Patterns of use of primary and first-line chemotherapy for recurrence among patients with cervical cancer.

BACKGROUND: Little is known about real-world patterns of chemotherapy use in patients with cervical cancer. OBJECTIVE: To examine the patterns of chemotherapy use in patients with cervical cancer METHODS: We identified patients with cervical cancer in the IBM MarketScan Database who underwent primary hysterectomy or radiation therapy between 2011 and 2020 and described their treatment in the primary setting and at first recurrence. RESULTS: We identified 5390 patients: 2667 (49.5%) underwent primary hysterectomy and 2723 (50.5%) primary radiotherapy. Among patients who underwent primary hysterectomy, 979 (36.7%) received adjuvant radiation, and 617 (23.1%) received primary chemotherapy. The most common chemotherapy regimens were single-agent platinum (51.7%), platinum combination therapy (42.9%), and non-platinum (3.4%). Among patients treated with primary radiation, 73.6% received primary/concurrent chemotherapy, either platinum alone (66.4% of those who received chemotherapy), platinum combinations (32.2%), or non-platinum (1.4%). The median duration of primary chemotherapy was 1.2 months. Therapy for recurrent cervical cancer was initiated in 959 patients. The most common regimens were platinum combination (63.9%), non-platinum cytotoxic agents (16.5%), single-agent platinum (14.9%), targeted therapy with bevacizumab (6.0%), and immunotherapy with pembrolizumab (3.2%). Overall, the proportion of patients treated with single-agent platinum therapy increased from 17.4% in 2011 to 32.1% in 2019, while platinum combinations decreased from 64.1% to 41.5% over the same years. Use of non-platinum agents increased from 18.5% in 2011 to 32.9% in 2018 and 26.4% in 2019. CONCLUSIONS: Platinum-based chemotherapy is the most commonly used therapy in patients with cervical cancer in the primary setting and at the time of recurrence. The rate of use of non-platinum agents at first recurrence has increased over time.

Graph-based algorithms to dissect long-distance water-mediated H-bond networks for conformational couplings in GPCRs.

Changes in structure and dynamics elicited by agonist ligand binding at the extracellular side of G protein coupled receptors (GPCRs) must be relayed to the cytoplasmic G protein binding side of the receptors. To decipher the role of water-mediated hydrogen-bond networks in this relay mechanism, we have developed graph-based algorithms and analysis methodologies applicable to datasets of static structures of distinct GPCRs. For a reference dataset of static structures of bovine rhodopsin solved at the same resolution, we show that graph analyses capture the internal protein-water hydrogen-bond network. The extended analyses of static structures of rhodopsins and opioid receptors suggest a relay mechanism whereby inactive receptors have in place much of the internal core hydrogen-bond network required for long-distance relay of structural change, with extensive local H-bond clusters observed in structures solved at high resolution and with internal water molecules.

Carbon cycle responses to climate change across China's terrestrial ecosystem: Sensitivity and driving process.

Investigations into the carbon cycle and how it responds to climate change at the national scale are important for a comprehensive understanding of terrestrial carbon cycle and global change issues. Contributions of carbon fluxes to the terrestrial sink and the effects on climate change are still not fully understood. In this study, we aimed to explore the relationship between ecosystem production (GPP/SIF/NDVI) and net ecosystem carbon exchange (NEE) and to investigate the sensitivity of carbon fluxes to climate change at different spatio-temporal scales. Furthermore, we sought to delve into the carbon cycle processes driven by climate stress in China since the beginning of the 21st century. To achieve these objectives, we employed correlation and sensitivity analysis techniques, utilizing a wide range of data sources including ground-based observations, remote sensing observations, atmospheric inversions, machine learning, and model simulations. Our findings indicate that NEE in most arid regions of China is primarily driven by ecosystem production. Climate variations have a greater influence on ecosystem production than respiration. Warming has negatively impacted ecosystem production in Northeast China, as well as in subtropical and tropical regions. Conversely, increased precipitation has strengthened the terrestrial carbon sink, particularly in the northern cool and dry areas. We also found that ecosystem respiration exhibits heightened sensitivity to warming in southern China. Moreover, our analysis revealed that the control of terrestrial carbon cycle by ecosystem production gradually weakens from cold/arid areas to warm/humid areas. We identified distinct temperature thresholds (ranging from 10.5 to 13.7 °C) and precipitation thresholds (approximately 1400 mm yr-1) for the transition from production-dominated to respiration-dominated processes. Our study provides valuable insights into the complex relationship between climate change and carbon cycle in China.

New ways for (in)validating the forest carbon neutrality hypothesis.

Over 50 years ago, Eugene Odum postulated that mature or climax forests reside in carbon neutrality. As climate change rose to prominence in the international environmental agenda, the neutrality hypothesis transformed from an ecological principle to a justification for using forest management in combating climate change. Despite persistent efforts, Odum's neutrality hypothesis has resisted both confirmation and refutation. In this opinion we show the limitations of past efforts to (in)validate Odum's neutrality hypothesis and propose new research directions for the community to permit a more general confirmation or refutation with current and near-future observations. We then demonstrate such an approach by using metabolic theory to formulate testable predictions for the total sink strength considering soil, litter, and biomass of mature or climax forests based on observations of tree biomass and individual density. In doing so, we show that ecological theory can create additional relevant, testable hypotheses to provide timely support to decision-makers seeking to address one of the world's most pressing environmental challenges.

Prehospital early warning scores for adults with suspected sepsis: retrospective diagnostic cohort study.

BACKGROUND: Ambulance services need to identify and prioritise patients with sepsis for early hospital assessment. We aimed to determine the accuracy of early warning scores alongside paramedic diagnostic impression to identify sepsis that required urgent treatment. METHODS: We undertook a retrospective diagnostic cohort study involving adult emergency medical cases transported to Sheffield Teaching Hospitals ED by Yorkshire Ambulance Service in 2019. We used routine ambulance service data to calculate 21 early warning scores and categorise paramedic diagnostic impressions as sepsis, infection, non-specific presentation or other presentation. We linked cases to hospital records and identified those meeting the sepsis-3 definition who received urgent hospital treatment for sepsis (reference standard). Analysis determined the accuracy of strategies that combined early warning scores at varying thresholds for positivity with paramedic diagnostic impression. RESULTS: We linked 12 870/24 955 (51.6%) cases and identified 348/12 870 (2.7%) with a positive reference standard. None of the strategies provided sensitivity greater than 0.80 with positive predictive value greater than 0.15. The area under the receiver operating characteristic curve for the National Early Warning Score, version 2 (NEWS2) applied to patients with a diagnostic impression of sepsis or infection was 0.756 (95% CI 0.729, 0.783). No other early warning score provided clearly superior accuracy to NEWS2. Paramedic impression of sepsis or infection had sensitivity of 0.572 (0.519, 0.623) and positive predictive value of 0.156 (0.137, 0.176). NEWS2 thresholds of >4, >6 and >8 applied to patients with a diagnostic impression of sepsis or infection, respectively, provided sensitivities and positive predictive values of 0.522 (0.469, 0.574) and 0.216 (0.189, 0.245), 0.447 (0.395, 0.499) and 0.274 (0.239, 0.313), and 0.314 (0.268, 0.365) and 0.333 (0.284, 0.386). CONCLUSION: No strategy is ideal but using NEWS2 alongside paramedic diagnostic impression of infection or sepsis could identify one-third to half of sepsis cases without prioritising unmanageable numbers. No other score provided clearly superior accuracy to NEWS2. TRIAL REGISTRATION NUMBER: researchregistry5268, https://www.researchregistry.com/browse-the-registry%23home/registrationdetails/5de7bbd97ca5b50015041c33/.

Comparative Efficacy of Adjuvant Nonopioid Analgesia in Adult Cardiac Surgical Patients: A Network Meta-Analysis.

OBJECTIVES: To compare the relative efficacy of adjuvant nonopioid analgesic regimens in adult cardiac surgical patients. DESIGN: This frequentist, random-effects network meta-analysis (NMA) was prospectively registered on PROSPERO (CRD42021282913) and conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses for Network Meta-Analyses (PRISMA-NMA). The risk of bias (RoB) and confidence of evidence were assessed by RoB 2 and Confidence in Network Meta-Analysis, respectively. Relevant databases were searched from inception to October 9, 2021. SETTING: A total of 124 (N = 26,257) randomized controlled trials were included, of which 110 were analyzed. PARTICIPANTS: Trials enrolling adults (≥18 years of age) undergoing cardiac surgery that compared nonopioid analgesics against other nonopioid analgesics, placebo, or no additional treatment, as adjuvants to standard analgesic management, and reported at least 1 of the outcomes of interest. MEASUREMENT AND MAIN RESULTS: Outcomes of interest included resting postoperative pain scores at 24 hours. Compared with standard care and/or placebo, pain scores were reduced significantly by 10 different regimens, including acetaminophen (N = 176; mean difference [MD] -0.66 points, 95% CI -1.16 to -0.15 points; high confidence), magnesium (N = 323; -0.05 points, 95% CI -0.07 to -0.02 points; high confidence), gabapentin (N = 96; MD -0.40 points, 95% CI -0.71 to -0.09; moderate confidence), and clonidine (N = 64; MD v0.38 points, 95% CI -0.73 to v0.04 points; moderate confidence). Indomethacin, diclofenac, magnesium, and gabapentin significantly reduced 24-hour opioid consumption. Four regimens significantly decreased the intensive care unit length of stay. Hydrocortisone, dexmedetomidine, and clonidine significantly decreased the duration of mechanical ventilation. Magnesium decreased, while methylprednisolone significantly increased, the risk of myocardial infarction. CONCLUSIONS: Given the increasing emphasis on enhanced recovery after surgery(ERAS) protocols and the eventual goal of limiting opiate prescriptions postoperatively, the authors' data suggested far greater use of nonopioid adjuncts to minimize pain and enhance recovery following cardiac surgery.

Risk Stratification of Elderly Patients Undergoing Spinal Surgery Using the Modified Frailty Index.

STUDY DESIGN: Retrospective cohort. OBJECTIVES: To validate the 11-item modified Frailty Index (mFI) as a perioperative risk stratification tool in elderly patients undergoing spine surgery. METHODS: All consecutive cases of spine surgery in patients aged 65 years or older between July 2016 and June 2018 at a state-wide trauma center were retrospectively reviewed. The primary outcome was post-operative major complication rate (Clavien-Dindo Classification ≥ III). Secondary outcome measures included the rate of all complications, 6-month mortality and surgical site infection. RESULTS: A total of 348 cases were identified. The major complication rate was significantly lower in patients with an mFI of 0 compared to ≥ 0.45 (18.3% versus 42.5%, P = .049). As the mFI increased from 0 to ≥ 0.45 there was a stepwise increase in risk of major complications (P < .001). Additionally, 6-month mortality rate was considerably lower when the mFI was 0 rather than ≥ 0.27 (4.2% versus 20.4%, P = .007). Multivariate analysis demonstrated an mFI ≥ 0.27 was significantly associated with an increased incidence of major complication (OR 2.80, 95% CI 1.46-5.35, P = .002), all complication (OR 2.93, 95% CI 1.70-15.11, P < .001), 6-month mortality (OR 7.39, 95% CI 2.55-21.43, P < .001) and surgical site infection (OR 4.43, 95% CI 1.71-11.51, P = .002). The American Society of Anesthesiologists' (ASA) index did not share a stepwise relationship with any outcome. CONCLUSION: The mFI is significantly associated in a gradated fashion with increased morbidity and mortality. Patients with an mFI ≥ 0.27 are at greater risk of major complications, all-complications, 6-monthy mortality, and surgical site infection.

Ten-year incidence and treatment outcomes of closed degloving injuries (Morel-Lavallee lesions) in a level 1 trauma centre.

INTRODUCTION: Morel-Lavallée lesions (MLL), also referred to as closed degloving injuries, result from traumatic shearing forces with separation of the subcutaneous fat from the underlying fascia. The aim of this study was to determine the incidence and treatment of MLLs at a level 1 trauma centre. METHODS: Single-centre retrospective cross-sectional study of consecutive patients with an imaging diagnosis of a Morel-Lavallee lesion from 1/1/2010-31/12/2019. Demographic data, mechanism of injury, volume of lesion, management and outcome data were collated. RESULTS: Sixty-six MLLs were identified in 63 patients (64% Male) with a median age of 49.5 years (19-94 years). Mechanism of injury were road traffic accidents in the majority (66%). Median injury severity score (ISS) was 17 (range 1-33). Patients on oral anti-coagulants had significantly larger lesions (181.9 cc v 445.5 cc, P = 0.044). The most common lesion location was the thigh (60.5%). Patients that underwent imaging within 72 h of injury had significantly larger lesions than those imaged more than 72 h after the inciting trauma (65 cc v 167 cc, P < 0.05). Management data were documented in 59% of lesions (39/66) in which 66.6% (n = 26) had invasive treatment. In the 31 patients where follow-up was available, 64.5% (n = 20) were persistent but decreasing in size. There was no significant difference in follow-up size for those who had invasive compared to conservative treatment (P = 0.3). CONCLUSION: The diagnosis of MLL should be considered for soft-tissue swelling in the context of shearing trauma. A variety of management options have been employed, with good overall outcomes.

Income assistance use among young adults who were in British Columbia special education: A longitudinal cohort study.

BACKGROUND: Persons with disability (PWD) experience disproportionately high poverty rates in Canada. This trend is apparent especially among youth compared to those who develop disabilities later in life. PWD in poverty have additional needs that increase barriers to full participation in society and translate to higher basic costs for daily living. Despite the existence of income assistance programs in Canada to mitigate income inequalities faced by PWDs, access to these programs can be limited. OBJECTIVE: To describe use of income assistance for young adults with disability in British Columbia for the development of potential approaches to improve realized access to these programs. METHODS: We conducted a population-based retrospective cohort study using British Columbia linked administrative data. We described differences in income assistance use among PWD by the level of special education funding received during primary school education (from most to least; Level 1, Level 2, Level 3, Unfunded, and no special education) and family composition. We also provided longitudinal patterns of income assistance use. RESULTS: Of 218,324 young adults, 88% received no special education, 0.1% used Level One, 1.6% used Level Two, 2.9% used Level Three, and 7.1% used Unfunded special education coding. Young adults with Level One special education funding had the highest rates of hospitalizations and continuing care, with no hospitalization due to homelessness. Those with Level Three special education coding had higher rates of hospitalization and hospitalization due to homelessness than Level Two young adults. When transitioning to adulthood initially, Level One and Two funded individuals used relatively more disability income assistance than individuals from the other funding levels. Nearly all BCEA users with higher funded special education codes used this disability-specific program, while lesser funded special education codes used the Temporary Assistance more frequently, for a longer duration and were more likely to be persistent Temporary Assistance users. CONCLUSIONS: Sustainable and reliable access to income assistance programs remains an issue across the heterogeneity of needs faced by young adults with disability.

Thinking of Me or Thinking of You? Behavioral Correlates of Self vs. Other Centered Worry and Reappraisal in Late-Life.

Psychotherapeutic approaches in late-life anxiety have limited effect on reducing worry severity. The self-referential processing of worry contents (self- vs. other-focused worry) and reappraisal styles (internal vs. external locus of control) are important elements in psychotherapy, but little is known about these processes in late-life. We aimed to characterize severe worry from a self-referential processing perspective. We recruited 104 older adults with various levels of worry and used a personalized task to induce and reappraise worry. We analyzed the association between (1) worry severity/frequency for worry content (self- or other-focused) and (2) for reappraisal style (internal vs. external locus of control) with clinical inventories measuring anxiety, worry, depression, rumination, neuroticism, emotion regulation strategies, perceived stress, and physical illness burden. Higher self-worry severity was associated with higher scores of clinical inventories of worry, depression, perceived stress, and neuroticism, whereas other-worry severity did not show any association. Greater self-worry frequency was associated with higher medical burden. External locus of control in reappraisal statements was associated with lower worry severity in men. Overall, more severe and frequent self-focused worry was associated with a greater psychological and physiological burden. These results are useful in tailoring psychotherapy for older adults with severe worry.

The transition to adult income supports for youth that received special education in British Columbia, Canada: A cohort study.

Youth in special education have complex needs that are supported across multiple systems. Our research investigates the use of adult income assistance, as one structure that supports youth as they transition to adulthood. We created a cohort of youth (5-22 years old) using linked administrative data from British Columbia government ministries from 1996 to 2018. Youth were grouped by their special education funding (most to least; Level 1, Level 2, Level 3, Unfunded, and no special education). We investigated (1) youth characteristics and service use patterns, (2) which youth used income supports after the child-to-adult transition (19-22 years old), and what youth characteristics and service use patterns were associated with use, and (3) how much income support they used (CAD$). Of 174,527 youth, 254 (0.1%) were Level 1, 6020 (3.4%) were Level 2, 4409 (2.5%) were Level 3, 21,232 (12.2%) were Unfunded, and 142,612 (81.7%) were not in special education. Youth assigned higher funding levels, compared to lower levels, generally had increased service use, and in the transition to adult services were more likely to use income supports, and received more income support. An important exception was youth with serious behavioural/mental health special education funding (Level 3), who had increased service use for their level of funding, but received less income support due to a reliance on Temporary versus Disability Assistance. Youth that received an accredited diploma were less likely to use income supports. Factors related to the use of income supports are further described. This study highlights differences in access to income support when youth transition to adult services and considerations around equitable access to support.

Transitioning from insulin to dipeptidyl-peptidase 4 (DPP-4) inhibitors for type 2 diabetes.

Insulin administration is time intensive and costly in facility staffing. When we started nursing home patients with type 2 diabetes (T2D) on DPP-4 inhibitors, we tapered insulin when finger stick blood sugar levels dropped to <200 mg/dL. Of 34 patients we were able to stop mealtime insulin in 28 (82%) and stop all insulin in 20 (59%). On average, hemoglobin A1c (HbA1c) decreased 0.5% and weight by 2.8 pounds. Among the 20 who stopped all insulin, HbA1c improved in 11 on average 1% (p=0.02), and weight decreased in 11 on average 4.1 pounds (p=0.66). 12 patients were switched in one day because of a low insulin dose or low HbA1c Tapering duration in the other 8 ranged from 10-727 days with an insulin dose of 28 to 84 units daily. Larger studies are needed to confirm our findings, develop a protocol for tapering insulin, and measure hypoglycemia, comfort and cost.

Derivation and validation of a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality in 20 countries.

INTRODUCTION: Existing risk assessment tools to identify children at risk of hospitalised pneumonia-related mortality have shown suboptimal discriminatory value during external validation. Our objective was to derive and validate a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality across various settings. METHODS: We used primary, baseline, patient-level data from 11 studies, including children evaluated for pneumonia in 20 low-income and middle-income countries. Patients with complete data were included in a logistic regression model to assess the association of candidate variables with the outcome hospitalised pneumonia-related mortality. Adjusted log coefficients were calculated for each candidate variable and assigned weighted points to derive the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) risk assessment tool. We used bootstrapped selection with 200 repetitions to internally validate the PREPARE risk assessment tool. RESULTS: A total of 27 388 children were included in the analysis (mean age 14.0 months, pneumonia-related case fatality ratio 3.1%). The PREPARE risk assessment tool included patient age, sex, weight-for-age z-score, body temperature, respiratory rate, unconsciousness or decreased level of consciousness, convulsions, cyanosis and hypoxaemia at baseline. The PREPARE risk assessment tool had good discriminatory value when internally validated (area under the curve 0.83, 95% CI 0.81 to 0.84). CONCLUSIONS: The PREPARE risk assessment tool had good discriminatory ability for identifying children at risk of hospitalised pneumonia-related mortality in a large, geographically diverse dataset. After external validation, this tool may be implemented in various settings to identify children at risk of hospitalised pneumonia-related mortality.

Sex-specific DNA methylation and associations with in utero tobacco smoke exposure at nuclear-encoded mitochondrial genes.

Sex-linked differences in mitochondrial ATP production, enzyme activities, and reactive oxygen species generation have been reported in multiple tissue and cell types. While the effects of reproductive hormones underlie many of these differences, regulation of sexually dimorphic mitochondrial function has not been fully characterized. We hypothesized that sex-specific DNA methylation contributes to sex-specific expression of nuclear genes that influence mitochondrial function. Herein, we analysed DNA methylation data specifically focused on nuclear-encoded mitochondrial genes in 191 males and 190 females. We found 596 differentially methylated sites (DMSs) (FDR p < 0.05), corresponding to 324 genes, with at least a 1% difference in methylation between sexes. To investigate the potential functional significance, we utilized gene expression microarray data. Of the 324 genes containing DMSs, 17 showed differences in gene expression by sex. Particularly striking was that ATP5G2, encoding subunit C of ATP synthase, contains seven DMSs and exhibits a sex difference in expression (p = 0.04). Finally, we also found that alterations in DNA methylation associated with in utero tobacco smoke exposure were sex-specific in these nuclear-encoded mitochondrial genes. Interestingly, the level of sex differences in DNA methylation at nuclear-encoded mitochondrial genes and the level of methylation changes associated with smoke exposure were less prominent than that of other genes. This suggests more conservative regulation of DNA methylation at these nuclear-encoded mitochondrial genes as compared to others. Overall, our findings suggest that sex-specific DNA methylation may help establish sex differences in expression and function and that sex-specific alterations in DNA methylation in response to exposures could contribute to sex-variable toxicological responses.

One-Year Functional, Cognitive, and Psychological Outcomes Following the Use of Extracorporeal Membrane Oxygenation in Coronavirus Disease 2019: A Prospective Study.

To prospectively describe 1-year outcomes, with a focus on functional outcome, cognitive outcome, and the burden of anxiety, depression, and post-traumatic stress disorder, in coronavirus disease 2019 patients managed with extracorporeal membrane oxygenation. DESIGN: Prospective case series. SETTING: Tertiary extracorporeal membrane oxygenation center in the United States. PATIENTS: Adult coronavirus disease 2019 acute respiratory distress syndrome patients managed with extracorporeal membrane oxygenation March 1, 2020, to July 31, 2020. INTERVENTIONS: Baseline variables, treatment measures, and short-term outcomes were obtained from the medical record. Survivors were interviewed by telephone, a year following the index intensive care admission. Functional outcome was assessed using the modified Rankin Scale and the World Health Organization Disability Assessment Scale 2.0. Cognitive status was assessed with the 5-minute Montreal Cognitive Assessment. The Hospital Anxiety and Depression Scale was used to screen for anxiety and depression. Screening for post-traumatic stress disorder was performed with the Posttraumatic Stress Disorder Checklist 5 instrument. MEASUREMENTS AND MAIN RESULTS: Twenty-three patients were managed with extracorporeal membrane oxygenation, 14 (61%) survived to hospital discharge. Thirteen (57%) were alive at 1 year. One patient was dependent on mechanical ventilation, another intermittently required supplemental oxygen at 1 year. The median modified Rankin Scale score was 2 (interquartile range, 1-2), median World Health Organization Disability Assessment Scale 2.0 impairment score was 21% (interquartile range, 6-42%). Six of 12 previously employed individuals (50%) had returned to work, and 10 of 12 (83%) were entirely independent in activities of daily living. The median Montreal Cognitive Assessment score was 14 (interquartile range, 13-14). Of 10 patients assessed with Hospital Anxiety and Depression Scale, 4 (40%) screened positive for depression and 6 (60%) for anxiety. Four of 10 (40%) screened positive for post-traumatic stress disorder. CONCLUSIONS: Functional impairment was common a year following the use of extracorporeal membrane oxygenation in coronavirus disease 2019, although the majority achieved independence in daily living and about half returned to work. Long-term anxiety, depression, and post-traumatic stress disorder were common, but cognitive impairment was not.

Cross-ministry data on service use and limitations faced by children in special education.

BACKGROUND: Children with disabilities often face limitations that cross support sectors. OBJECTIVE: Our aim was to measure cross-ministry service use, outcomes, and functional limitations faced by children who qualified for special education. METHODS: We used longitudinal British Columbia ministry data linked to children (0-18y) registered in K-12 education. Children were grouped by special education funding (most to least; Level 1, Level 2, Level 3, Unfunded, and no special education), and related to 1) service use patterns, 2) the age they first used disability services, and 3) functional limitations reported in health visits. We also reported how length of special education use related to disability service use. RESULTS: Of 111,274 children, 154(0.1%) were Level 1, 4427(4.0%) Level 2, 2897(2.6%) Level 3, 13472(12.1%) Unfunded, and 90324(81.2%) not in special education. Children with higher funding levels, compared to lower levels of funding, generally were more likely to experience poorer outcomes, have functional limitations, have service needs, and receive early support. One exception was children with serious behavioral/mental health special education coding, which had poorer outcomes for their level of funding. Children received child disability supports early (about half of users started by 4y), but use was mostly limited to those with many years (9+years) of funded special education (70.7% of the all users) and biased to certain special education codes (i.e., Level 1, severe intellectual disability, and autism). CONCLUSIONS: This study provides evidence of the long-term, diverse needs of children in special education and may be used to inform decisions surrounding their support.

Linking Altered Flow Regimes to Biological Condition: an Example Using Benthic Macroinvertebrates in Small Streams of the Chesapeake Bay Watershed.

Regionally scaled assessments of hydrologic alteration for small streams and its effects on freshwater taxa are often inhibited by a low number of stream gages. To overcome this limitation, we paired modeled estimates of hydrologic alteration to a benthic macroinvertebrate index of biotic integrity data for 4522 stream reaches across the Chesapeake Bay watershed. Using separate random-forest models, we predicted flow status (inflated, diminished, or indeterminant) for 12 published hydrologic metrics (HMs) that characterize the main components of flow regimes. We used these models to predict each HM status for each stream reach in the watershed, and linked predictions to macroinvertebrate condition samples collected from streams with drainage areas less than 200 km2. Flow alteration was calculated as the number of HMs with inflated or diminished status and ranged from 0 (no HM inflated or diminished) to 12 (all 12 HMs inflated or diminished). When focused solely on the stream condition and flow-alteration relationship, degraded macroinvertebrate condition was, depending on the number of HMs used, 3.8-4.7 times more likely in a flow-altered site; this likelihood was over twofold higher in the urban-focused dataset (8.7-10.8), and was never significant in the agriculture-focused dataset. Logistic regression analysis using the entire dataset showed for every unit increase in flow-alteration intensity, the odds of a degraded condition increased 3.7%. Our results provide an indication of whether altered streamflow is a possible driver of degraded biological conditions, information that could help managers prioritize management actions and lead to more effective restoration efforts.

Circular Economy of Construction and Demolition Waste: A Literature Review on Lessons, Challenges, and Benefits.

Conventionally, in a linear economy, C&D (Construction and Demolition) waste was considered as zero value materials, and, as a result of that, most C&D waste materials ended up in landfills. In recent years, with the increase in the awareness around sustainability and resource management, various countries have started to explore new models to minimize the use of limited resources which are currently overused, mismanaged, or quickly depleting. In this regard, the implementation of CE (Circular Economy) has emerged as a potential model to minimize the negative impact of C&D wastes on the environment. However, there are some challenges hindering a full transition to CE in the construction and demolition sectors. Therefore, this review paper aims to critically scrutinize different aspects of C&D waste and how CE can be integrated into construction projects. Reviewing of the literature revealed that the barriers in the implementation of CE in C&D waste sectors fall in five main domains, namely legal, technical, social, behavioral, and economic aspects. In this context, it was found that policy and governance, permits and specifications, technological limitation, quality and performance, knowledge and information, and, finally, the costs associated with the implementation of CE model at the early stage are the main barriers. In addition to these, from the contractors' perspective, C&D waste dismantling, segregation, and on-site sorting, transportation, and local recovery processes are the main challenges at the start point for small-scale companies. To address the abovementioned challenges, and also to minimize the ambiguity of resulting outcomes by implementing CE in C&D waste sectors, there is an urgent need to introduce a global framework and a practicable pathway to allow companies to implement such models, regardless of their scale and location. Additionally, in this paper, recommendations on the direction for areas of future studies for a reduction in the environmental impacts have been provided. To structure an effective model approach, the future direction should be more focused on dismantling practices, hazardous material handling, quality control on waste acceptance, and material recovery processes, as well as a incentivization mechanism to promote ecological, economic, and social benefits of the CE for C&D sectors.

SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.

Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic.

Novel coronavirus 2019 (COVID-19): Emergence and implications for emergency care.

A novel coronavirus (COVID-19) causing acute illness with severe symptoms has been isolated in Wuhan, Hubei Province, China. Since its emergence, cases have been found worldwide, reminiscent of severe acute respiratory syndrome and Middle East respiratory syndrome outbreaks over the past 2 decades. Current understanding of this epidemic remains limited due to its rapid development and available data. While occurrence outside mainland China remains low, the likelihood of increasing cases globally continues to rise. Given this potential, it is imperative that emergency clinicians understand the preliminary data behind the dynamics of this disease, recognize possible presentations of patients, and understand proposed treatment modalities.