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Cotton male fertility-associated gene GhGLP4, encoding a germin-like protein, is essential for anthers development by keeping ROS homeostasis through reducing H2O2 level. Utilization of heterosis is an important way to increase cotton yield and improve fiber quality in hybrid cotton development programs. Male sterility is used in the development of cotton hybrids to reduce the cost of hybrid seed production by eliminating the process of emasculation. From the transcriptome analysis of genic male sterile mutant (ms1) and its background C312 of G. hirsutum, a gene encoding germin-like protein (GhGLP4) was found significantly down-regulated in different developmental stages of ms1 anthers. To explore the gene function in cotton fertility, GhGLP4 was further studied and interfered by virus-induced gene silencing. In the GhGLP4 interfered cotton lines, the expression level of GhGLP4 was significantly decreased in the stamens, and the down-regulation of GhGLP4 resulted in pollen sac closure, stigma exertion, filament shortening, decrease in the number of anthers and complete male sterility. The expression levels of respiratory burst oxidase homologs (Rboh, NADPH oxidase) were significantly altered. Further investigation showed that the SOD activity decreased while the H2O2 content increased in the atypical stamens. These results indicated that GhGLP4 gene affected the cotton anther development through maintenance of ROS homeostasis by H2O2 reduction.

Endoscopy remains the gold standard for evaluating postoperative recurrence in Crohn's disease. Timely therapy adjustment according to endoscopic findings can improve long-term outcomes.We aimed to determine the characteristics, clinical values, and safety of the endoscopic evaluation at 1 month after surgery.This was a prospective observational study.This study was conducted in a tertiary referral hospital.Patients with Crohn's disease undergoing ileocolic resection between January 2016 and November 2018 were included.The first postoperative ileocolonoscopy was performed at 4-5 weeks after surgery.The primary outcome was postoperative recurrence within 12 months after surgery. Univariate and multivariate analyses were performed to identify risk factors.Among 84 ileocolonoscopies at 4-5 weeks, no endoscopic complication occurred. The main endoscopic findings at the first evaluation were anastomotic circumferential ulcers (10, 11.9%), anastomotic scattered ulcers (35, 41.7%), ulcers in the neoterminal ileum (16, 19.0%), edema in anastomosis (50, 59.5%), mild narrowing in anastomosis (7, 8.3%), and mild narrowing in neoterminal ileum (3, 3.6%). Anastomotic scattered ulcers were associated with future postoperative recurrence (OR, 2.532 (95% CI, 1.02-6.32), p = 0.046). Fecal calprotectin150 ug/g on postoperative day 14 could predict anastomotic scattered ulcers (OR' 2.91 (95% CI, 1.31-7.47), p = 0.027). The modified Rutgeerts score was used to define endoscopic findings: i0, 37 (44.0%); i1, 4 (4.8%); i2a, 29 (34.5%); i2b, 11 (13.1%); i3, 0; i4, 3 (3.6%). Score ≥i2a were associated with future postoperative recurrence (OR, 3.17 (95% CI, 1.22-8.27), p = 0.018). No factor was associated with a Rutgeerts score of ≥i2a at the first endoscopic evaluation.This was a single-center study with a small cohort of patients.Endoscopic evaluation at 1 month after surgery in CD was safe. Anastomotic scattered ulcers occurred in nearly half of patients and were associated with future postoperative recurrence. See Video Abstract at http://links.lww.com/DCR/B760.LA EVALUACIÓN ENDOSCÓPICA A UN MES DESPUÉS DE LA RESECCIÓN ILEOCÓLICA PARA LA ENFERMEDAD DE CROHN, PREDICE FUTURA RECURRENCIA POSOPERATORIA Y ES SEGURAANTECEDENTES:La endoscopia sigue siendo el estándar de oro para evaluar la recurrencia posoperatoria en la enfermedad de Crohn (EC). El ajuste oportuno en la terapia de acuerdo con los hallazgos endoscópicos, puede mejorar los resultados a largo plazo.OBJETIVO:Determinar las características, valores clínicos y seguridad de la evaluación endoscópica, al mes de la cirugía.DISEÑO:Estudio observacional prospectivo.ENTORNO CLINICO:El estudio se llevó a cabo en un hospital de referencia terciario.PACIENTES:Se incluyeron pacientes con EC sometidos a resección ileocólica entre enero de 2016 y noviembre de 2018.INTERVENCIONES:La primera ileocolonoscopia posoperatoria se realizó a las 4-5 semanas posteriores a la cirugía.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la recurrencia posoperatoria dentro de los 12 meses posteriores a la cirugía. Se realizaron análisis univariados y multivariados para identificar factores de riesgo.RESULTADOS:Entre 84 ileocolonoscopias a las 4-5 semanas, no ocurrió ninguna complicación endoscópica. Los principales hallazgos endoscópicos en la primera evaluación, fueron úlceras anastomóticas circunferenciales (10, 11,9%), úlceras anastomóticas dispersas (35, 41,7%), úlceras en el íleon neo-terminal (16, 19,0%), edema en la anastomosis (50, 59,5%), estrechamiento leve en la anastomosis (7, 8,3%) y estrechamiento leve en el íleon neo-terminal (3, 3,6%). Las úlceras anastomóticas dispersas se asociaron con recurrencia posoperatoria futura (OR, 2,532 (95% CI, 1,02-6,32), p = 0,046). La calprotectina fecal en el post d 14150 ug / g podría predecir úlceras anastomóticas dispersas (OR' 2,91 (95% CI, 1,31-7,47), p = 0,027). Se utilizó la puntuación de Rutgeerts modificada para definir los hallazgos endoscópicos: i0, 37 (44,0%); i1, 4 (4,8%); i2a, 29 (34,5%); i2b, 11 (13,1%); i3, 0; i4, 3 (3,6%). La puntuación ≥i2a se asoció con recurrencia posoperatoria futura (OR, 3,17 (95% CI, 1,22-8,27), p = 0,018). Ningún factor se asoció con ≥i2a en la primera endoscopia.LIMITACIONES:Estudio de un solo centro con una pequeña cohorte de pacientes.CONCLUSIONES:La evaluación endoscópica al mes de la cirugía en EC, fue segura. Se produjeron úlceras anastomóticas dispersas en casi la mitad de los pacientes y se asociaron con una futura recurrencia posoperatoria. Consulte Video Resumen en http://links.lww.com/DCR/B760. (Traducción - Dr. Fidel Ruiz Healy).

Summary Background & aims Exclusive enteral nutrition (EEN) as a primary therapy is safe and effective for inducing the clinical remission of active luminal Crohn's disease (CD). Whether isolated colonic involvement affects the efficacy of EEN is controversial. We aimed to identify the influence of isolated colonic CD on the efficacy of EEN and to determine other potential predictors of the response to induction therapy with EEN in adult patients with CD. Methods Data for adult CD patients treated with EEN as an induction therapy at our centre from January 1, 2014, to May 31, 2017, were reviewed. Eligible patients were divided into an isolated colonic Crohn's disease (cCD) group and a non-isolated colonic Crohn's disease (non-cCD) group according to the disease location. The rates of clinical remission and inflammatory and nutritional serum markers were compared between the groups. Possible relationships between isolated colonic involvement or other potential factors and the efficacy of EEN were assessed by univariate and multivariate analyses. The propensity score matching method was used to confirm the results. Results Overall, 241 patients were included in the analysis: 52 patients in the cCD group and 189 patients in the non-cCD group. The rates of clinical remission differed between the two groups (cCD group: 51.9% versus non-cCD group: 68.3%, P = 0.029). Multivariate analyses indicated that isolated colonic involvement was associated with a reduced response to EEN (OR = 2.74; [CI] 95% = [1.2–6.23], P = 0.016). Additionally, the lean body mass index (LBMI) before treatment was associated with the efficacy of EEN (OR = 0.636; [CI] 95% = [0.444–0.912], P = 0.014). These associations were confirmed using the propensity score model. For patients with isolated colonic CD, multivariate analysis showed that pancolitis (OR = 16.7; [CI] 95% = [1.074–260.5], P = 0.044) was another independent factor for the efficacy of EEN. Further analysis showed that even in patients who achieved clinical remission after EEN, inflammatory serum markers declined more slowly in the cCD group than in the non-cCD group, and the time to remission was longer in the cCD group. Conclusions Isolated colonic CD showed a reduced response to induction therapy with EEN compared with ileal or ileocolonic disease in adult patients. Patients with isolated colonic CD required more time to benefit from EEN therapy compared with patients with non-colonic CD. Additionally, LBMI before treatment was associated with the efficacy of EEN.

Background The use of face masks remains contentious, with international variation in practice. Their prevalence in the UK, is likely to increase due to new legislation. Clear information regarding the appropriate use of masks is needed, to ensure compliance with policies to reduce transmission of COVID-19. We aimed to assess the impact of visual representations of guidance, or infographics, upon the knowledge of appropriate face mask usage in a representative UK cohort. Methods Adult patients were recruited to this randomised internet-based questionnaire study during the 12–14 May 2020 from across the UK. Respondents viewed one of five public health stimuli regarding the use of face masks, or no stimulus. The groups accessed aids by the European Centre for Disease Control (EUCDC), World Health Organisation (WHO), Singaporean Ministry of Health (SMOH), text from the UK government (UK Gov), or an infographic designed by the Behavioural Insights Team (BIT). The primary outcome was to evaluate the effect of each infographic upon participants’ recall of face mask technique, sentiments and willingness to wear a face covering. Secondary outcomes included the effect of symptomology and socio-demographic factors. Results 4099 respondents were randomised (1009 control, 628 EUCDC, 526 WHO, 639 SMOH, 661 UKGOV and 606 BIT). Stimuli from the WHO, SMOH and BIT demonstrated significantly higher average recall scores compared to the controls (7.40 v. 7.38 v. 7.34 v. 6.97, P Conclusions To ensure the appropriate use of masks, as mandated by UK law, guidance must provide sufficient information, yet remain understandable. Infographics can aid the recall of correct mask techniques by highlighting salient steps and reducing cognitive burden. They have also demonstrated greater trustworthiness than text-only guidance. The effect of infographics upon COVID-19-related anxiety was poor, and they should be further developed to address this sentiment. A willingness to wear face masks has, however, been demonstrated.

Crohn's disease (CD)-associated adherent invasive Escherichia coli (AIEC) has been implicated as a causative or contributory factor in CD pathology. MicroRNA let-7b/Toll-like receptor 4 (TLR-4) signaling pathways may play an important role in microbiota-mucosa interactions. We aimed to investigate whether AIEC influences IECs' function of expressing TLR4, and the potential role of let-7b in regulating AIEC induced gut inflammation. Wild type (WT) and interleukin-10 knockout (IL-10 KO) mice in specific pathogen free (SPF) housing were infected by AIEC LF82, and IL-10 KO mice were treated with pre-let7b or anti-let-7b. Besides, T84 cells were infected by AIEC LF82 or E. coli K-12, and treated with let-7b mimics or inhibitor. let-7b/TLR4 signaling pathway was investigated and the therapeutic effects of let-7b treatment on colitis in IL-10-mice and on cytokines release in T84 were assessed. We found AIEC elicited/exacerbated colitis in WT/IL-10 KO mice, and promoted proinflammatory cytokines release in T84 cells that correlated with increased TLR4 expression and decreased let-7b. Overexpression of let-7b significantly ameliorated the severity of colitis in AIEC infected IL-10 KO mice, and reduced secretion of cytokines in AIEC-infected T84 cells via regulating TLR4 expression. Besides, overexpression of TLR4 caused by inhibition of let-7b led to increased proinflammatory cytokines release in K-12 infected T84 cells. These results suggest AIEC instigates excessive mucosal immune response against gut microbiota via let-7b/TLR4 signaling pathway. Let-7b may be a potential therapeutic target of CD, especially for CD with AIEC infection.

Background Over one in five UK doctors reports feeling burnt out because of their work. This study aimed to determine if a novel text message intervention could reduce burnout in UK trainee anaesthetists. Methods In this two-arm, non-blinded, randomised controlled trial, we recruited 2nd to 4th year trainees registered with the Royal College of Anaesthetists, UK. Eligible trainees were given information about the trial and asked to provide their mobile phone numbers to indicate consent to participate. Participation was optional. Participants who signed up to the trial were randomly assigned (using a random number generator in the statistical programme Stata) to receive either fortnightly text messages over 10 months (treatment group) or no intervention messages (control group). Randomisation was stratified by training year and region. A literature review and qualitative study informed the intervention design and content: our intervention was low cost to deliver and minimally time-intensive for participants (contrasting many previous interventions), and it aimed to address factors identified as contributing to burnout. The message content also drew on 11 themes from the behavioural science and wellbeing literature (eg, gratitude, social support, self-compassion) to improve burnout and wellbeing. The co-primary outcomes were burnout (measured by the work-related subscale of the Copenhagen Burnout Inventory) and wellbeing (Short Warwick-Edinburgh Mental Wellbeing Scale). Secondary outcomes were meaning in work, professional value, sickness absence, and consideration of career break. Exploratory outcomes were factors potentially affecting wellbeing, including COVID-19. Outcomes were measured via an online survey. Intervention impact for those who completed the endline survey was evaluated using regression adjusting for gender, training year, training region, and baseline measurement. We conducted exploratory analyses of intervention impact in subgroups of participants using the same regression model. The Imperial College Research Ethics Committee approved the study on Aug 14, 2019 (reference number 19IC5205). The Imperial Joint Research Compliance Office approved the additional exploratory outcomes in an amendment on July 21, 2020. This trial is registered with the ISRCTN registry, ISRCTN11418903. Findings In September-October 2019, 279 trainees were randomised, of whom 153 (80 female; 73 male) completed the endline survey (74 in the treatment group; 79 in the control group). There were no significant group differences in burnout (β=–1·82, 95% CI –6·54 to 2·91, p=0·45), wellbeing (–0·52, –1·73 to 0·69, p=0·40), or secondary outcomes (all p values ≥0·24). However, 49 (66%) of 74 participants in the treatment group recommended the messages be sent to future trainees. Exploratory analyses found the intervention was associated with reduced burnout in participants who reported personal or work-related difficulties (β=–9·56, –17·35 to –1·77), and those for whom COVID-19 had a large negative wellbeing impact (β=–10·38, –20·57 to –0·19). Interpretation The intervention had no impact overall, but was recommended by most, and associated with reduced burnout in participants reporting difficult personal or work circumstances. Given this intervention is low cost and requires minimal time commitment, it may warrant adaptation (eg, based on participant feedback) and further evaluation. Funding National Institute for Health Research.

Introduction The mesentery is involved in Crohn's disease. The impact of the extent of mesenteric resection on postoperative disease progression in Crohn's disease remains unconfirmed. This study aimed to determine the association between resection of the mesentery and postoperative outcomes in patients with Crohn's colitis (CC) undergoing colorectal surgery. Methods Patients with CC who underwent colorectal resection between January 2000 and December 2018 were reviewed, and the data were gathered from a prospectively maintained database. Patients were divided into 2 groups according to the extent of mesenteric resection, the extensive mesenteric excision (EME) group and the limited mesenteric excision (LME) group. Outcomes including early postoperative morbidities and surgical recurrence were compared between the 2 groups. Results Of the 126 patients included, 60 were in the LME group and 66 in the EME group. There was no significant difference between the 2 groups in early postsurgical outcomes except the intraoperative blood loss was increased in the LME group (P = 0.002). Patients in the EME group had a longer postoperative surgical recurrence-free survival time when compared with those in the LME group (P = 0.01). LME was an independent predictor of postoperative surgical recurrence (hazard ratio 2.67, 95% confidence interval 1.04-6.85, P = 0.04). This was further confirmed in the subgroup analysis of patients undergoing colorectal resection and anastomosis (hazard ratio 2.83, 95% confidence interval 1.01-7.96, P = 0.048). Discussion In patients undergoing surgery for CC, inclusion of the mesentery is associated with similar short-term outcomes and improved long-term outcomes compared with those seen when the mesentery is retained.

Purpose: Whether isocitrate dehydrogenase (IDH) gene aberrations affected prognosis of patients with acute myeloid leukemia (AML) was controversial. Here, we conducted a meta-analysis to evaluate their prognostic value. Experimental Design: PubMed, Embase, Cochrane, and Chinese databases were searched to identify studies exploring how IDH gene aberrations affected AML outcome. Pooled HRs and relative risks (RR) were calculated, along with 95% confidence intervals (CI). Results: Thirty-three reports were included. IDH mutations seemed not to affect overall survival (OS: HR, 1.05; 95% CI, 0.89–1.23) and event-free survival (EFS: HR, 0.97; 95% CI, 0.80–1.18) when considered as a single factor, but improved accumulative incidence of relapse (CIR: HR, 1.44; 95% CI, 1.18–1.76) in patients with intermediate-risk karyotypes (IR-AML). However, IDH1 mutation conferred worse OS (HR, 1.17; 95% CI, 1.05–1.31) and EFS (HR, 1.29; 95% CI, 1.07–1.56), especially in patients with normal cytogenetics (OS: HR, 1.21; 95% CI, 1.01–1.46; EFS: HR, 1.56; 95% CI, 1.23–1.98). Prognosis of the IDH1 single-nucleotide polymorphism rs11554137 was also poor (OS: HR, 1.34; 95% CI, 1.03–1.75). IDH2 mutation improved OS (HR, 0.78; 95% CI, 0.66–0.93), particularly in IR-AML patients (OS: HR, 0.65; 95% CI, 0.49–0.86). The IDH2 (R140) mutation was associated with better OS among younger cases (HR, 0.64; 95% CI, 0.49–0.82). Treatment outcome was poor [RR for complete remission rates in IDH1 mutation: 1.21; 95% CI, 1.02–1.44; IDH2 (R172) mutation: 2.14; 95% CI, 1.61–2.85]. Conclusions: Various subtypes of IDH mutations might contribute to different prognosis and be allowed to stratify IR-AML further. Clin Cancer Res; 23(15); 4511–22. ©2017 AACR.

Background: Prox1 is a transcription factor necessary for lymphatic function. The main aim of the current study was to investigate the potential role of Prox1 in lymphangiogenesis and lymphatic function, and analyze Prox1-dependent stimulation of lymphatic function on mesenteric lesions and the composition of microbiota in Crohn’s disease. Methods: Prox1flox/+, Tie2-CreERT2 and IL-10 KO mice were included. Disease activity and enterocolitis inflammation were assessed using a grading system. Lymphatic vessel density and lymphatic function were analyzed using immunohistochemistry and lymphangiography. The potential mechanism of Prox1 was analyzed. The effects of lymphatic function on mesenteric adipose tissue (MAT) and the composition of microbiota were evaluated. Results: Systemic delivery of AAV-Prox1 reduced disease activity index and the severity of chronic inflammation in IL-10 KO mice. Without compensatory response of Prox1, IL-10 KO+Prox1 KO mice developed serious inflammation in the colon. For lymphatic vessel, IL-10 KO+Prox1 KO mice showed lower lymphatic vessel density and less functional lymphatic vessels. IL-10 KO+AAV-Prox1 mice showed significantly increased lymphatic vessel density. Delivery of AAV-Prox1 also promoted lymphatic drainage function. The Prox1/VEGFC/VEGFR3 pathway played an important role in lymphangiogenesis and lymphatic function. Additionally, Prox1-dependent stimulation of lymphatic function ameliorated hypertrophy of MAT in IL-10 KO mice. Delivery of AAV-Prox1 also modified the composition of microbiota, the proportion of Firmicutes increased and Bacteroidetes decreased in IL-10 KO+AAV-Prox1 mice compared with IL-10 KO mice. An increase in the diversity of gut microbiota in IL-10 KO+ AAV-Prox1 mice was observed. Conclusions: Our findings demonstrated that Prox1 played the critical role in the lymphangiogenesis and lymphatic function. Additionally, Prox1-dependent stimulation of lymphatic function could ameliorate hypertrophy of MAT and modify the composition of microbiota in experimental Crohn’s disease. Funding Statement: This work was partly supported by National Natural Science Foundation of China (Grant 81670471, 81770556 and 81570500). Declaration of Interests: The authors declare that they have no conflicts of interests. Ethics Approval Statement: All animal protocols were approved by the Institutional Ethics Committee of the Jinling Hospital, Medical School of Nanjing University, Nanjing, China.

Background: Isolated colonic Crohn’s disease (cCD) responds less well to induction therapy with exclusive enteral nutrition (EEN) compared with ileal or ileocolonic disease in adult patients; therefore, we aimed to identify the factors that influence the response to EEN and develop a predictive nomogram model to optimize the use of EEN in cCD patients. Materials and methods: Eighty-five cCD patients treated with EEN as first-line therapy at our center between 1 June 2012 and 30 June 2018 were retrospectively analyzed as the primary cohort. The primary endpoint was clinical remission after EEN therapy. Potential predictive factors for the efficacy of EEN were assessed by univariate and multivariate analyses, and a nomogram to predict the response to EEN therapy in cCD patients was designed. Another 19 cCD patients were retrospectively included in the validation cohort to verify the accuracy of the nomogram model. Results: The clinical remission rates for the primary cohort and validation cohort were 52.9% and 47.4%, respectively. Pancolitis was the greatest contributor to the risk of failure to respond to EEN [odds ratio (OR) = 4.896; 95% confidence interval (CI) = 1.223–19.607; p = 0.025], lean body mass index (LBMI), colonic lesion features, simple endoscopic scores for Crohn’s disease, C-reactive protein before treatment and ∆prealbumin were also related to the efficacy of EEN in cCD. The nomogram model showed robust discrimination, with an area under the receiving operating characteristic curve of 0.906. Conclusion: Several predictive factors for response to EEN therapy in cCD adult patients were identified, and a promising nomogram that can predict the effect of EEN in cCD was developed.

Patient: Male, 49 Final Diagnosis: T-lymphoid/myeloid bilineal blastic transformation of CML Symptoms: Rapidly enlarging mass in left neck Medication: — Clinical Procedure: Biopsy of the left submandibular lymph nodes Specialty: Hematology Objective: Rare co-existance of disease or pathology Background: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the Philadelphia chromosome generated by the reciprocal translocation t(9: 22)(q34;q11). CML is usually diagnosed in the chronic phase. Blast crisis represents an advanced phase of CML. Extramedullary blast crisis as the initial presentation of CML with bone marrow remaining in chronic phase is an unusual event. Further, extramedullary blast crisis with T lymphoid/myeloid bilineal phenotype as an initial presentation for CML is extremely unusual. Case Report: Here, we report the case of a 49-year-old male with rapidly enlarged submandibular lymph nodes. Biopsy specimen from the nodes revealed a characteristic appearance with morphologically and immunohistochemically distinct myeloblasts and T lymphoblasts co-localized in 2 adjacent regions, accompanied by chronic phase of the disease in bone marrow. The presence of the BCR/ABL1 fusion gene within both cellular populations in this case confirmed the extramedullary disease represented a localized T lymphoid/myeloid bilineal blastic transformation of CML. After 3 courses of combined chemotherapy plus tyrosine kinase inhibitor treatment, the mass was completely regressed with a 3-log decrease in BCR/ABL1 transcript from baseline. Five months after the diagnosis, the patient showed diminished vision, hand tremors, and weakness of lower extremities. Flow cytometric immunophenotyping of cerebrospinal fluid revealed the presence of myeloid blasts. An isolated central nervous system relapse of leukemia was identified. Following high-dose systemic and intrathecal chemotherapy, the patient continued to do well. Conclusions: The possibility of extramedullary blast crisis as an initial presentation in patients with CML should be considered. Further, an isolated central nervous system blast crisis should be considered if neurological symptoms evolve in patients who have shown a good response to therapy.

Background Acute high altitude illness is defined as a group of cerebral and pulmonary syndromes that can occur during travel to high altitudes. It is more common above 2500 metres, but can be seen at lower elevations, especially in susceptible people. Acute high altitude illness includes a wide spectrum of syndromes defined under the terms 'acute mountain sickness' (AMS), 'high altitude cerebral oedema' and 'high altitude pulmonary oedema'. There are several interventions available to treat this condition, both pharmacological and non-pharmacological; however, there is a great uncertainty regarding their benefits and harms. Objectives To assess the clinical effectiveness, and safety of interventions (non-pharmacological and pharmacological), as monotherapy or in any combination, for treating acute high altitude illness. Search methods We searched CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science, CINAHL, Wanfang database and the World Health Organization International Clinical Trials Registry Platform for ongoing studies on 10 August 2017. We did not apply any language restriction. Selection criteria We included randomized controlled trials evaluating the effects of pharmacological and non-pharmacological interventions for individuals suffering from acute high altitude illness: acute mountain sickness, high altitude pulmonary oedema or high altitude cerebral oedema. Data collection and analysis Two review authors independently assessed the eligibility of study reports, the risk of bias for each and performed the data extraction. We resolved disagreements through discussion with a third author. We assessed the quality of evidence with GRADE. Main results We included 13 studies enrolling a total of 468 participants. We identified two ongoing studies. All studies included adults, and two studies included both teenagers and adults. The 13 studies took place in high altitude areas, mostly in the European Alps. Twelve studies included participants with acute mountain sickness, and one study included participants with high altitude pulmonary oedema. Follow-up was usually less than one day. We downgraded the quality of the evidence in most cases due to risk of bias and imprecision. We report results for the main comparisons as follows.Non-pharmacological interventions (3 studies, 124 participants)All-cause mortality and complete relief of AMS symptoms were not reported in the three included trials. One study in 64 participants found that a simulated descent of 193 millibars versus 20 millibars may reduce the average of symptoms to 2.5 vs 3.1 units after 12 hours of treatment (clinical score ranged from 0 to 11 ‒ worse; reduction of 0.6 points on average with the intervention; low quality of evidence). In addition, no complications were found with use of hyperbaric chambers versus supplementary oxygen (one study; 29 participants; low-quality evidence).Pharmacological interventions (11 trials, 375 participants)All-cause mortality was not reported in the 11 included trials. One trial found a greater proportion of participants with complete relief of AMS symptoms after 12 and 16 hours when dexamethasone was administered in comparison with placebo (47.1% versus 0%, respectively; one study; 35 participants; low quality of evidence). Likewise, when acetazolamide was compared with placebo, the effects on symptom severity was uncertain (standardized mean difference (SMD) -1.15, 95% CI -2.56 to 0.27; 2 studies, 25 participants; low-quality evidence). One trial of dexamethasone in comparison with placebo in 35 participants found a reduction in symptom severity (difference on change in the AMS score: 3.7 units reported by authors; moderate quality of evidence). The effects from two additional trials comparing gabapentin with placebo and magnesium with placebo on symptom severity at the end of treatment were uncertain. For gabapentin versus placebo: mean visual analogue scale (VAS) score of 2.92 versus 4.75, respectively; 24 participants; low quality of evidence. For magnesium versus placebo: mean scores of 9 and 10.3 units, respectively; 25 participants; low quality of evidence). The trials did not find adverse events from either treatment (low quality of evidence). One trial comparing magnesium sulphate versus placebo found that flushing was a frequent event in the magnesium sulphate arm (percentage of flushing: 75% versus 7.7%, respectively; one study; 25 participants; low quality of evidence). Authors' conclusions There is limited available evidence to determine the effects of non-pharmacological and pharmacological interventions in treating acute high altitude illness. Low-quality evidence suggests that dexamethasone and acetazolamide might reduce AMS score compared to placebo. However, the clinical benefits and harms related to these potential interventions remain unclear. Overall, the evidence is of limited practical significance in the clinical field. High-quality research in this field is needed, since most trials were poorly conducted and reported.

Background Mesenteric fat wrapping and thickening are typical characteristics of Crohn's disease (CD). The purpose of this study was to explore the cause of mesenteric adipose hypertrophy and analyze the role of lymphatic vessels in mesenteric adipose tissue in CD. Methods Twenty-three CD patients who underwent ileocolonic resection were included. In CD patients, specimens were obtained from hypertrophic mesenteric adipose tissue (htMAT) next to the diseased ileum. The mesenteric lymphatic vessels in mesenteric adipose tissue were separated under stereoscope microscope. Transmission electron microscopy and immunofluorescence were used to observe the structure of mesenteric lymphatic vessels. The NF-κB signaling pathway in mesenteric adipose tissue was detected in CD specimens using Western blotting. Results Electron microscopy showed that the structure of mesenteric lymphatic vessel was discontinuous, and the microstructure of lymphatic endothelial cells appeared ruptured and incomplete. Through an immunofluorescence technique, we found that the surface of lymphatic endothelial cells lacked tight junction protein staining in CD. Also, the expression of claudin-1, occludin, and ZO-1 in the mesenteric lymphatic vessel of htMAT was significantly lower than that of control. These results indicated that the structure of the mesenteric lymphatic vessel in htMAT was mispatterned and ruptured, which could lead to lymph leakage. Leaky lymph factors could stimulate adipose tissue to proliferate. Antigens that leaked into the mesenteric adipose tissue could effectively elicit an immune response. The levels of cytokines (TNF-a, IL-1β, IL-6) was increased in the htMAT of CD patients by activated NF-κB signaling pathway. Conclusions Our findings demonstrated that the hypertrophy of mesenteric adipose tissue may result from mispatterned and ruptured lymphatic vessels. Alteration of mesenteric adipose tissue was associated with activated NF-κB signaling pathway. This study enhances support for elucidating the importance of mesenteric lymphatic vessels and adipose tissue in CD.

Intermediate-risk acute myeloid leukemia (IR-AML), which accounts for a substantial number of AML cases, is highly heterogeneous. Although several mutations have been identified, the heterogeneity of AML is uncertain because novel mutations have yet to be discovered. Here we applied next generation sequencing (NGS) platform to screen mutational hotspots in 410 genes relevant to hematological malignancy. IR-AML samples (N=95) were sequenced by Illumina Hiseq and mutations in 101 genes were identified. Only seven genes (CEBPA, NPM1, DNMT3A, FLT3-ITD, NRAS, IDH2 and WT1) were mutated in more than 10% of patients. Genetic interaction analysis identified several cooperative and exclusive patterns of overlapping mutations. Mutational analysis indicated some correlation between genotype and phenotype. FLT3-ITD mutations were identified as independent factors of poor prognosis, while CEBPA mutations were independent favorable factors. Co-occurrence of FLT3-ITD, NPM1 and DNMT3A mutations was identified with associated with specific clinical AML features and poor outcomes. Furthermore, by integrating multiple mutations in the survival analysis, 95 IR-AML patients could be stratified into three distinct risk groups allowing reductions in IR-AML by one-third. Our study offers deep insights into the molecular pathogenesis and biology of AML and indicated that the prognosis of IR-AML could be further stratified by different mutation combinations which may direct future treatment intervention.

We report the development of a new ultrasensitive approach for label-free DNA detection using [...]

Seasonality is one of the most influential yet subtle factor that affects people's life. At biological level, it affects people's weight, appetite, mood, and susceptibility to certain pathogens and health conditions. At socio-cultural level, it is embedded in the school calendar, holiday plans, and fashion trends. This study investigates the relationship between the seasonality of wedding and the seasonality of people’s health-seeking behaviors. We propose that the seasonality of wedding affects seasonality of health-seeking behaviors (e.g. getting fit, diet, and quitting addictions) among the general public. We develop two hypotheses based on this preposition and test them with Google Trends data. We find the seasonality of wedding is associated with some health-seeking behaviors with certain temporal lags, and discuss the implications for health communication.

The mechanisms by which AML1/ETO (A/E) fusion protein induces leukemogenesis in acute myeloid leukemia (AML) without mutagenic events remain elusive. Here we show that interactions between A/E and hypoxia-inducible factor 1α (HIF1α) are sufficient to prime leukemia cells for subsequent aggressive growth. In agreement with this, HIF1α is highly expressed in A/E-positive AML patients and strongly predicts inferior outcomes, regardless of gene mutations. Co-expression of A/E and HIF1α in leukemia cells causes a higher cell proliferation rate in vitro and more serious leukemic status in mice. Mechanistically, A/E and HIF1α form a positive regulatory circuit and cooperate to transactivate DNMT3a gene leading to DNA hypermethylation. Pharmacological or genetic interventions in the A/E-HIF1α loop results in DNA hypomethylation, a re-expression of hypermethylated tumor-suppressor p15(INK4b) and the blockage of leukemia growth. Thus high HIF1α expression serves as a reliable marker, which identifies patients with a poor prognosis in an otherwise prognostically favorable AML group and represents an innovative therapeutic target in high-risk A/E-driven leukemia.

Background Mortality increases during heat waves have been reported worldwide. The magnitude of these increases can vary within regions according to sociodemographic and urban landscape characteristics. The objectives of this study were to explore this variation and its determinants, and to identify the most heat-vulnerable areas by mapping heat vulnerability. Methods We conducted a time-stratified case-crossover analysis using daily mortality in the Barcelona metropolitan area during the warm seasons of 1999-2006. Temperature data on the date of death were assigned to each individual, which were assigned to their census tract of residence. Eight census tract-level variables on socioeconomic or built environment characteristics were obtained from the census. Residence surrounding greenness was obtained from satellite data. The relative risk (RR) of mortality after three consecutive hot days (defined as those exceeding the 95th percentile of maximum temperature) was calculated via conditional logistic regression. Effect modification was examined by including interaction terms. Results Analyses were based on 52 806 deaths. The effect of three consecutive hot days was a 30% increase in all-cause mortality (RR=1.30, 95% CI 1.24 to 1.38). Heterogeneity of this effect was observed across census tracts. The effect of heat on mortality was higher in the census tracts with a large percentage of old buildings (RR = 1.21, 95% CI 1.00 to 1.46), manual workers (RR = 1.25, 95% CI 0.96 to 1.64) and residents perceiving little surrounding greenness (RR = 1.29, 95% CI 1.01 to 1.65). After three consecutive hot days, mortality doubled in the most heat-vulnerable census tracts. Conclusions Sociodemographic and urban landscape characteristics are associated to mortality risk during heat waves and are useful to build heat vulnerability maps.

The t(8;21)(q22;q22) translocation, resulting in a chimeric protein AML1/ETO (A/E), is one of the most common chromosomal abnormalities in acute myeloid leukemia (AML). It has been reported that additional mutagenic “hits” are required for A/E to be a leukemic driver, but it is unclear why most A/E-positive patients don’t carry such gene mutations. We hypothesized that unconventional and more universal events might cooperate with A/E to drive leukemogenesis. Hypoxia inducible factor 1a (HIF1a) is a transcription factor mediating the cellular response to hypoxia in malignant cells. To identify the key molecule responsible for A/E-driven leukemia, we focused on HIF1a signaling, as it is selectively activated in AML stem cells in a hypoxia-independent fashion. Using qPCR analysis, we measured HIF1a mRNA levels in bone marrow mononuclear cells from 73 A/E-positive and 59 A/E-negative patients with newly diagnosed AML and 15 healthy donors. HIF1a was highly expressed in A/E-positive patients, as compared to A/E-negative patients and healthy controls. The expression of HIF1a was positively correlated with the expression of A/E, independent of KIT mutation. Patients were grouped into quartiles according to HIF1a expression levels (Q1-Q4, each quartile containing 25% of patients) and divided into high HIF1a (HIF1a high, Q4; n = 33) and low HIF1a (HIF1a low, Q1-Q3; n = 99). AE-positive patients with high HIF1a expression had a significantly shorter OS (median = 19.0 months vs. not reached, P = 0.015) and EFS (median = 9.0 months vs. 24.0 months, P = 0.001) compared to those with low HIF1a expression. Notably, HIF1a-associated inferior prognosis in A/E-positive patients was KIT mutation-independent. In patients carrying wild-type KIT [n = 53, about 73% (53/73) of the entire A/E-patients], those with high HIF1a levels had a shorter OS (median = 23.1 months vs. not reached, P = 0.008) and EFS (median = 9.4 months vs. not reached, P = 0.001) than those with low HIF1a levels. Multivariate analysis revealed that high HIF1a levels were independent prognostic indicators for both OS and EFS (P = 0.014, HR = 3.574 and P = 0.004, HR = 4.304, respectively) in AE-positive patients. Mechanistic studies revealed that A/E and HIF1a formed a positive regulatory circuit, in which A/E bound to HIF1a gene promoter and transactivated HIF1a or vice versa. Co-expression of AE and HIF1a in leukemia cells caused a higher cell proliferation rate in vitro and more serious leukemic status in mice. To gain insight into the molecular basis of A/E-HIF1a functional cooperation in leukemogenesis, we examined the mRNA levels of DNMT1, DNMT3a and DNMT3b expression in bone marrow samples from above-mentioned AML patients and healthy donors using qPCR. The result showed that DNMT3a, but not DNMT1 and DNMT3b, was significantly overexpressed in A/E-positive patients, as compared to A/E-negative patients and healthy donors. DNMT3a levels were positively correlated with both A/E and HIF1a levels. We therefore focused on evaluating the role of DNMT3a in A/E-positive AML. We found that DNMT3a expression was positively correlated with both A/E and HIF1a levels. As an individual event, A/E or HIF1a was enriched on DNMT3a gene promoter and synergistically increased DNMT3a transcription and enhanced global DNA methylation. Pharmacological or genetic interventions in the AE-HIF1a loop resulted in DNA hypomethylation, a reexpression of hypermethylated tumor suppressor p15INK4band the blockage of leukemia growth. In summary, we showed that A/E and HIF1a form a regulatory circuit and cooperatively control aggressive leukemia growth through DNMT3a transactivation and subsequent DNA hypermethylation. Thus, the HIF1a-DNMT3a nexus serves as a reliable marker, which identifies patients with a poor prognosis in an otherwise prognostically favorable AML group, and represents an innovative therapeutic target in high-risk AE-positive leukemia. Disclosures No relevant conflicts of interest to declare.

Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+), but not CD4(+) T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.