuances between rabbinic portrayals of protest and rebuke can provide insight into thinking about effective interpersonal confrontation today.

Prolonged exposure to high temperatures can cause heat-related illnesses and accelerate death, especially in the elderly. We developed a locally-appropriate Healthy Environment Assessment Tool, or ‘HEAT’ tool, to assess heat-health risks among communities. HEAT was co-developed with stakeholders and practitioners/professionals from the Rustenburg Local Municipality (RLM), a setting in which heat was identified as a risk in an earlier study. Feedback was used to identify vulnerable groups and settings in RLM, consider opportunities and barriers for interventions, and conceptualize a heat-health vulnerability assessment tool for a heat-resilient town. Using information provided by the RLM Integrated Development Plan, the HEAT tool was applied in the form of eight indicators relating to heat-health vulnerability and resilience and areas were evaluated at the ward level. Indicators included population, poverty, education, access to medical facilities, sanitation and basic services, public transport, recreation/community centres, and green spaces. Out of 45 wards situated in the municipality, three were identified as critical risk (red), twenty-eight as medium-high risk (yellow), and six as low risk (green) in relation to heat-health vulnerability. Short-term actions to improve heat health resilience in the community were proposed and partnerships between local government and the community to build heat health resilience were identified.

Objective Rare genetic diseases of obesity typically present with hyperphagia, a pathologic desire to consume food. Cost-utility models assessing the value of treatments for these rare diseases will require health state utilities representing hyperphagia. This study estimated utilities associated with various hyperphagia severity levels. Methods Four health state vignettes were developed using published literature and clinician input to represent various severity levels of hyperphagia. Utilities were estimated for these health states in a time trade-off elicitation study in a UK general population sample. Results In total, 215 participants completed interviews (39.5% male; mean age 39.1 years). Mean (SD) utilities were 0.98 (0.02) for no hyperphagia, 0.91 (0.10) for mild hyperphagia, 0.70 (0.30) for moderate hyperphagia, and 0.22 (0.59) for severe hyperphagia. Mean (SD) disutilities were −0.08 (0.10) for mild, −0.28 (0.30) for moderate, and −0.77 (0.58) for severe hyperphagia. Conclusions These data show increasing severity of hyperphagia is associated with decreased utility. Utilities associated with severe hyperphagia are similar to those of other health conditions severely impacting quality of life (QoL). These findings highlight that treatments addressing substantial QoL impacts of severe hyperphagia are needed. Utilities estimated here may be useful in cost-utility models of treatments for rare genetic diseases of obesity.

Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines a transient population of progenitors in human neural differentiation. Testing ASCL1's pioneer function using a knockout model to define the unbound state, we found that endogenous expression of ASCL1 drives progenitor differentiation bycis-regulation both as a classical pioneer factor and as a nonpioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor, and we provide evidence for codependent DNA binding and remodeling at a subset of ASCL1 and SWI/SNF cotargets. Our findings provide new insights into ASCL1 function regulating activation of long-range regulatory elements in human neurogenesis and uncover a novel mechanism of its chromatin remodeling function codependent on partner ATPase activity.

Though genre fiction is now ubiquitous, and though both book history and literary studies have devoted considerable attention to individual genres like science fiction and romance novels, the history of the system of popular fiction categories has been little studied. This essay traces the origins of the genre-fiction system in United States magazine and book publishing, bringing sociological and book-historical analysis to bear on changing practices of categorization in publishing, advertising, librarianship, and reader response from the 1890s through the 1950s. Genre categories were only intermittently in use through the 1910s; they were first institutionalized in pulp magazines in the 1920s and 1930s. The genre-fiction system was transmitted to book publishing only in the course of the so-called "paperback revolution" of the 1940s and 1950s, which made room for fiction-book production by categories while relegating it to a permanently low-status position. This transmission across publishing formats was far from deliberate; instead, the essay argues, the system of genre fiction arose and endured as a stable compromise articulating an expanded fiction-reading public to an expansive print culture industry, making new readers and new fiction—and new kinds of fiction—regularly available to each other in an enduringly hierarchized field.

Submission note: A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Clinical Psychology to the School of Psychological Science, Faculty of Science, Technology and Engineering, La Trobe University, Bundoora, Victoria.

Objectives: To examine access and equity to induced abortion services in Australia, including factors associated with presenting beyond nine weeks gestation. Methods: Cross-sectional survey of 2,326 women aged 16+ years attending for an abortion at 14 Dr Marie clinics. Associations with later presentation assessed using multivariate logistic regression. Results: Over a third of eligible women opted for a medical abortion. More than one in 10 (11.2%) stayed overnight. The median Medicare rebated upfront cost of a medical abortion was $560, compared to $470 for a surgical abortion at ≤9 weeks. Beyond 12 weeks, costs rose considerably. More than two-thirds (68.1%) received financial assistance from one or more sources. Women who travelled ≥4 hours (AdjOR: 3.0, 95%CI 1.2–7.3), had no prior knowledge of the medical option (AdjOR: 2.1, 95%CI 1.4–3.1), had difficulty paying (AdjOR: 1.5, 95%CI 1.2–1.9) and identified as Aboriginal and/or Torres Strait Islander (AdjOR: 2.1, 95%CI 1.2–3.4) were more likely to present ≥9 weeks. Conclusions: Abortion costs are substantial, increase at later gestations, and are a financial strain for many women. Poor knowledge, geographical and financial barriers restrict method choice.

Somatic mutations commonly occur in hematopoietic stem cells (HSCs). Some mutant clones outgrow through clonal hematopoiesis (CH) and produce mutated immune progenies shaping host immunity. Individuals with CH are asymptomatic but have an increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Using genetic engineering of human HSCs (hHSCs) and transplantation in immunodeficient mice, we describe how a commonly mutated gene in CH, TET2, affects human neutrophil development and function. TET2 loss in hHSCs produce a distinct neutrophil heterogeneity in bone marrow and peripheral tissues by increasing the repopulating capacity of neutrophil progenitors and giving rise to low-granule neutrophils. Human neutrophils that inherited TET2 mutations mount exacerbated inflammatory responses and have more condensed chromatin, which correlates with compact neutrophil extracellular trap (NET) production. We expose here physiological abnormalities that may inform future strategies to detect TET2-CH and prevent NET-mediated pathologies associated with CH.

Supplementary Material 1: Appendix A-D