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The practice of oncology continues to evolve over time. Educators find themselves in a position where they are no longer able to teach a topic in its entirety. Moreover, the rapid expansion of information available through research and discovery in the field of oncology makes it difficult for learners to process the constant barrage of new content. Lecturers continue to impart knowledge using didactic techniques, often trying to include as much material as possible in the time permitted. The question becomes: In the face of an impossibly large field, how can one assist learners in learning, and retaining, what is most important? The science of learning continues to develop, and we now recognize that there are ways to teach that optimally facilitate the retention and application of knowledge. By using these strategies, educators can make it easier for learners to absorb and retain key information. This article will touch upon several such techniques: cognitive load optimization, analogy, contrasting cases, elaboration, and just-in-time telling. By applying these methods to didactic presentations, educators can ensure that their lessons are heard, understood, and ultimately transformed into something unforgettable.

PDF file - 80 KB, Supplementary Table S1 lists the cell lines and their respective IC50s for all three of the PI3K inhibitors evaluated in this study.

PDF file - 72 KB, Supplementary Figure S1 shows the results for the experiment to determine if there was a therapeutic window between malignant and normal cells. Both IPA-3 and BEZ235 individually and in combination were selectively toxic to malignant B cells (Ly8 cell line) compared to normal B cells.

Purpose: The phosphoinositide 3-kinase (PI3K) pathway is known to play an active role in many malignancies. The role of PI3K inhibition in the treatment of lymphomas has not been fully delineated. We sought to identify a role for therapeutic PI3K inhibition across a range of B-cell lymphomas.Experimental Design: We selected three small molecule inhibitors to test in a panel of 60 cell lines that comprised diverse lymphoma types. We tested the selective PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in these cell lines. We applied gene expression profiling to better understand the molecular mechanisms associated with responsiveness to these drugs.Results: We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA–interference-mediated knockdown of the PAK1 gene, we showed a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small-molecule inhibitor of PAK1 and found significant synergy between PI3K and PAK1 inhibition.Conclusion: Thus, we show that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition. Clin Cancer Res; 19(5); 1106–15. ©2012 AACR.

PDF file - 38 KB, The Supplementary Data Legend provides the legends for Supplementary Table S1 and Supplementary Figure S1.

The internal medicine (IM) subinternship (also referred to as acting internship) plays a crucial part in preparing medical students for residency. The roles, responsibilities, and support provided to subinternship directors have not been described. We sought to describe the current role of IM subinternship directors with respect to their responsibilities, salary support, and reporting structure. Nationally representative, annually recurring thematic survey of IM core clerkship directors with membership in an academic professional association as of September 2017. A total of 129 core clinical medicine clerkship directors at Liaison Committee on Medical Education fully accredited U.S./U.S.-territory-based medical schools. Responsibilities, salary support, and reporting structure of subinternship directors. The survey response rate was 83.0% (107/129 medical schools). Fifty-one percent (54/107) of respondents reported overseeing both core clerkship inpatient experiences and/or one or more subinternships. For oversight, 49.1% (28/53) of subinternship directors also reported that they were the clerkship director, 26.4% (14/53) that another faculty member directed all medicine subinternships, and 18.9% (10/53) that each subinternship had its own director. The most frequently reported responsibilities for the subinternship directors were administration, including scheduling, and logistics of student schedules (83.0%, 44/53), course evaluation (81.1%, 43/53), and setting grades 79.2% (42/53). The modal response for estimated FTE per course was 10–20% FTE, with 33.3% (16/48) reporting this level of support and 29.2% (14/54) reporting no FTE support. The role of the IM subinternship director has become increasingly complex. Since the IM subinternship is critical to preparing students for residency, IM subinternship directors require standard expectations and adequate support. Future studies are needed to determine the appropriate level of support for subinternship directors and to define essential roles and responsibilities.

Trauma in older people leads to substantial morbidity and mortality. The National Hip Fracture Database (NHFD) has driven improved practice with units compared to identify outliers. In 2013, our unit was an outlier for mortality post hip fracture (30-day mortality 12.2% vs. 8.3% nationally). This triggered external review. In 2019 the unit was highlighted as an exemplar in the UK. We describe the process that moved us from outlier to outstanding. After the initial review process, we made changes to our healthcare system, with regular reassessment of progress and care quality. Examples include a dedicated hip fracture unit, strong leadership (Nursing, Orthopaedic, Geriatrician, Anaesthetic), consultant-led in-depth monthly mortality reviews, changes to admission pathways and delirium prevention. Improvements were seen in all aspects of hip fracture care in 2019 compared with 2012. Thirty-day case-mixed adjusted mortality halved (12.2–6.1%), with substantial reductions in reoperations and pressure sores. Length of stay reduced by 5.9 days. In 2019 our unit’s performance was significantly above the national average for all six indicators assessed by NHFD: prompt orthogeriatric review (97% vs. 91% national average), prompt surgery (85% vs. 68%); NICE compliant surgery (85% vs. 74%); prompt mobilisation (93% vs. 81%); not delirious postoperatively (77% vs. 69%); return to original residence (78% vs. 71%). The NHFD highlighted our Unit as one of nine (from 175 total) highly performing UK trusts. We summarise our service development and improvement work undertaken to achieve ‘outstanding’ status, which provides a valuable template to units managing trauma in older people.

The newly evolved coronavirus, SARS‐CoV‐2, which has precipitated a global COVID‐19 pandemic among the human population, has been shown to be associated with disease in captive wild animals. Bats (Chiroptera) have been shown to be susceptible to experimental infection and therefore may be at risk from disease when in contact with infected people. Numerous conservation fieldwork activities are undertaken across the United Kingdom bringing potentially infected people into close proximity with bats. In this study, we analysed the risks of disease from SARS‐CoV‐2 to free‐living bat species in England through fieldworkers undertaking conservation activities and ecological survey work, using a qualitative, transparent method devised for assessing threats of disease to free‐living wild animals. The probability of exposure of bats to SARS‐CoV‐2 through fieldwork activities was estimated to range from negligible to high, depending on the proximity between bats and people during the activity. The likelihood of infection after exposure was estimated to be high and the probability of dissemination of the virus through bat populations medium. The likelihood of clinical disease occurring in infected bats was low, and therefore, the ecological, economic and environmental consequences were predicted to be low. The overall risk estimation was low, and therefore, mitigation measures are advisable. There is uncertainty in the pathogenicity of SARS‐CoV‐2 in bats and therefore in the risk estimation. Disease risk management measures are suggested, including the use of personal protective equipment, good hand hygiene and following the existing government advice. The disease risk analysis should be updated as information on the epidemiology of SARS‐CoV‐2 and related viruses in bats improves. The re‐analysis may be informed by health surveillance of free‐living bats.

Very low protein (VLP) diets decrease the nitrogen excretion from pigs, but these diets depress the performance even when the first four limiting amino acids (FFL; i.e. Lys, Met, Thr and Trp) are added. Supplementation of Val above and Ile at NRC (2012) levels has shown promising effects on performance of pigs fed with VLP diets. The objective of this study was to investigate the effect of a mixture of Val above and Ile at NRC levels on growth and gut microbiota in pigs fed with VLP diets. Three-week-old, weaned piglets (n = 40) were assigned to: 1) positive control (PC): normal protein diet; 2) negative control (NC): VLP diet with FFL at NRC levels; 3) VA: NC with Val above NRC; 4) IL: NC with Ile at NRC level; 5) VAIL: NC with Val above and Ile at NRC levels. Following 5 weeks of data collection, colon contents were collected. The data were analyzed by GLM procedure followed a t-test with Benjamini-Hochberg correction (SPSS). Pigs fed with NC had decreased average daily gain (ADG) and average daily feed intake (ADFI), compared with PC (P< 0.05). VAIL had less ADG than PC, but that tended to have greater ADG than NC (P< 0.1). Further, VAIL had a similar ADFI as PC (P>0.05) and tended to have greater ADFI than NC (P< 0.1). Compared with PC and NC, pigs fed with VAIL had a higher thermal radiation (P< 0.05). Relative to PC, the colon content of NC was enriched in Pasteurellaceae while those fed with VAIL had a greater abundance of Bacillus, Brevibacillus, Enterococcus, Actinobacteria, which might contribute to improved performance of pigs fed with VAIL diets. Overall, supplementation of a mixture of Val greater than NRC and Ile at NRC into the VLP diets partially improved the performance, which is likely linked with alterations in gut microbiota composition.

It is important to monitor species populations to identify changes in Red List assessment, whether increases from conservation or continued declines. This can be more difficult when there are multiple modelling options available. Using data from the National Dormouse Monitoring Programme, provided by the People’s Trust for Endangered Species, we explore the change in British Hazel Dormice (Muscardinus avellanarius) populations using two appropriate generalised additive models. The first uses the negative binomial distribution, and second the Poisson distribution, with a fixed effect of month included. Both models indicate that dormice have declined by >70% between 1994 and 2018 in Great Britain, indicating a continuation of the chronic decline of the species. Our models do not differ significantly in their evaluation of the population trend, but do indicate different Red List categories, leading us to ask: when is the dormouse population considered ‘endangered’?

While large trinucleotide repeat expansions at the FMR1 locus cause Fragile X Syndrome (FXS), smaller “premutations” are associated with the late-onset condition Fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features, with no clear molecular explanation for these marked differences. One prevailing theory posits that the premutation uniquely causes neurotoxic increases in FMR1 mRNA (i.e., 4-8-fold increases), but evidence to support this hypothesis is largely derived from analysis of peripheral blood. We applied single- nucleus RNA-sequencing to post-mortem frontal cortex and cerebellum from 9 individuals with Fragile X mutations as well as age and sex matched controls (n=6) to assess cell-type specific molecular neuropathology. We found robust reduction of FMR1 mRNA in FXS as expected, with modest but significant upregulation (∼1.3 fold) of FMR1 in glial clusters associated with premutation expansions. In premutation cases we identified alterations in glia number in cortex and cerebellum. Differential expression analysis demonstrated altered cortical oligodendrocyte development, while gene ontology analysis revealed alterations in neuroregulatory roles of glia, such as glial modulation of neurotransmission and synaptic structure. We identified significant enrichment of known FMR1 protein target genes in differentially expressed gene lists in FXS as well as the premutation, suggesting FMR1 protein target pathways may represent a shared source of dysfunction in both conditions despite opposite FMR1 mRNA changes. These findings challenge existing dogma regarding FXTAS and implicate glial dysregulation as a critical facet of premutation pathophysiology, representing novel therapeutic targets directly derived from the human condition.

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.

BACKGROUND Hemoglobin-Based Oxygen Carriers (HBOCs) can act as an "oxygen bridge" in acute severe anemia when transfusion is indicated, but not possible. We present data on 10 Expanded Access (EA) patients treated with high cumulative doses of Hemopure (HBOC-201), to assess the ability of HBOC-201 to safely treat life threatening anemia in situations where high volumes of product were administered over an extended period of time. STUDY DESIGN AND METHODS Inclusion in this study required that the patient receive at least 10 units of HBOC-201 between 2014 and 2017 under the FDA-sanctioned EA program. Depending on a patient's geographical location, treatment with HBOC-201 was obtained through either a single patient emergency Investigational New Drug (IND) application, or an intermediate size population IND. Of the 41 patients who were treated during this period, 10 patients received 10 or more units of the product. Data were obtained from medical records. RESULTS Treatments with HBOC-201 started within 24 hours of signing consent and were administered at an average rate of 1.99 (SD 0.17) units per day over a mean of 8.2 days (SD 2.9), during which patients received on average 16.2 units (SD 5.7 units) of HBOC-201. The median pre-treatment nadir corpuscular hemoglobin (Hb) concentration was 3.3 (SD 0.9) g/dL and post-treatment Hemoglobin was 7.3 (SD 1.7) g/dL. Common side effects included methemoglobinemia, gastrointestinal symptoms, and hypertension. However, no product-related serious adverse events (SAEs) were noted. All patients survived. CONCLUSIONS Administration of HBOC-201 over an extended period is a feasible and safe oxygen bridge for severely anemic patients who cannot be transfused with RBC.

PURPOSE To discover whether internal medicine (IM) residency program directors use lower-than-required caps on general medicine wards, critical care units, and inpatient subspecialty wards; describe justifications for lower-than-required general medicine ward caps and strategies for when caps have been exceeded or the number of patients is a detriment to critical thinking or education; and assess whether caps were associated with program characteristics. METHOD From August to December 2016, the Association of Program Directors in Internal Medicine surveyed all member program directors about team caps and their effects on the learning environment. Responses were appended with publicly available or licensed third-party data. Programs were categorized by type, size, and region. RESULTS Overall response rate was 65.7% (251/382 programs). Nearly all (244/248; 98.4%) reported caps for general medicine ward teams (mean = 17.0 [standard deviation (SD) = 4.2]). Fewer (171/247; 69.2%) had caps for critical care teams (mean = 13.8 [SD = 5.4]). Fewer still (131/225; 58.2%) had caps for inpatient subspecialty ward teams (mean = 14.8 [SD = 6.0]). Fewer first-quartile programs (0-28 residents) reported having caps on inpatient subspecialty teams (P < .001). Directors reported higher caps compromised education (109/130; 83.8%), patient care (89/130; 68.5%), and/or resident wellness (77/130; 59.2%). Nonteaching services (181/249; 72.7%), patient transfers (110/249; 44.2%), or "backup" residents (67/249; 26.9%) were used when caps are reached or the number of patients is detrimental to critical thinking or education. CONCLUSIONS IM program directors frequently exercise discretion when setting caps. Accrediting bodies should explicitly encourage such adjustments and allow differentiation by setting.

Purpose Trust in and comparability of assessments are essential in clerkships in undergraduate medical education for many reasons, including ensuring competency in clinical skills and application of knowledge important for the transition to residency and throughout students' careers. The authors examined how assessments are used to determine internal medicine (IM) core clerkship grades across U.S. medical schools. Methods A multisection web-based survey of core IM clerkship directors at 134 U.S. medical schools with membership in the Clerkship Directors in Internal Medicine was conducted in October through November 2018. The survey included a section on assessment practices to characterize current grading scales used, who determines students' final clerkship grades, the nature/type of summative assessments, and how assessments are weighted. Respondents were asked about perceptions of the influence of the National Board of Medical Examiners (NBME) Medicine Subject Examination (MSE) on students' priorities during the clerkship. Results The response rate was 82.1% (110/134). There was considerable variability in the summative assessments and their weighting in determining final grades. The NBME MSE (91.8%), clinical performance (90.9%), professionalism (70.9%), and written notes (60.0%) were the most commonly used assessments. Clinical performance assessments and the NBME MSE accounted for the largest percentage of the total grade (on average 52.8% and 23.5%, respectively). Eighty-seven percent of respondents were concerned that students' focus on the NBME MSE performance detracted from patient care learning. Conclusions There was considerable variability in what IM clerkships assessed and how those assessments were translated into grades. The NBME MSE was a major contributor to the final grade despite concerns about the impact on patient care learning. These findings underscore the difficulty in comparing learners across institutions and serve to advance discussions for how to improve accuracy and comparability of grading in the clinical environment.

This phase I trial sought to determine a biologically safe and effective dose of AR-42, a novel histone deacetylase inhibitor, which would lead to a doubling of miR-29b prior to decitabine administration. Thirteen patients with previously untreated or relapsed/refractory AML were treated at 3 dose levels (DL): AR-42 20 mg qd on d1,3,5 in DL1, 40 mg qd on d1,3,5 in DL2 and 40 mg qd on d1,3,4,5 in DL3. Patients received decitabine 20 mg/m(2) on d6–15 of each induction cycle and 20 mg/m(2) on d6–10 of each maintenance cycle. One DLT of polymicrobial sepsis and multi-organ failure occurred at DL3. Two patients achieved a CRi and one patient achieved a CR for an ORR of 23.1%. The higher risk features of this patient population and the dosing schedule of AR-42 may have led to the observed clinical response and failure to meet the biologic endpoint.

The profession of social work has a long-standing history of considering the impact of social class on society and current social work training emphasizes the influence of intersectionality and dif...

BackgroundIn the rapidly changing landscape of undergraduate medical education (UME), the roles and responsibilities of clerkship directors (CDs) are not clear.ObjectiveTo describe the current roles and responsibilities of Internal Medicine CDs.DesignNational annual Clerkship Directors in Internal Medicine (CDIM) cross-sectional survey.ParticipantsOne hundred twenty-nine clerkship directors at all Liaison Committee on Medical Education accredited US medical schools with CDIM membership as of September 1, 2017.Main measuresResponsibilities of core CDs, including oversight of other faculty, and resources available to CDs including financial support and dedicated time.Key resultThe survey response rate was 83% (107/129). Ninety-four percent of the respondents oversaw the core clerkship inpatient experience, while 47.7% (n = 51) and 5.6% (n = 6) oversaw the outpatient and longitudinal integrated clerkships respectively. In addition to oversight, CDs were responsible for curriculum development, evaluation and grades, remediation, scheduling, student mentoring, and faculty development. Less than one-third of CDs (n = 33) received the recommended 0.5 full-time equivalent (FTE) support for their roles, and 15% (n = 16) had less than 20% FTE support. An average 0.41 FTE (SD .2) was spent in clinical work and 0.20 FTE (SD .21) in administrative duties. Eighty-three percent worked with other faculty who assisted in the oversight of departmental UME experiences, with FTE support varying by role and institution. Thirty-five percent of CDs (n = 38) had a dedicated budget for managing their clerkship.ConclusionsThe responsibilities of CDs have increased in both number and complexity since the dissemination of previous guidelines for expectations of and for CDs in 2003. However, resources available to them have not substantially changed.

Very low-protein (VLP) diets are beneficial for reducing the nitrogen excretion from swine production, but these diets depress the performance of pigs while supplemented with first four limiting amino acids (FFL; i.e. Lys, Met, Thr and Trp). The objective of this study was to investigate the effect of supplementation of Val and Ile above NRC (2012) levels on performance, thermal radiation and blood metabolites of pigs fed with VLP diets. Three-week-old weaned barrows (n = 40) were assigned to: positive control (PC): normal protein diet; negative control (NC): VLP diet containing FFL at NRC levels; HV: NC with Val above NRC; HI: NC with Ile above NRC; HVI: NC with both Val and Ile above NRC. After 5 weeks of data collection, blood samples were collected. Univariate GLM with Tukey post-hoc test was used to analyze the data (SPSS). Pigs fed with NC had a decreased average daily gain (ADG) and average daily feed intake (ADFI) compared with PC (P< 0.05). HVI pigs had less ADG than PC, but greater ADG than NC (P< 0.05). ADFI of pigs fed with HVI was similar to PC and it was greater than NC (P< 0.05). HVI pigs had a higher thermal radiation than NC (P< 0.05). While HVI pigs had greater blood glucose than PC and NC at baseline (P< 0.05), no differences among these groups were observed on postprandial blood glucose concentration. HVI pigs had less blood triglycerides than PC. All groups increased the blood cholesterol compared with PC (P< 0.05). There were no differences in blood urea nitrogen (BUN) for NC vs. PC; however, pigs fed with HVI reduced the BUN compared with NC (P< 0.05). In conclusion, supplementation of Val and Ile greater than NRC into VLP diets partially restored the performance and fully recovered the ADFI, reduced the blood triglycerides and BUN, and improved the glucose tolerance.

Measures of mood and effective coping strategies have notable correlations with quality of life and treatment responses. There is evidence that patients with previously diagnosed anxiety disorders have less improvement in patient-reported outcome measures (PROMs) after laparoscopic anti-reflux surgery (LARS) and that objective pathology does not correlate well with symptom severity. We were interested in investigating whether anxiety and hypervigilance, as measured preoperatively with the esophageal hypervigilance anxiety scale (EHAS), is associated with the improvement in GERD-specific PROMs and EHAS scores 6 months after LARS.We performed a retrospective cohort study of 102 adult patients (31% men, average age 64) who underwent LARS. In the preoperative evaluation, baseline gastroesophageal reflux disease-health-related quality of life (GERD-HRQL), laryngopharyngeal reflux symptom index (LPR-RSI) and EHAS scores were collected in addition to the standard reflux workup, including endoscopy, manometry, barium swallow, and pH study. For all three surveys, a higher score represents worse symptom severity. At 6 months postoperatively, 70 patients completed repeat GERD-HRQL, LPR-RSI, and EHAS surveys. We then analyzed for surgical and patient-related factors associated with improvement in the 6-month postoperative GERD-HRQL and LPR-RSI scores.There was a statistically significant decrease in the GERD-HRQL (25 vs. 2, p lt; 0.001), LPR-RSI (17 vs. 3, p lt; 0.001) and EHAS (34 vs. 15, p lt; 0.001) 6 months after LARS. On multivariable linear regression, a higher baseline EHAS score was independently associated with a greater improvement in GERD-HRQL (β 0.35, p lt; 0.001) and LPR-RSI (β 0.19, p = 0.03) 6-months after LARS. Additionally, the degree of improvement in EHAS, GERD-HRQL, and LPR-RSI was not influenced by the type of LARS performed or by the severity of disease.These findings are consistent with literature suggesting that measures of psychoemotional health correlate better with symptom intensity than objective pathology. We found that patients with a higher EHAS score have greater symptom severity and lower quality of life at baseline. Novel findings to this study are that patients with a higher preoperative EHAS, a measure of psychoemotional health, actually benefitted more from surgery and not less, which has been the traditional view in the literature. Future studies are warranted to establish directionality and explore the role of preoperative cognitive behavioral therapy with LARS for patients with significant symptoms of hypervigilance and anxiety.

To explore faculty perspectives on which characteristics of high-performing clerkship students are most important when determining an honors or top grade designation for clinical performance.In 2016-2017, the authors surveyed faculty (teaching ward attendings) for internal medicine clerkships and 1 pediatrics clerkship in inpatient settings at 5 U.S. academic medical centers. Survey items were framed around competencies, 24 student characteristics, and attitudes toward evaluation. Factor analysis examined constructs defining high-performing students.Of 516 faculty invited, 319 (62%) responded. The top 5 characteristics as rated by respondents were taking ownership, clinical reasoning, curiosity, dependability, and high ethical standards (in descending order). Twenty-one characteristics fit into 3 factors (Cronbach alpha, 0.81-0.87). Clinical reasoning did not fit into a factor. Factor 1 was the most important (mean rating, 8.7/10 [95% confidence interval (CI), 8.6-8.8]). It included professionalism components (ownership, curiosity, dependability, high ethical standards), presentation and interviewing skills, seeking feedback, and documentation. Factor 2 (mean, 7.9 [95% CI, 7.7-8.0]) included aspects of teamwork and communication, such as positive attitude and comments from others. Factor 3 (mean, 7.6 [95% CI, 7.4-7.7]) addressed systems-based thinking, including patient safety and care transitions.Professionalism components, clinical reasoning, and curiosity were among the most important characteristics distinguishing high-performing clerkship students. These may represent behaviors that are highly valued, observable, and relevant to training stage. Improved definition of the characteristics associated with clinical honors would assist students, faculty, and residency program directors when interpreting clinical performance within core clerkships.

Summary Background Guadecitabine is a next-generation hypomethylating agent whose active metabolite decitabine has a longer in-vivo exposure time than intravenous decitabine. More effective hypomethylating agents are needed for the treatment of myelodysplastic syndromes. In the present study, we aimed to compare the activity and safety of two doses of guadecitabine in hypomethylating agent treatment-naive or relapsed or refractory patients with intermediate-risk or high-risk myelodysplastic syndromes. Methods This phase 2 part of the phase 1/2, randomised, open-label study enrolled patients aged 18 years or older from 14 North American medical centres with International Prognostic Scoring System intermediate-1-risk, intermediate-2-risk, or high-risk myelodysplastic syndromes, or chronic myelomonocytic leukaemia. They were either hypomethylating agent treatment-naive or had relapsed or refractory disease after previous hypomethylating agent treatment as determined by the investigators' judgment. Eligible patients had Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1) using a computer algorithm for dynamic randomisation to subcutaneous guadecitabine 60 or 90 mg/m2 on days 1–5 of a 28-day treatment cycle. Treatment was stratified by previous treatment with hypomethylating agents and neither patients nor investigators were masked. The primary endpoint was overall response (a composite of complete response, partial response, marrow complete response, and haematological improvement) assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01261312. Findings Between July 9, 2012, and April 7, 2014, 105 patients were enrolled: 55 (52%) were allocated to guadecitabine 60 mg/m2 (28 patients were treatment-naive and 27 had relapsed or refractory disease after previous hypomethylating agent treatment) and 50 (48%) patients to 90 mg/m2 (23 patients were treatment-naive and 27 had relapsed or refractory disease). Three (3%) patients of 105 did not receive study treatment and were excluded from analyses. Median follow-up was 3·2 years (IQR 2·8–3·5). The proportion of patients achieving an overall response did not significantly differ between dose groups (21 of 53 [40%, 95% CI 27–54] with 60 mg/m2 and 27 of 49 [55%, 95% CI 40–69] with 90 mg/m2; p=0·16). 25 of 49 (51%, 95% CI 36–66) patients who were treatment-naive and 23 of 53 (43%, 30–58) patients with relapsed or refractory disease achieved an overall response. The most common grade 3 or worse adverse events in both groups, regardless of relationship to treatment, were thrombocytopenia (22 [41%] of 53 patients in the 60 mg/m2 group and 28 [57%] of 49 in the 90 mg/m2 group), neutropaenia (21 [40%] and 25 [51%]), anaemia (25 [47%] and 24 [49%]), febrile neutropaenia (17 [32%] and 21 [43%]), and pneumonia (13 [25%] and 15 [31%]). Seven (7%) of 102 patients died due to adverse events (three with 90 mg/m2 and four with 60 mg/m2), and all except one were in the relapsed or refractory cohort. Two deaths were deemed treatment related (septic shock with 60 mg/m2; pneumonia with 90 mg/m2). Interpretation Guadecitabine was clinically active with acceptable tolerability in patients with intermediate-risk and high-risk myelodysplastic syndromes. Responses and overall survival in the relapsed or refractory cohort offer the potential of a new therapeutic option for patients for whom currently available hypomethylating agents are not successful. We therefore recommend guadecitabine at a dose of 60 mg/m2 on a 5-day schedule for these patients. Funding Astex Pharmaceuticals and Stand Up To Cancer.

Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.

Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high‐risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose‐limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non‐hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level −1, consisting of 25 mg/d lenalidomide D1‐21, 1 g/m2 cytarabine D5‐8, and 8 mg/m2 idarubicin D5‐7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre‐planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1‐year and 2‐year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1‐year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. (ClinicalTrials.gov identifier: NCT01132586).

Systematic loss of function studies reveal the influence that each family of Rho of plants (ROP) regulators has on tip growth in the moss, Physcomitrella patens., Rho/Rac of plants (ROP) GTPases are plant-specific small GTPases that regulate cell morphology. ROP activity is controlled by several families of regulatory proteins. However, how these diverse regulators contribute to polarized growth remains understudied. In a system-wide approach, we used RNAi to silence each gene family of known ROP regulators in the juvenile tissues of the moss Physcomitrella patens. We found that the GTPase activating proteins, but not the ROP enhancers, are essential for tip growth. The guanine exchange factors (GEFs), which are comprised of ROPGEFs and Spikes, both contribute to growth. However, silencing Spikes results in less-polarized plants as compared to silencing ROPGEFs, suggesting that Spikes contribute more to establishing cell polarity. Silencing the single-gene family of guanine dissociation inhibitors also inhibits growth, resulting in small, unpolarized plants. In contrast, silencing the ROP effector ROP-interactive CRIB-containing (RIC) protein, which is encoded by a single gene, results in plants larger than the controls, suggesting that RIC functions to inhibit tip growth in moss. Taken together, this systematic loss-of-function survey provides insights into the function of ROP regulators during polarized growth.

KMT2A partial tandem duplication occurs in approximately 5-10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of KMT2A wildtype contributes to KMT2A partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse. We developed a regimen for this unique molecular subset, but due to relatively low frequency of KMT2A partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter2 daily on days 1-10 and vorinostat 400 milligrams daily on days 5-10. Cytarabine was dose-escalated from 1.5 grams/meter2 every 12 hours to 3 grams/meter2 every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting toxicity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with KMT2A partial tandem duplication. Combination therapy with decitabine, vorinostat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the KMT2A partial tandem duplication subset. (clinicaltrials.gov identifier 01130506).

While performance assessments of constructed wetlands sites around the world have appraised their capacity for effective removal of organics, a large variance remains in these sites' reported ability to retain nutrients, which appears to depend on differences in design, operation and climate factors. Nutrient retention is a very important objective for constructed wetlands, to avoid eutrophication of aquatic environments receiving their effluents. This study assessed the performance of constructed wetlands in terms of nutrient retention and associated parameters under the humid conditions of Ireland's temperate maritime climate. A review of the performance of 52 constructed wetland sites from 17 local authorities aimed to identify the best performing types of constructed wetlands and the treatment factors determining successful compliance with environmental standards. Data analysis compared effluent results from constructed wetlands with secondary free surface flow or tertiary horizontal subsurface flow, hybrid systems and integrated constructed wetlands with those from small-scale mechanical wastewater treatment plants of the same size class. Nutrient concentrations in effluents of constructed wetlands were negatively correlated (p < .01) with specific area, i.e. the ratio of surface area and population equivalents. The latest generation of integrated constructed wetlands, which had applied design guidelines issued by the Department of the Environment, performed best. Storm management design features improved treatment performance of constructed wetlands significantly (p < .05) for total suspended solids concentrations and exceedance frequency of limit values for total nitrogen. Mechanical wastewater treatment plants, secondary free surface water and tertiary horizontal subsurface flow wetlands showed a very large variance in effluent concentrations for organic and nutrient parameters. E. coli numbers in effluents were lowest for integrated constructed wetlands with an arithmetic mean of 89 MPN/100 ml. Despite Ireland's humid climate, some constructed wetland sites achieved long or frequent periods of zero effluent discharge and thus did not transfer any waterborne pollution to their receptors during these periods.

Acute myeloid leukemia (AML) is the second most common type of leukemia in adults. Incidence of AML increases with age with a peak incidence at 67 years. Patients older than 60 years have an unfavorable prognosis due to resistance to conventional chemotherapy. Volasertib (BI 6727) is a cell-cycle regulator targeting polo-like kinase which has been evaluated in clinical trials in AML. We evaluated effects of volasertib in primary patient samples and NK cells. At equivalent doses, volasertib is cytotoxic to AML blasts but largely spares healthy NK cells. We then evaluated the effect of volasertib treatment in combination with BI 836858 on primary AML blast samples using antibody-dependent cellular cytotoxicity (ADCC) assays. Volasertib treatment of NK cells did not impair NK function as evidenced by comparable levels of BI 836858 mediated ADCC in both volasertib-treated and control-treated NK cells. In summary, volasertib is cytotoxic to AML blasts while sparing NK cell viability and function. Higher BI 836858 mediated ADCC was observed in patient samples pretreated with volasertib. These findings provide a strong rationale to test combination of BI 836858 and volasertib in AML.

Background Outcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next-generation hypomethylating agent, could be useful in treating such patients. Methods In this multicenter, open-label, phase 2 dose-expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90 mg/m2 on 5 consecutive days in each 28-day cycle (5-day regimen). Subsequently, another cohort was treated for 10 days with 60 mg/m2 (10-day regimen). Results Between June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90 mg/m2 /d, respectively [5-day regimen] and 53 patients who were assigned to 60 mg/m2 /d [10-day regimen]). The 90 mg/m2 dose showed no benefit in clinical outcomes in comparison with 60 mg/m2 in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10-day regimen versus the 5-day regimen (CRc, 30.2% vs 16.0%; P = .1061; CR, 18.9% vs 8%; P = .15). Adverse events (grade ≥ 3) were mainly hematologic, with a higher incidence on the 10-day regimen. Early all-cause mortality was low and similar between regimens. Twenty patients (8 on the 5-day regimen and 12 on the 10-day regimen) were bridged to hematopoietic cell transplantation. Conclusions Guadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population. Cancer 2018;124:325-34. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

There are good data regarding the prevalence and patterns of dual diagnosis among the general population; however, data regarding the older adult cohort are limited. We aimed to extend the knowledge of the point prevalence and patterns of dual diagnosis among older adults and the impact of dual diagnosis on the utilization of alcohol and other drug treatment services.A 12-month medical chart audit of clients discharged from an Australian older adult-specific alcohol and other drug treatment service was performed. Measures included the Alcohol Use Disorders Identification Test-Consumption, the Drug Use Disorders Identification Test-Consumption, the Kessler 10, and the Modified MINI Screen. Additional data collected included mental health diagnoses, number of session types, and treatment outcomes.There were 79 (n = 45, 57% male) medical charts audited, with a mean age of 65.9 years (SD = 5.8). There were 68 (89%) clients having at least one comorbid mental illness. Clients with a dual diagnosis were younger (p = .011) than those without. Some comorbid mental health conditions were associated with additional service utilization (p.05). Clients with personality disorders required more telephone calls and outreach services (p.05). The number of mental health diagnoses was associated with additional treatment sessions (p.05).Further research with a larger sample size of older adults seeking age-specific alcohol and other drug treatment services is required. Older adult-specific alcohol and other drug treatment services need to allow for longer episodes of care for clients with certain dual diagnoses and a focus on reducing anxiety to increase treatment retention.

Summary Background The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m 2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. Methods We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m 2 on days 1–5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m 2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312. Findings Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m 2 and 28 to 90 mg/m 2 ) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62–92), and median follow-up was 953 days (IQR 721–1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8–74·4] with 60 mg/m 2 on the 5-day schedule; 16 [59%; 38·8–77·6] with 90 mg/m 2 on the 5-day schedule; and 26 [50%, 35·8–64·2] with 60 mg/m 2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort). Interpretation More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m 2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m 2 in a 5-day schedule versus standard of care. Funding Astex Pharmaceuticals and Stand Up To Cancer.

Introduction This study aimed to determine the practicality and estimate the effect of administering pre-operative blood product resuscitation to a consecutive, prospectively recruited cohort of 100 patients admitted to a single centre with a hip fracture with all other treatment unchanged. Method 100 patients aged 65 years or over admitted acutely to our unit with unilateral fractured femoral neck during the study period were included in this study, regardless of cognitive function. Patients were excluded only if there were relevant medical comorbidities or consent was declined. Each patient was resuscitated with a single unit of packed red cells in the immediate perioperative period in addition to standard care. The primary outcome was to establish the feasibility of the study protocol employed in using blood products to resuscitate eligible patients and recording reasons for any failures to include eligible patients. Additional data regarding mortality at 30 days following injury, subsequent blood product use, any transfusion related adverse reactions and total blood product use was measured. Results We were able to show that it is safe and practicable to deliver blood as an early resuscitative strategy in the frail elderly hip fracture population. The mortality rate of the study cohort was 3%. No adverse reaction was observed in any of the 99 patients given blood as a result of the resuscitation strategy and no morbidity was seen that could be attributed to the effect of giving blood. The total amount of blood received by comparable cohorts in the study period and the two preceding years were similar. Conclusions The study suggests that in the hip fracture population it is both practical and beneficial to move away from reactive transfusion regimens, and instead centre efforts instead on optimal resuscitation at the initial presentation.

Ensuring students&rsquo, access to safe drinking water at school is essential. However, many schools struggle with aging infrastructure and subsequent water safety problems and have turned to bottled water delivery systems. Little is known about whether such systems are feasible and effective in providing adequate student water access. This study was a mixed-methods investigation among six schools in an urban district in the U.S. with two types of water delivery systems: (1) tap water infrastructure, with updated water fountains and bottle fillers, and (2) bottled water coolers. We measured students&rsquo, water consumption and collected qualitative data from students and teachers about their perceptions of school drinking water. Student water consumption was low&mdash, between 2.0 (SD: 1.4) ounces per student and 2.4 (SD: 1.1) ounces per student during lunch. Students and teachers reported substantial operational hurdles for relying on bottled water as a school&rsquo, s primary source of drinking water, including difficulties in stocking, cleaning, and maintaining the units. While students and teachers perceived newer bottle filler units positively, they also reported a distrust of tap water. Bottled water delivery systems may not be effective long-term solutions for providing adequate school drinking water access and robust efforts are needed to restore trust in tap water.

Introduction: Despite awareness of overall poor survival rates following cardiopulmonary resuscitation (CPR), some orthopedic patients with significant comorbidities continue to have inappropriate resuscitation plans. Furthermore, in certain injury groups such as patients with hip fractures, survival outcome data are very limited; current discussions regarding resuscitation plans may be inaccurate. This study assesses survival in orthopedic patients following CPR, to inform decision-making between physicians, surgeons, and patients. Methods: A dual center, retrospective cohort study was performed analyzing all orthopedic admissions that received CPR over a 25-month period, with a minimum of 1 year follow-up. National Cardiac Arrest Audit data, “mortality and morbidity” meeting records, National Hip Fracture Databases, and electronic notes were analyzed. Survival duration was measured, alongside reason for admission, location CPR occurred, and initial rhythm encountered. Results: Thirty-two patients received CPR over the 25-month period (median age: 83; range: 30-96). Three (9%) of 32 patients survived to discharge. Only 1 of the 26 patients older than 65 years survived to discharge. Fifteen (47%) of 32 had hip fractures, where 4 (27%) of 15 of this group survived 24 hours; none survived to discharge. When recorded, 22 (92%) of 24 initially had a nonshockable rhythm. Discussion: Cardiopulmonary resuscitation was conceptualized as a treatment for reversible cardiopulmonary causes. When used in trauma and orthopedic patients, especially older and/or hip fracture patients, it seldom led to hospital discharge. Different admission practices such as “front door” orthogeriatric reviews may explain the contrast in usage of CPR between the hospitals. Conclusion: Survival rates following CPR were very low, with it proving specifically ineffective in hip fracture patients. Although every decision about resuscitation should be patient centered and individualized, this study will allow clinicians to be more realistic about outcomes from CPR, particularly in the hip fracture group.