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BackgroundThe majority of those living with HIV in the United States are men who have sex with men (MSM), and young, minority MSM account for more new HIV infections than any other group. HIV transmission can be reduced through detection and early treatment initiation or by starting pre-exposure prophylaxis (PrEP), but rates of testing are lower than recommended among MSM, and PrEP uptake has been slow. Although promoting HIV testing and PrEP uptake by placing advertisements on web-based platforms — such as social media websites and dating apps — is a promising approach for promoting HIV testing and PrEP, the relative effectiveness of HIV prevention advertising on common web-based platforms is underexamined. ObjectiveThis study aims to evaluate the relative effectiveness of advertisements placed on 3 types of web-based platforms (social media websites, dating apps, and informational websites) for promoting HIV self-testing and PrEP uptake. MethodsAdvertisements will be placed on social media websites (Facebook, Instagram, and Twitter), dating apps (Grindr, Jack’d, and Hornet), and informational search websites (Google, Yahoo, and Bing) to recruit approximately 400 young (18-30 years old), minority (Black or Latino) MSM at elevated risk of HIV exposure. Recruitment will occur in 3 waves, with each wave running advertisements on 1 website from each type of platform. The number of participants per platform is not prespecified, and recruitment in each wave will occur until approximately 133 HIV self-tests are ordered. Participants will complete a baseline survey assessing risk behavior, substance use, psychological readiness to test, and attitudes and then receive an electronic code to order a free home-based HIV self-test kit. Two follow-ups are planned to assess HIV self-test results and PrEP uptake. ResultsRecruitment was completed in July 2020. ConclusionsFindings may improve our understanding of how the platform users’ receptivity to test for HIV differs across web-based platforms and thus may assist in facilitating web-based HIV prevention campaigns. Trial RegistrationClinicalTrials.gov NCT04155502; https://clinicaltrials.gov/ct2/show/NCT04155502 International Registered Report Identifier (IRRID)DERR1-10.2196/20417

Abstract: Platelet factor 4 (PF4) is an abundant chemokine that is released from platelet α-granules on activation. PF4 is central to the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT) in which antibodies to PF4 form immune complexes with PF4, which activate platelets and neutrophils through Fc receptors. In this study, we show that PF4 binds and activates the thrombopoietin receptor, cellular myeloproliferative leukemia protein (c-Mpl), on platelets. This leads to the activation of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription (STAT) 3 and STAT5, leading to platelet aggregation. Inhibition of the c-Mpl-JAK2 pathway inhibits platelet aggregation to PF4, VITT sera, and the combination of PF4 and IgG isolated from VITT patient plasma. The results support a model in which PF4-based immune complexes activate platelets through binding of the Fc domain to FcγRIIA and PF4 to c-Mpl., (© 2024 by American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Src tyrosine kinases and spleen tyrosine kinase (Syk) have recently been shown to contribute to sustained platelet aggregation on collagen under arterial shear. In the present study, we have investigated whether Src and Syk are required for aggregation under minimal shear following activation of glycoprotein VI (GPVI) and have extended this to C-type lectin-like receptor-2 (CLEC-2) which signals through the same pathway. Aggregation was induced by the GPVI ligand collagen-related peptide (CRP) and the CLEC-2 ligand rhodocytin and monitored by light transmission aggregometry (LTA). Aggregation and tyrosine phosphorylation by both receptors were sustained for up to 50 min. The addition of inhibitors of Src, Syk or Bruton's tyrosine kinase (Btk) at 150 sec, by which time aggregation was maximal, induced rapid loss of tyrosine phosphorylation of their downstream proteins, but only Src kinase inhibition caused a weak (~10%) reversal in light transmission. A similar effect was observed when the inhibitors were combined with apyrase and indomethacin or glycoprotein IIb-IIIa (GPIIb-IIIa) antagonist, eptifibatide. On the other hand, activation of GPIIb-IIIa by GPVI in a diluted platelet suspension, as measured by binding of fluorescein isothiocyanate-labeled antibody specific for the activated GPIIb-IIIa (FITC-PAC1), was reversed on the addition of Src and Syk inhibitors showing that integrin activation is rapidly reversible in the absence of outside-in signals. The results demonstrate that Src but not Syk and Btk contribute to sustained aggregation as monitored by LTA, possibly as a result of inhibition of outside-in signaling from GPIIb-IIIa to the cytoskeleton through a Syk-independent pathway. This is in contrast to the role of Syk in supporting sustained aggregation on collagen under arterial shear.

Background: Platelets are multifunctional cellular mediators in many physiological and pathophysiological processes such as thrombosis, angiogenesis, and inflammation. Several members of galectins, a family of carbohydrate-binding proteins with a broad range of immunomodulatory actions, have been reported to activate platelets., Objective: In this study, we investigated the role of galectin-9 (Gal-9) as a novel ligand for platelet glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2)., Methods: Platelet spreading, aggregation, and P-selectin expression in response to Gal-9 were measured in washed platelet suspensions via static adhesion assay, light transmission aggregometry, and flow cytometry, respectively. Solid-phase binding assay and protein phosphorylation studies were utilized to validate the interaction between Gal-9 and GPVI, and immunoprecipitation for detecting CLEC-2 phosphorylation. Wild-type (WT), GPVI-knockout (Gp6 -/- ), and GPVI and CLEC-2-double knockout (Gp6 -/- /Gp1ba-Cre-Clec1b fl / fl ) mice were used., Results: We have shown that recombinant Gal-9 stimulates aggregation in human and mouse washed platelets dose-dependently. Platelets from both species adhere and spread on immobilized Gal-9 and express P-selectin. Gal-9 competitively inhibited the binding of human recombinant D1 and D2 domains of GPVI to collagen. Gal-9 stimulated tyrosine phosphorylation of CLEC-2 and proteins known to lie downstream of GPVI and CLEC-2 including spleen tyrosine kinase and linker of activated T cells in human platelets. GPVI-deficient murine platelets exhibited significantly impaired aggregation in response to Gal-9, which was further abrogated in GPVI and CLEC-2-double-deficient platelets., Conclusions: We have identified Gal-9 as a novel platelet agonist that induces activation through interaction with GPVI and CLEC-2., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

GPVI and CLEC-2 have emerged as promising targets for long-term prevention of both arterial thrombosis and thrombo-inflammation with a decreased bleeding risk relative to current drugs. However, while there are potent blocking antibodies of both receptors, their protein nature comes with decreased bioavailability, making formulation for oral medication challenging. Small molecules are able to overcome these limitations, but there are many challenges in developing antagonists of nanomolar potency, which is necessary when considering the structural features that underlie the interaction of CLEC-2 and GPVI with their protein ligands. In this review, we describe current small-molecule inhibitors for both receptors and strategies to overcome such limitations, including considerations when it comes to in silico drug design and the importance of complex compound library selection.

Objective: Obesity is associated with a proinflammatory and prothrombotic state that supports atherosclerosis progression. The goal of this study was to gain insights into the phosphorylation events related to platelet reactivity in obesity and identify platelet biomarkers and altered activation pathways in this clinical condition. Approach and Results: We performed a comparative phosphoproteomic analysis of resting platelets from obese patients and their age- and gender-matched lean controls. The phosphoproteomic data were validated by mechanistic, functional, and biochemical assays. We identified 220 differentially regulated phosphopeptides, from at least 175 proteins; interestingly, all were up-regulated in obesity. Most of the altered phosphoproteins are involved in SFKs (Src-family kinases)-related signaling pathways, cytoskeleton reorganization, and vesicle transport, some of them validated by targeted mass spectrometry. To confirm platelet dysfunction, flow cytometry assays were performed in whole blood indicating higher surface levels of GP (glycoprotein) VI and CLEC (C-type lectin-like receptor) 2 in platelets from obese patients correlating positively with body mass index. Receiver operator characteristics curves analysis suggested a much higher sensitivity for GPVI to discriminate between obese and lean individuals. Indeed, we also found that obese platelets displayed more adhesion to collagen-coated plates. In line with the above data, soluble GPVI levels-indicative of higher GPVI signaling activation-were almost double in plasma from obese patients., Conclusions: Our results provide novel information on platelet phosphorylation changes related to obesity, revealing the impact of this chronic pathology on platelet reactivity and pointing towards the main signaling pathways dysregulated.

Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: This study assesses emergency contraception (EC) dispensed before and after a 3-min video counseling intervention on EC., Methods: We used a quasi-experimental design and two data sources to assess the impact of offering the video counseling intervention. We used electronic health records from six Planned Parenthood Association of Utah health centers with onsite oral EC dispensing to determine pre- and postintervention EC distribution. Beginning July 2015, three participating locations offered the video counseling intervention to English-speaking EC clients. These clients completed a brief survey assessing EC knowledge and uptake, providing a patient-level data source. We used a difference-in-difference analysis of the clinic-level data to assess the effect of the video counseling intervention. This analysis compares the variation in oral EC distribution between clinics offering the video intervention and clinics not offering the video counseling before and after the video counseling was introduced. Multivariable logistic regression assessed client characteristics associated with receiving ulipristal., Results: The six health centers served 8269 English-language EC clients during 2015. At participating sites, provision of ulipristal increased from 12% (269/2315) preintervention to 28% (627/2266) postintervention (p<.001). Nonparticipating sites did not see a change. Clients seeking EC at sites offering video counseling were more likely to receive ulipristal even after controlling for age, insurance and ethnicity (adjusted OR 3.4, 95% CI 3.0-3.9). Using the difference-in-difference analysis, the video counseling intervention accounted for an 18% (95% CI 14%-21%) increase in ulipristal provision at the participating health centers. Among the 2266 women seeking EC who were offered video counseling, 19% (425/2266) watched the video, and 60% (254/425) reported the video affected their EC preferences. Knowledge of the IUD for EC increased, but reported uptake of this method remained low (6.8%)., Conclusions: Exposure to video counseling increased use of more effective oral EC and increased knowledge about all EC options., Implications: Use of a brief informational video about EC options at family planning clinics may increase the proportion of EC clients receiving more effective EC methods., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Peripheral nerve injury can result in muscle atrophy and long-term disability. We hypothesize that creating a side-to-side bridge to link an injured nerve with a healthy nerve will reduce muscle atrophy and improve muscle function., Methods: Sprague-Dawley rats were divided into four groups (n = 7 per group). Group 1: transection only--a 10-mm gap was created in the proximal tibial nerve; group 2: transected plus repaired--the transected tibial nerve was repaired; group 3: transected plus repaired plus nerve bridge--transected nerve repaired with a distal nerve bridge between the tibial and peroneal nerves via epineurial windows; and group 4: transected plus nerve bridge--transected tibial nerve left unrepaired and distal bridge added. Gait was assessed every 2 wk. At 90 d the following measures were determined: gastrocnemius mass, muscle and nerve nuclear density, and axonal infiltration into the nerve bridge., Results: Groups 3 and 4 had greater improvements in walking track recovery than groups 1 and 2. Group 3's gastrocnemius muscles exhibited the least amount of atrophy. Groups 1, 2, and 4 exhibited greater histologic appearance of muscle breakdown compared with group 3 and control muscle. Finally, most bridges in groups 3 and 4 had neuronal sprouting via the epineurial windows., Conclusions: Our study demonstrated reduced muscle atrophy with a side-to-side nerve bridge in the setting of peripheral nerve injury. These results support the application of novel side-to-side bridges in combination with traditional end-to-end neurorrhaphy to preserve muscle viability after peripheral nerve injuries., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The scope of plastic surgery is not well understood by people outside the field. Better educating medical students about plastic surgery may improve understanding of the field, establish appropriate referral patterns early on, and assist with career decision-making. The purpose of this study was to assess medical student understanding of plastic surgery and to analyze the impact of prior plastic surgery clinical exposure on this understanding., Methods: An online survey consisting of 24 clinical scenarios was administered to medical students of the University of Utah. After indicating their level of training and whether they had prior clinical exposure to plastic surgery or other surgical subspecialties, students selected one or more appropriate surgical subspecialties to manage each scenario., Results: Of 408 students, 230 (56.4%) responded to the survey. Prior clinical exposure to plastic surgery was reported by 15.8% to 29.4% of students (first to fourth year). Overall, 92% of students chose at least one acceptable surgical specialty for referral. Plastic surgery was selected by only 54% of students for all conditions, and this did not improve throughout medical school. Senior students (third and fourth years) with prior plastic surgery exposure chose plastic surgery more often than those without prior exposure (71% vs. 51%, P < 0.0001). Plastic surgery was chosen most frequently for rhinoplasty and breast reconstruction and less frequently for hand/peripheral nerve surgery and wound surgery., Conclusions: Improved medical student education about the scope of plastic surgery is needed, especially in the areas of hand/peripheral nerve surgery and general reconstructive surgery.

Context: Emergency department (ED) physicians often are uncertain about where in the hospital to triage patients with suspected acute cardiac ischemia. Many patients are triaged unnecessarily to intensive or intermediate cardiac care units., Objective: To determine whether use of a clinical decision rule improves physicians' hospital triage decisions for patients with suspected acute cardiac ischemia., Design and Setting: Prospective before-after impact analysis conducted at a large, urban, US public hospital., Participants: Consecutive patients admitted from the ED with suspected acute cardiac ischemia during 2 periods: preintervention group (n = 207 patients enrolled in March 1997) and intervention group (n = 1008 patients enrolled in August-November 1999)., Intervention: An adaptation of a previously validated clinical decision rule was adopted as the standard of care in the ED after a 3-month period of pilot testing and training. The rule predicts major cardiac complications within 72 hours after evaluation in the ED and stratifies patients' risk of major complications into 4 groups--high, moderate, low, and very low--according to electrocardiographic findings and presence or absence of 3 clinical predictors in the ED., Main Outcome Measures: Safety of physicians' triage decisions, defined as the proportion of patients with major cardiac complications who were admitted to inpatient cardiac care beds (coronary care unit or inpatient telemetry unit); efficiency of decisions, defined as the proportion of patients without major complications who were triaged to an ED observation unit or an unmonitored ward., Results: By intention-to-treat analysis, efficiency was higher in the intervention group (36%) than the preintervention group (21%) (difference, 15%; 95% confidence interval [CI], 8%-21%; P<.001). Safety was not significantly different (94% in the intervention group vs 89%; difference, 5%; 95% CI, -11% to 39%; P =.57). Subgroup analysis of intervention-group patients showed higher efficiency when physicians actually used the decision rule (38% vs 27%; difference, 11%; 95% CI, 3%-18%; P =.01). Improved efficiency was explained solely by different triage decisions for very low-risk patients. Most surveyed physicians (16/19 [84%]) believed that the decision rule improved patient care., Conclusions: Use of the clinical decision rule had a favorable impact on physicians' hospital triage decisions. Efficiency improved without compromising safety.

Reducing the number of items in a health-related quality of life instrument will enhance efficiency. However, it is important to maintain measurement properties. We determined the effect of reducing items from each domain (dyspnea, fatigue, emotion and mastery) of the 20-item Chronic Respiratory Questionnaire (CRQ). Three randomized trials of respiratory rehabilitation provided data. We removed items one at a time from each domain in three orders: by item impact, item responsiveness, and at random. Responsiveness, test-retest reliability and construct validity were evaluated at each step. Responsiveness and reliability, evaluated by intraclass correlation coefficients (ICC), were reduced marginally as the number of items was reduced to two items per domain. The deterioration was greatest when reducing from two items to one. To detect a particular effect, sample size would increase by about 10% when reducing the number of items in a domain to 2. Construct validity showed a more marked deterioration. Reducing to two items per domain would maintain responsiveness and reliability of the CRQ at an acceptable level, with a trade-off of reduced construct validity and increase in sample size requirements.

Objective: To develop and test a direct utility measure (McSad) for major, unipolar depression., Methods: A depression specific, multi-attribute health state classification system was created; clinical validity was evaluated by experts using specially designed structured exercises; a cross-sectional survey was conducted to obtain directly measured utilities for depression health states., Setting: Tertiary care, university medical centre., Participants: Three psychiatrists, 3 psychiatric nurses and 3 social workers assessed depression health state clinical validity. Survey participants were referred by psychiatrists and consisted of 105 outpatients, currently in remission with at least one episode of major, unipolar depression in the past two years., Survey Results: Respondent self-health state utility (mean and 95% confidence interval (CI)) was 0.79 (0.74-0.83). Utilities for hypothetical, untreated depression health states were: mild depression, 0.59 (0.55-0.62); moderate depression, 0.32 (0.29-0.34); severe depression, 0.04 (0.01-0.07). Fifty-six percent of respondents rated severe depression worse than being dead. Utilities for the hypothetical health states were not correlated with self-health utility. The intra-class correlation coefficient (ICC) was satisfactory for 13 of the 14 health states assessed., Conclusions: McSad was feasible and acceptable in patients with a history of major unipolar depression. The utilities for mild, moderate and severe untreated depression show the low health-related quality of life associated with depression. Initial assessments of test-retest reliability and validity yielded satisfactory results but further studies are needed to extend our knowledge of the measurement properties of McSad.

The methods and tools of health services research have been applied to a diverse number of health care areas. Surprisingly, they have been adopted only recently in diagnostic imaging, by a small number of professionals, in response to the severe fiscal constraints and widespread structural changes in the health industry, as well as to a growing concern that the value of social and individual investment in high-cost imaging services could not be validated objectively. As a result of the need for accountability for the use of scarce resources, regulators and payers of health services increasingly demand that a reasoned and objective evaluative process be adopted. To undertake a statistically driven evaluative approach that stands up to objective assessment of methodological rigour, an organized data-collection system is needed. Without this fundamental cornerstone, evaluators are left with little more than anecdotal evidence and professional and personal opinion to guide decision-making. It then becomes difficult to learn from both the successes and failures that are routinely experienced during times of rapid and fundamental change. This article describes the efforts made to integrate health services research in radiology into the routine daily activities and supporting systems of a large academic health system, the Hamilton Health Sciences Corporation and McMaster University Department of Radiology, in an attempt to move in the direction of evidence-based decision-making. The authors hope this will allow others to learn and improve on this work. Radiologists may then move the vast data systems and infrastructure associated with all imaging services to an evidence-based model for managing and guiding the vast resources entrusted to our collective stewardship.

Guideline Questions: 1) Should dexrazoxane be used routinely in patients with advanced or metastatic cancer who are at risk of developing cardio toxicity when receiving chemotherapy containing doxorubicin or epirubicin? 2) Do the available data support the use of dexrazoxane when anthracyclines are being used in the adjuvant setting for patients at risk of developing cardiotoxicity?, Objective: To make recommendations regarding the use of dexrazoxane to prevent cardiotoxicity in patients with nonhematological malignancies who are receiving anthracycline- containing chemotherapy., Outcomes: Clinical and subclinical cardiotoxicity, noncardiac toxicity and impact on efficacy outcomes such as response and overall survival are considered., Perspective (values): Evidence was selected, reviewed and synthesized by 2 members of Cancer Care Ontario's Systemic Treatment Disease Site Group (STDSG), formerly the Systemic Treatment Program Committee. Drafts of this document have been circulated and reviewed by members of the STDSG. The STDSG comprises medical oncologists, pharmacists, supportive care personnel and administrators. Community representatives did not participate in the development of this guideline, but they will be included in future guidelines., Quality of Evidence: Seven randomized controlled trials (RCTs), 2 with placebo control, were available for analysis., Benefits: Data for clinical cardiotoxicity from 6 trials were pooled (n = 1070). The meta-analysis indicated that the risk of experiencing clinical cardiotoxicity was significantly reduced by dexrazoxane (risk ratio 0.24; 95% confidence interval [CI] 0.11 to 0.52; p = 0.00031). There was no significant benefit shown in individual trials for objective response or survival., Harms: One of the RCTs revealed a significantly lower objective response rate in the dexrazoxane arm. However, a meta-analysis of objective response across 5 trials of breast cancer patients (n = 818) did not confirm this effect (odds ratio 0.85; 95% CI 0.61 to 1.18; p = 0.33). The use of dexrazoxane increased the incidence of myelosuppression and other noncardiac toxicities, but these were generally mild., Practice Guideline: The evidence supports the use of dexrazoxane to provide protection against the cardiotoxicity associated with conventional-dose doxorubicin in patients with advanced but anthracycline-sensitive cancer, in whom the continued use of anthracycline-containing chemotherapy is indicated in the opinion of the treating physician and who have received 300 mg/m2 or more of doxorubicin. The evidence supports the use dexrazoxane to provide protection against the cardiotoxicity associated with conventional-dose epirubicin in patients with advanced but anthracycline-sensitive cancer, in whom the continued use of anthracycline-containing chemotherapy is indicated in the opinion of the treating physicians. There are no data indicating the optimal cumulative dose of epirubicin at which dexrazoxane should be instituted. For doxorubicin, use of dexrazoxane is recommended after the cumulative dose reaches 300 mg/m2 (i.e., 55% of the recommended maximum). A similar formula could be used for epirubicin, that is, institution of dexrazoxane when the cumulative dose of epirubicin reaches 550 mg/m2, as the recommended maximum cumulative dose in Canada is 1000 mg/m2. Preclinical studies did not show any cardioprotectant effect for dexrazoxane when used with mitoxantrone, and no clinical studies have been done. Therefore, dexrazoxane is not recommended for use with mitoxantrone. There is no evidence for or against the use of dexrazoxane in the adjuvant setting for any tumour type. Because of concerns that dexrazoxane may reduce the efficacy of anthracyclines, and because data are not yet available on long-term toxicities, further studies should be performed before the drug is used in this setting.

Objective: 1. To develop McKnee, a classification system and direct utility measure for health states associated with knee replacement (KR) surgery. 2. To apply McKnee in a before-after study of KR surgery to: (i) gain experience with McKnee in an elderly population; (ii) confirm the practicality and usefulness of the McKnee system; (iii) assess self-health utility one week before and 3 mo after surgery; (iv) evaluate the stability of 3 clinical marker health states describing mild, moderate, and severe knee disability; (v) compare self-health utility scores with Short Form 36 (SF-36)., Methods: 1. Instrument development: The McKnee modified Health Utilities Index was developed and used to describe self-health and clinical marker health states: the clinical validity of the clinical marker states was evaluated by 5 clinicians involved in the care off KR patients. 2. Instrument evaluation: McKnee and the SF-36 were administered to 48 patients with osteoarthritis one week before and 3 mo after KR surgery., Results: Before-after study: McKnee was feasible and acceptable in the older patient group studied (mean age in years, SD: 69.9, 8.6). No change in self-health utility (mean, SD) was observed at 3 mo postsurgery: before -0.78, 0.17; after -0.78, 0.21. On the SF-36, only the change scores for pain and health transition were statistically significant. Utilities (mean, SD) for the clinical marker health states were: mild -0.80, 0.20; moderate -0.55, 0.28; and severe -0.48, 0.31. The clinical marker mean utility scores were stable between the baseline and 3 mo assessment, but the intraclass correlation coefficients for individual scores were low., Conclusion: McKnee provides a preference based measure of health related quality of life that can be used to obtain and interpret clinically the knee disability utility scorers needed for cost-utility studies and medical decision-making models about KR surgery. The McKnee system provides a practical and useful method for classifying knee disability health states and obtaining direct measurements of utility scores for selected health states.

Guideline Questions: 1) Does erythropoietin (EPO) reduce the need for transfusion of red blood cells in patients receiving chemotherapy for a nonhematologic cancer? 2) Does the administration of EPO improve the quality of life of these cancer patients?, Objective: To make recommendations regarding the use of EPO to reduce the need for transfusion of red blood cells in patients receiving chemotherapy for a nonhematologic cancer., Outcomes: First transfusion requirement from the start of chemotherapy is the main outcome of interest. Quality of life and costs are also considered., Perspective (values): Evidence was selected and reviewed by 5 members of the Ontario Cancer Treatment Practice Guidelines Initiative (OCTPGI) and the Systemic Treatment Program Committee (STPC). Drafts of this document have been circulated to and reviewed by members of the STPC. The STPC comprises medical oncologists, pharmacists, supportive care personnel and administrators. No community representative participated in the development of this practice guideline., Quality of Evidence: Eleven randomized controlled trials (RCTs), most placebo-controlled, were available for review. A meta-analysis was performed with 8 trials that shared a clinically relevant outcome measure. Only 1 trial assessed quality of life., Benefits: The meta-analysis showed a relative risk for transfusion among EPO patients of 0.64 (95% confidence interval 0.53-0.78), which translates into a 36% relative reduction in the proportion of patients requiring transfusion (p = 0.00001). Reduction in transfusion requirements was similar across strata defined by methodological quality, EPO dose, hematologic status, tumour type at trial entry and chemotherapy regimen. In the 1 trial that assessed quality of life, EPO was associated with improved quality of life., Harms: Hypertension has been noted rarely in EPO-treated cancer patients. The RCTs did not report adverse effects in EPO-treated patients compared with control patients during the follow-up period. Long-term adverse effects are unknown. EPO is more costly than transfusion, but formal cost-effectiveness studies are unavailable., Practice Guideline: For patients receiving chemotherapy for nonhematologic cancer in whom symptoms of anemia are expected and in whom transfusion of red blood cells is not considered an acceptable treatment option, EPO can be recommended as a safe, effective treatment alternative. The evidence in support of using EPO is stronger for patients receiving platinum-based chemotherapy regimens that for those receiving non-platinum-based regimens. CLINICAL PRACTICE GUIDELINE DATE: Apr. 4, 1997.

Background: An effort was made to assess the respiratory outcomes of laparoscopic Nissen fundoplication (LNF)., Methods: Prospective follow-up of 69 patients undergoing LNF for gastroesophageal reflux disease. Outcomes included pulmonary function testing, 24-h pH recording, esophageal manometry, and symptom assessment., Results: There was an improvement (p < 0.0001) in heartburn and cough scores. There was a significant fall in spirometry (p < 0001), diffusing capacity (p < 0.0001), and respiratory muscle strength (p < 0.0001) 36 h after surgery, which had returned to baseline by 1 month. At 6 months, the patients (n = 16) with impaired preoperative diffusing capacity showed improvement (17.8 +/- 3.7 to 19.8 +/- 4.6 ml/min/mmHg, p = 0.0245)., Conclusion: Patients undergoing LNF have impaired gas exchange before surgery which tends to improve 6 months after surgery. There is an early reversible impairment in respiratory function due to diaphragm dysfunction. Patients with a preoperative 1-s forced expired volume > 1.5, or 50% predicted, are unlikely to develop significant early respiratory complication.

We report the results of a questionnaire survey of manufacturing workplaces related to the lost-time frequency rates (LTFR) for Workers' Compensation claims. Six types of industry were chosen.' metal articles, plastic articles, grain products, textile manufacturing, printing, and automobile manufacturing. LTFR were standardized by type of industry. Stratifying simultaneously by number of employees and LTFR category, we sampled 718 workplaces. A mail questionnaire to labor and management representatives provided at least some information on 58%. Response rates were similar across LTFR categories, and telephone interviews of non-responders showed little difference in their replies from those obtained in completed questionnaires. A large number of variables were examined. Apart from statistical significance, we looked for consistency in trends across LTFR categories and in patterns for similar questions. Significant associations grouped into several areas. Lower LTFR were associated with: concrete demonstration by management of its concern for the workforce; greater involvement of workers in general decision-making; greater willingness of the Joint Health and Safety Committee to solve problems internally; and greater experience of the workforce. Variables that were not significant included profitability and financial performance. A final stepwise multiple regression explained 19% of the variance in LTFR, although this analysis suffered from several limitations.

We have determined the nucleotide sequence of a stress-inducible mouse Hsp70-encoding gene named hsp70A1. The gene encodes a 641-amino-acid protein whose deduced sequence is similar to those of other members of the HSP70 family. The 5' end (tsp) of a heat-inducible mRNA is 225 bp upstream from the start codon, and several consensus recognition sequences for transcription factors lie upstream from this tsp. There are 17 putative binding sites for heat-shock transcription factor (HSF), including three clusters of multiple binding sites. We show that this upstream region is sufficient to direct heat-inducible expression of a hsp70A1::cat hybrid gene in mouse and human cells.

Immunoglobulin heavy chain binding protein (BiP) is present in the lumen of the mammalian endoplasmic reticulum, where it associates transiently with a variety of newly synthesized secretory and membrane proteins or permanently with mutant proteins that are incorrectly folded. We describe a unique member of the Saccharomyces cerevisiae 70-kDa heat shock protein gene family (HSP70) that encodes a protein homologous to mammalian BiP. The DNA sequence contains a 2046-nucleotide open reading frame devoid of introns, and examination of the predicted amino acid sequence reveals features not found in most other yeast HSP70 proteins but which are present in BiP. Most notable are a 42-residue sequence at the N terminus that exhibits characteristics of a cleavable signal sequence and a C-terminal sequence, -His-Asp-Glu-Leu, that is involved in determining endoplasmic reticulum localization in yeast. The 5' flanking region of this gene contains two overlapping sequences between nucleotides -146 and -169 that closely resemble consensus heat shock elements. The yeast BiP gene is strongly heat shock-inducible, whereas the BiP genes in various other species are either weakly or non-heat-inducible. We demonstrate that a functional BiP gene is essential for vegetative growth. An evolutionary comparison of amino acid sequences of 34 HSP70 proteins from 17 species suggests that BiP genes share a common ancestor, which diverged from other HSP70 genes near the time when eukaryotes first appeared.

A 3.52-kilobase (kb) segment of Drosophila melanogaster DNA carrying the 2.15-kb transcribed sequence for the 70 000-dalton heat-shock protein (hsp70) and 1.14-kb of the 5' flanking sequence was inserted into an autonomously replicating chimeric plasmid and used to transform the yeast Saccharomyces cerevisiae. The Drosophila gene is efficiently transcribed in the transformed cells, yielding a transcript which is 21 nucleotides shorter than the normal Drosophila mRNA at the 5' end. Significant increases in the amount of Drosophila-specific RNA occur when the transformed cells are subjected to heat shock, indicating that the Drosophila gene is inducible in the yeast cells.

We have used cloned fragments from a Drosophila melanogaster hsp70 gene and a mouse hsp68 cDNA in recombinational screens of mouse genomic libraries. Using the mouse probe we have isolated two overlapping recombinant lambda phages comprising 22 kb of cloned DNA. Southern analysis has localized the homology with the Drosophila hsp70 coding region to a 2.2-kb fragment containing the mouse heat-shock gene. Insertion accompanying recombinational screening can disrupt interesting sequences; we have overcome this inconvenience by developing a simple one-step genetic selection for phage which have precisely excised the microplasmid probe.

Transcription of the mouse hsp68 and hsc70 genes in embryonal carcinoma cells, various embryonic and extraembryonic tissues, and some adult tissues has been assessed using cloned probes to the mouse hsp68 gene. The results from Northern blots showed that both F9 and P19 cells respond in the expected manner to a heat shock. Hsp68 expression was only detected in heat-induced F9 and P19 cells. Hsc70 transcripts were present in uninduced cells and their levels increased after induction. In adult tissues, the hsp68 gene was expressed constitutively in the kidney. A different hsp68-like transcript was detected at significant levels in adult testes. Constitutive expression of hsp68 was observed in both the placenta (beginning at Day 8.5) and yolk sac (beginning at Day 11.5). No hsp68 expression was detected in embryonic tissues until Day 15.5. Expression of the mouse hsp68 gene during embryogenesis suggests that it may play some role in development.

We used a cloned Drosophila melanogaster hsp70 gene to hybrid-select heat shock-induced mouse mRNA and showed that this mRNA encodes the major mouse heat shock protein. This result suggests that the sequence of the hsp70 gene(s) is highly conserved.

Heat shock induces the synthesis of a 70-kdalton protein in Escherichia coli, Drosophila, yeast, and mouse. We show that the genes for this heat-shock protein in mouse, yeast, and Drosophila share extensive sequence homology as determined by heteroduplex formation at different stringencies. We calculate that the heat-shock gene homology is 74% between yeast and Drosophila and 85% between mouse and Drosophila. The organization of the six copies of the Drosophila gene for the 70-kdalton heat-shock protein at two separate loci is summarized and evidence is presented that the yeast and mouse genomes each contain multiple copies of sequences related to the Drosophila gene for the 70-kdalton heat-shock protein. These results demonstrate that not only the sequence but also the repetitive organization of the major heat-shock genes is conserved.