Digital Adoption by an Organization Supporting Informal Caregivers During COVID-19 Pandemic Showing Impact on Service Use, Organizational Performance, and Carers' Well-Being: Retrospective Population-Based Database Study With Embedded User Survey.

BACKGROUND: The COVID-19 pandemic has catalyzed a move from face-to-face to digital delivery of services by hospitals and primary care. However, little is known about the impact of digital transformation on organizations supporting unpaid caregivers. Since the start of the COVID-19 pandemic, the value of care provided by such informal caregivers is estimated to be £111 billion (US$ 152.7 billion) in England. OBJECTIVE: This study aims to analyze service uptake patterns (including digital service options) over the pandemic period in an English caregivers' support organization covering a population of 0.98 million; measure changes in organizational performance, service efficiency, and quality; and identify the views of caregivers on service provision and future digital delivery. METHODS: This was a retrospective analysis of the use of digital versus nondigital support services (January 2019 to June 2021) by caregivers in city and rural geographic areas. We compared organizational performance and service quality indicators for 2 financial years (2019-2020 and 2020-2021). A survey was conducted to identify barriers and facilitators to digital service uptake, the computer proficiency of caregivers (the Computer Proficiency Questionnaire, 12-item version), and preferences for future digital service provision. Quantitative data were analyzed using Stata 13 (StataCorp LLC). Thematic analysis was used for open-text survey responses. RESULTS: The number of caregivers registered with the organization rose from 14,817 in 2019 to 20,237 in 2021. Monthly contacts rose from 1929 to 6741, with remote contacts increasing from 48.89% (943/1929) to 86.68% (5843/6741); distinctive patterns were observed for city versus rural caregivers. There was an increase in one-to-one contacts (88.8%) and caregiver assessments (20.9%), with no expansion in staffing. Service quality indicators showed an improvement in 5 of 8 variables (all P<.05). The 152 carers completing the survey had similar demographics to all registered caregivers. The Computer Proficiency Questionnaire, 12-item version, mean score of 25.61 (SD 4.40) indicated relatively high computer proficiency. The analysis of open-text responses identified a preference for the organization to continue to offer face-to-face services as well as web-based options. The digital services that were the most highly rated were carers' well-being assessments, support needs checks, and peer support groups. CONCLUSIONS: Our findings show that staff in the caregiver support organization were agile in adapting their services to digital delivery while dealing with increased numbers of registered clients and higher monthly contacts, all without obvious detriment to service quality. Caregivers indicated a preference for blended services, even while recording high computer proficiency. Considering the economic importance of unpaid caregivers, more attention should be given to organizations funded to provide support for them and to the potential for technology to enhance caregivers' access to, and engagement with, such services.

MDM2 Amplification Status in a Cohort of Well-Characterized Myxofibrosarcoma: A Clinicopathologic Analysis of 22 Tumors.

Myxofibrosarcomas (MFS) present as slowly enlarging superficial masses in elderly patients. Even though these tumors fail to exhibit a distinct immunophenotype, diagnosis is straightforward when they present in subcutaneous tissue. Intramuscular MFS, however, are more challenging to diagnose as the differential also includes dedifferentiated liposarcoma with myxoid features. The vast majority of dedifferentiated liposarcomas show MDM2 amplification, whereas limited data exists as to the MDM2 status of MFS. We sought to explore the rate of MDM2 amplification in cases of classic MFS. Our archives were searched for MFS; only subcutaneous well-sampled resections were included. FISH for MDM2 amplification was performed on each tumor. A cohort of myxoid dedifferentiated liposarcoma resections was studied for comparison. Twenty-two MFS arose in patients aged 44 to 85 years. All tumors contained an infiltrative population of atypical cells embedded in a myxoid stroma with curvilinear blood vessels. MDM2 amplification by FISH was identified in 3 (of 22; 14%) tumors. Available follow up on 17 patients (range 1-96 months; median 13 months) revealed 6 patients with local recurrence and 1 with distant metastasis. Of 3 patients with MDM2- amplified MFS, 1 experienced recurrence and died of unrelated causes, while the second was alive without disease 12 months after diagnosis. Even though the rate of MDM2 amplification by FISH in MFS appears to be low, a subset of cases may show this genetic alteration, which pathologists should be aware of to avoid misclassification as myxoid dedifferentiated liposarcomas. Further studies are necessary to determine if amplification status adds prognostic value.

Alternative lengthening of telomeres in primary hepatic neoplasms.

The alternative lengthening of telomeres (ALT) phenotype is characterized by ultra-bright telomeres on fluorescence in situ hybridization (FISH) and is a marker of a unique mechanism of telomere maintenance in tumors. ALT does not occur in normal tissues. ALT has been described in hepatocellular carcinoma (5-10%) and in primary hepatic angiosarcomas (75%). To study the frequency of ALT in other primary hepatic tumors, a wide range of primary hepatic neoplasms were retrieved. The tumors included the following: intrahepatic and hilar cholangiocarcinomas (N = 110), hepatic adenomas (N = 35), hepatocellular carcinomas (N = 30), fibrolamellar carcinomas (n = 11), combined cholangiocarcinoma-hepatocellular carcinomas (N = 8), carcinosarcoma (N = 10), hepatoblastomas (N = 5), hemangiomas (N = 4), angiosarcomas (N = 8), epithelioid hemangioendotheliomas (N = 10), calcified nested stromal epithelial tumor (N = 2), embryonal sarcoma (N = 2), rhabdoid tumor (N = 1), bile duct adenoma (N = 1), and angiomyolipoma (N = 1). For epithelial tumors, ALT-FISH was positive in one carcinosarcoma (10% of cases), one cholangiocarcinoma (1% of cases), and one combined hepatocellular carcinoma-cholangiocarcinoma (13% of cases). In the hepatocellular carcinoma component of both the carcinosarcoma and the combined hepatocellular carcinoma-cholangiocarcinoma, the tumor cells showed patchy marked nuclear pleomorphism akin to that described previously for chromophobe hepatocellular carcinoma, which are typically ALT FISH positive. The ALT-positive cholangiocarcinoma also showed patchy, striking nuclear pleomorphism. For soft tissue tumors, ALT was positive in two angiosarcomas (N = 2; 25% of cases). In summary, this study shows that ALT-FISH is positive in rare carcinosarcomas, cholangiocarcinomas, and combined cholangiocarcinoma-hepatocellular carcinoma. ALT is not a significant mechanism of telomere maintenance in hepatocellular adenomas or fibrolamellar carcinomas and was negative in all other tested primary hepatic neoplasms. ALT-FISH is also positive in a subset of primary hepatic angiosarcomas.

"Going through the motions": A qualitative exploration of the impact of emergency medicine resident burnout on patient care.

Objectives: Burnout occurs frequently in emergency medicine (EM) residents and has been shown to have a negative impact on patient care. The specific effects of burnout on patient care are less well understood. This study qualitatively explores how burnout may change the way EM residents provide patient care. Methods: Qualitative data were obtained from a sample of 29 EM residents in four semistructured focus groups across four institutions in the United States in early 2019. Transcripts were coded and organized into major patient care themes. Results: Residents described many ways in which feelings of burnout negatively impacted patient care. These detrimental effects most often fit into one of four main themes: reduced motivation to care for patients, poor communication with patients, difficult interactions with health care colleagues, and impaired decision making. Conclusions: According to EM residents, burnout negatively impacts several important aspects of patient care. Resident engagement with clinical care, communication with patients and colleagues, and clinical care may suffer as a result of burnout.

Infrastructural nature.

The assertion that 'ecosystems are infrastructure' is now common in conservation science and ecosystem management. This article interrogates that claim, which we argue underpins diverse practices of environmental investment focused on the strategic management of ecosystem functions to sustain and secure human life. We trace the genealogies and geographies of infrastructural nature as a paradigm of investment that coexists (sometimes in tension) with extractivist commodity regimes. We draw links between literatures on the political economy of ecosystem services and infrastructure and highlight three themes that hold promise for future research: labor, territory, and finance.

BRAF Rearrangements and BRAF V600E Mutations Are Seen in a Subset of Pancreatic Carcinomas With Acinar Differentiation.

CONTEXT.­: Comprehensive genomic profiling has demonstrated that approximately 20% of pancreatic carcinomas with acinar differentiation harbor potentially targetable BRAF fusions that activate the MAPK pathway. OBJECTIVES.­: To validate the above finding by BRAF break-apart fluorescence in situ hybridization (FISH) in a large series of pure acinar cell carcinomas (ACCs), evaluate tumors for the presence of BRAF V600E mutations, and compare clinicopathologic features of tumors with BRAF rearrangements with those without. DESIGN.­: Thirty cases of pure ACC and 6 cases of mixed acinar-neuroendocrine carcinoma (ACC-NEC) were retrieved. A break-apart FISH probe was used to detect BRAF rearrangements. Immunohistochemistry for BRAF V600E was performed. RESULTS.­: BRAF rearrangements by FISH were found in 6 of 36 cases (17%), 5 of which were pure ACC and 1 was a mixed ACC-NEC. Follow-up was available in 29 of 36 cases (81%). The median survival was 22 months for BRAF-rearranged cases and 16 months for BRAF-intact cases; the 2-year overall survival was 50% for BRAF-rearranged cases and 35% for BRAF-intact cases. No significant clinicopathologic differences were identified in cases with BRAF rearrangement compared with those without BRAF rearrangement. BRAF V600E mutation was identified in 2 of 34 cases (6%), both of which were pure ACC and were BRAF-intact by FISH. CONCLUSIONS.­: This study supports the finding that BRAF rearrangements are present in approximately 20% of cases and identified BRAF V600E mutations in approximately 5% of cases. These cases may benefit from targeted therapy.

A newly characterized malaria antigen on erythrocyte and merozoite surfaces induces parasite inhibitory antibodies.

We previously identified a Plasmodium falciparum (Pf) protein of unknown function encoded by a single-copy gene, PF3D7_1134300, as a target of antibodies in plasma of Tanzanian children in a whole-proteome differential screen. Here we characterize this protein as a blood-stage antigen that localizes to the surface membranes of both parasitized erythrocytes and merozoites, hence its designation as Pf erythrocyte membrane and merozoite antigen 1 (PfEMMA1). Mouse anti-PfEMMA1 antisera and affinity-purified human anti-PfEMMA1 antibodies inhibited growth of P. falciparum strains by up to 68% in growth inhibition assays. Following challenge with uniformly fatal Plasmodium berghei (Pb) ANKA, up to 40% of mice immunized with recombinant PbEMMA1 self-cured, and median survival of lethally infected mice was up to 2.6-fold longer than controls (21 vs. 8 d, P = 0.005). Furthermore, high levels of naturally acquired human anti-PfEMMA1 antibodies were associated with a 46% decrease in parasitemia over 2.5 yr of follow-up of Tanzanian children. Together, these findings suggest that antibodies to PfEMMA1 mediate protection against malaria.

"Pulling the Parachute": A Qualitative Study of Burnout's Influence on Emergency Medicine Resident Career Choices.

OBJECTIVES: About half of all resident physicians report symptoms of burnout. Burnout negatively influences multiple aspects of their education and training. How burnout may impact residents' career choices remains unclear. The authors explored the role burnout played in residents' career decisions. METHODS: This was a qualitative study among a sample of 29 emergency medicine residents from four institutions. Qualitative data were generated through four semistructured focus groups. The authors employed a constructivist approach to thematic analysis. Transcripts were coded and organized into major themes. RESULTS: Five major themes connecting burnout with residents' career choices emerged: 1) residents' current burnout and the prevention of future burnout figured prominently in their career considerations, 2) residents aimed to mitigate sources of burnout through their career choices, 3) residents' view of clinical work as a burden and a burnout contributor spurred the pursuit of other interests, 4) faculty advice and role modeling in relation to burnout shaped residents' career perspectives, and 5) residents weighed long-term burnout concerns with short-term financial needs. CONCLUSION: Burnout played an important role in multiple aspects of residents' career considerations. Educators, program directors, and organization leaders can focus on identified target areas to address burnout's influence on residents' career decisions.

"Necessary Compromises": A Qualitative Exploration of the Influence of Burnout on Resident Education.

OBJECTIVE: Burnout is prevalent among resident physicians and has a negative impact on their well-being and effectiveness at work. How burnout shapes residents' educational experiences, attitudes, habits, and practices is not well understood. There is also a lack of research regarding self-identified mitigation strategies for residents. The authors qualitatively explored burnout's role in the educational experiences of resident physicians. METHODS: Qualitative data were generated from a sample of 29 emergency medicine residents through four semistructured focus groups across four institutions in January and February 2019. The authors employed a constructivist approach to thematic analysis. Transcripts were coded and organized into major and minor themes. RESULTS: Residents reported that a misalignment of their individual versus institutional priorities and a lack of agency were significant contributors to their burnout. Residents described how burnout affected multiple aspects of their education, including their motivation and curiosity to learn, engagement in scholarly activity, and teaching of others. Residents identified several ways of building a sense of community that they explained was most useful in mitigating their experiences with burnout. CONCLUSION: Burnout had a negative influence on many facets of residents' educational experiences during training. Program directors and educators can take resident-identified steps to moderate its detrimental role on trainee education.

Targeting MYC activity in double-hit lymphoma with MYC and BCL2 and/or BCL6 rearrangements with epigenetic bromodomain inhibitors.

Double/triple-hit lymphomas (DHL/THL) account for 5-10% of diffuse large B cell lymphoma (DLBCL) with rearrangement of MYC and BCL2 and/or BCL6 resulting in MYC overexpression. Despite the poor prognosis of DHL, R-CHOP chemotherapy remains the treatment backbone and new targeted therapy is needed. We performed comprehensive cytogenetic studies/fluorescence in situ hybridization on DLBCL and Burkitt lymphoma cell lines (n = 11) to identify the DHL/THL DLBCL in vitro model. We identified MYC/IG in Raji and Ramos (single hit); MYC/IG-BCL2 (DHL) in DOHH2, OCI-LY1, SUDHL2, and OCI-LY10; MYC/IG-BCL2/BCL6 (THL) in VAL; and no MYC rearrangement in U2932 and HBL1 (WT-MYC). Targeting MYC in the DHL/THL DLBCLs through bromodomain extra-terminal inhibitors (BETi) (JQ1, I-BET, and OTX015) significantly (p < 0.05) reduced proliferation, similar to WT-MYC cells, accompanied by decreased MYC but not BCL2 protein. Moreover, BETi suppressed MYC transcription and decreased BRD4 binding to MYC promoter in DHL cells. CD47 and PD-L1 are immunoregulatory molecules often expressed on tumors and regulated by MYC. High levels of surface CD47 but not surface PD-L1 was observed in DHL/THL, which was reduced by JQ1 treatment. BETi in combination with Pan-HDAC inhibitor had a limited effect on survival of DHL/THL, while combination of BETi and BCL2 inhibitor (ABT-199) had a significant (p < 0.005) inhibitory effect on survival followed by BCL-XL inhibition. Overall, the data suggests that MYC-expressing DLBCLs are probably addicted to the MYC-oncogenic effect regardless of MYC rearrangements. In summary, we identified an in vitro model for DHL/THL DLBCLs and provide evidence for the therapeutic potential of BET inhibitor alone or in combination with BCL2 inhibitor.

Using a National Representative Sample to Evaluate the Integrity of the 30-Day Surgical Mortality Metric.

The 30-day surgical mortality metric is endorsed by the National Quality Forum for value-based purchasing purposes. However, its integrity has been questioned, as there is documented evidence of hospital manipulation of this measure, by way of inappropriate palliative care designation and changes in patient selection. To determine if there is evidence of potential manipulation, we retrospectively analyzed 1,725,291 surgical admissions from 158 United States hospitals participating in the National Inpatient Sample from 2010 to 2011. As a way of evaluating unnecessary life-prolonging measures, we determined that a significant increase in mortality rate after post-operative day 30 (day 31-35) would indicate manipulation. We compared the post-operative mortality rates for each hospital between Post-Operative Day 26-30 and Post-Operative Day 31-35 using Wilcoxon signed-rank tests. After application of the Bonferroni correction, the results showed that none of the hospitals had a statistically significant increase in mortality after post-operative day 30. This analysis fails to impugn the integrity of this measure, as we did not identify any evidence of potential manipulation of the 30-day surgical mortality metric.

The impact of reduction of testing at a Preoperative Evaluation Clinic for elective cases: Value added without adverse outcomes.

STUDY OBJECTIVE: Protocol changes at Vanderbilt have been adopted with the intention of reducing unnecessary preoperative testing. We sought to evaluate their success and association with clinical decisions. DESIGN: Retrospective Observational Study SETTING: Vanderbilt's Preoperative Evaluation Clinic MEASUREMENTS: We reviewed and identified a key interval of change on clinical workup protocols which led to a reduction in preoperative testing. We queried Data Warehouse for preoperative chemistry tests, complete blood counts, coagulation blood draws, electrocardiograms, and chest x-rays done before and after these intervals. Chi-square, univariate and mixed effect multivariable regressions were performed to determine the significance of testing reduction and tendency of readmission rates and length-of-stay; Welch's t-test with Freeman-Tukey transformation was conducted to identify the differences in case cancellation rates. MAIN RESULTS: We analyzed 56,425 anesthetic cases and there was a statistically significant downward trend in all preoperative testing performed: electrocardiograms (61.90% to 31.66% [OR 0.151; 95% CI 0.144 to 0.159]), coagulation blood draws (37.57% to 29.74% [OR 0.392; 95% CI 0.370 to 0.416]), basic metabolic panels (70.64% to 51.29% [OR 0.294; 95% CI 0.280 to 0.309]), blood cell counts (71.38% to 51.42% [OR 0.264; 95% CI 0.251 to 0.277]) and chest x-rays (11.80% to 6.04% [OR 0.417; 95% CI 0.384 to 0.452], to 3.13% [OR 0.473; 95% CI 0.431 to 0.519]) after protocol changed. The changes didn't induce a significant increase in case cancellations, length-of-stay, readmission or most DOS testing; except for BMPs (0.28% to 0.66% [OR 1.307; 95% CI 1.104 to 1.549]). CONCLUSIONS: A net reduction in preoperative testing was seen at our institution from 2012 to 2015 due to anesthesia protocol changes intended to limit routine ordering of labs and imaging. While there was a significant increase in DOS testing for BMPs, these increases were not enough to offset the decrease in testing observed preoperatively.

Large Chromosomal Rearrangements Yield Biomarkers to Distinguish Low-Risk From Intermediate- and High-Risk Prostate Cancer.

OBJECTIVE: To test the hypothesis that chromosomal rearrangements (CRs) can distinguish low risk of progression (LRP) from intermediate and high risk of progression (IHRP) to prostate cancer (PCa) and if these CRs have the potential to identify men with LRP on needle biopsy that harbor IHRP PCa in the prostate gland. PATIENTS AND METHODS: Mate pair sequencing of amplified DNA from pure populations of Gleason patterns in 154 frozen specimens from 126 patients obtained between August 14, 2001, and July 15, 2011, was used to detect CRs including abnormal junctions and copy number variations. Potential CR biomarkers with higher incidence in IHRP than in LRP to cancer and having significance in PCa biology were identified. Independent validation was performed by fluorescence in situ hybridization in 152 specimens from 124 patients obtained between February 12, 2002, and July 12, 2008. RESULTS: The number of abnormal junctions did not distinguish LRP from IHRP. Loci corresponding to genes implicated in PCa were more frequently altered in IHRP. Integrated analysis of copy number variations and microarray data yielded 6 potential markers that were more frequently detected in Gleason pattern 3 of a Gleason score 7 of PCa than in Gleason pattern 3 of a Gleason score 6 PCa. Five of those were cross-validated in an independent sample set with statistically significant areas under the receiver operating characteristic curves (AUCs) (P≤.01). Probes detecting deletions in PTEN and CHD1 had AUCs of 0.87 (95% CI, 0.77-0.97) and 0.73 (95% CI, 0.60-0.86), respectively, and probes detecting gains in ASAP1, MYC, and HDAC9 had AUCs of 0.71 (95% CI, 0.59-0.84), 0.82 (95% CI, 0.71-0.93), and 0.77 (95% CI, 0.66-0.89), respectively (for expansion of gene symbols, use search tool at www.genenames.org). CONCLUSION: Copy number variations in regions encompassing important PCa genes were predictive of cancer significance and have the potential to identify men with LRP PCa by needle biopsy who have IHRP PCa in their prostate gland.

A retrospective evaluation of the risk of bias in perioperative temperature metrics.

The prevention and treatment of hypothermia is an important part of routine anesthesia care. Avoidance of perioperative hypothermia was introduced as a quality metric in 2010. We sought to assess the integrity of the perioperative hypothermia metric in routine care at a single large center. Perioperative temperatures from all anesthetics of at least 60 min duration between January 2012 and 2017 were eligible for inclusion in analysis. Temperatures were displayed graphically, assessed for normality, and analyzed using paired comparisons. Automatically-recorded temperatures were obtained from several monitoring sites. Provider-entered temperatures were non-normally distributed, exhibiting peaks at temperatures at multiples of 0.5 °C. Automatically-acquired temperatures, on the other hand, were more normally distributed, demonstrating smoother curves without peaks at multiples of 0.5 °C. Automatically-acquired median temperature was highest, 36.8 °C (SD = 0.8 °C), followed by the three manually acquired temperatures (nurse-documented postoperative temperature, 36.5 °C [SD = 0.6 °C]; intraoperative manual temperature, 36.5 °C [SD = 0.6 °C]; provider-documented postoperative temperature, 36.1 °C [SD = 0.6 °C]). Provider-entered temperatures exhibit values that are unlikely to represent a normal probability distribution around a central physiologic value. Manually-entered perioperative temperatures appear to cluster around salient anchoring values, either deliberately, or as an unintended result driven by cognitive bias. Automatically-acquired temperatures may be superior for quality metric purposes.

Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor.

Although it has been known for over a decade that the inflammatory mediator NGF sensitizes pain-receptor neurons through increased trafficking of TRPV1 channels to the plasma membrane, the mechanism by which this occurs remains mysterious. NGF activates phosphoinositide 3-kinase (PI3K), the enzyme that generates PI(3,4)P2 and PIP3, and PI3K activity is required for sensitization. One tantalizing hint came from the finding that the N-terminal region of TRPV1 interacts directly with PI3K. Using two-color total internal reflection fluorescence microscopy, we show that TRPV1 potentiates NGF-induced PI3K activity. A soluble TRPV1 fragment corresponding to the N-terminal Ankyrin repeats domain (ARD) was sufficient to produce this potentiation, indicating that allosteric regulation was involved. Further, other TRPV channels with conserved ARDs also potentiated NGF-induced PI3K activity. Our data demonstrate a novel reciprocal regulation of PI3K signaling by the ARD of TRPV channels.