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Objective: To compare intrauterine device (IUD) use at 6 months in women randomized to receive an intrauterine copper contraceptive 1 week compared with 1 month after medical abortion.Methods: We recruited women undergoing medical abortion with mifepristone and misoprostol and choosing the copper IUD for contraception. We randomly assigned participants to "immediate" insertion 1 week after mifepristone or "delayed" insertion 4-6 weeks later. We followed rates of IUD insertion, 6-month utilization, expulsion, removal, and pregnancy. Participants recorded bleeding in a diary for 4 weeks.Results: We randomized 156 participants. We inserted an IUD in 97% of participants in the immediate group and 76% in the delayed group (P<.001). At 6 months, 69% of participants in the immediate group used the IUD compared with 60% in the delayed group (P=.24). Expulsion rates were comparable; 12% (8 of 69) in the immediate group compared with 11% (7 of 65) in the delayed group. Removals occurred in 14% (10 of 69) of immediate and 8% (5 of 65) of delayed group participants (P=.21). Four pregnancies occurred in delayed group participants who did not return for IUD insertion (P=.09). The immediate and delayed groups reported a median of 20 and 19 bleeding or spotting days, respectively (P=.15). We detected no cases of serious infection, uterine perforation, or hemorrhage.Conclusion: Immediate insertion increased uptake of the IUD without increasing expulsions or bleeding.Clinical Trial Registration: Clinicaltrials.gov, www.clinialtrials.gov, .Level Of Evidence: I. [ABSTRACT FROM AUTHOR]

NuvaRing represents another useful contraceptive option for women. The vaginal administration confers benefits and women do not appear to dislike this route of hormone delivery. Efficacy and cycle control are the least comparable to conventional COCs and adverse events are minimal, though vaginal side effects are reported more commonly. Women may find that trying to insert the ring in the clinic will allay any concerns they have with regard to insertion and removal. [ABSTRACT FROM AUTHOR]

COVID-19 can cause severe respiratory failure, for which lung transplant (LTx) is a potentially lifesaving treatment. However, uncertainty still surrounds patient selection and timing of referral. Our study objective was to identify factors associated with recovery (weaning from ECMO and intensive care unit discharge) versus death of patients with severe COVID-19-related acute lung injury on Extracorporeal Membrane Oxygenation (ECMO) listed for lung transplantation. Retrospective review of all consecutive cases referred to our center and listed for LTx between July 1, 2020, to June 30, 2022. Patients were considered eligible for LTx in case they had shown no longitudinal evidence of lung recovery after at least 4 to 6 weeks had elapsed from the onset of severe COVID-19-related lung injury. Factors associated with recovery versus death were assessed. Twenty patients were included in the study: 4 underwent a LTx, 9 recovered, and 7 died. The median time from hospital admission to listing was 85.5 days [IQR 65.75, 140.25] and the median time on the transplant wait list was 25.5 days. Patients who recovered were younger (44 years [IQR 41,55] vs. 61 [IQR 49.5,65.5], P value=0.016). Time on ECMO was significantly shorter for those who recovered (59 days [IQR 53, 93] vs. 99 [IQR 83.5, 137.5], P value=0.044). Although the question regarding which patients are in a need for LTx remains unanswered, the present study informs on timing of consideration for LTx for patients with severe COVID-19-related lung injury. Based on our findings, we suggest delaying LTx consideration for 8-10 weeks from initiation of ECMO. Further, our experience demonstrates that current advances in management on ECMO allows prolonged support without significant complications in selected patients. [ABSTRACT FROM AUTHOR]

Objectives: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Due to the insufficient efficacy of antiarrhythmic drugs and their adverse side effects, there has been considerable interest in the interventional treatment of AF, including both catheter ablation and surgical ablation. Surgical ablation or the maze procedure is a treatment option for patients with AF undergoing concomitant or isolated cardiac surgery., Design: We performed a retrospective study of prospectively collected data to investigate short- and long-term outcomes of patients who underwent the surgical ablation of AF. Outcome variables included freedom from recurrent atrial arrhythmias and mortality at 1-, 3-, 5-, and 7-year follow-ups. We also identified risk factors for arrhythmia recurrence and mortality., Setting: Israel's largest university tertiary care center., Participants: The study population comprised 668 patients operated on between January 1, 2006, and June 30, 2022. All patient data were extracted from our departmental database., Interventions: Concomitant or stand-alone surgical AF ablation., Measurements and Main Results: The mean duration of follow-up was 106 ± 66.7 months. Freedom from AF was 97.6% (n = 615) and mortality was 3% (n = 20) at the 1-year follow-up, 95.3% (n = 574) and 6.1% (n = 45) at 3 years, 90.1% (n = 396) and 9.1% (n = 61) at 5 years, and 77.5% (n = 308) and 10.8% (n = 72) at 7 years. According to logistic regression analysis, age and female sex determined the 7-year freedom from AF, and risk factors for 7-year mortality included diabetes mellitus, age, and valve surgery., Conclusions: Surgical ablation had a high success rate, with freedom from recurrent atrial arrhythmia at 1-, 3-, 5-, and 7-year follow-ups. Age and female sex were factors determining the 5- and 7-year recurrence of AF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Trait and state physical fatigue (trait-PF and state-PF) negatively impact many people with multiple sclerosis (pwMS) but are challenging symptoms to measure. In this observational study, we explored the role of specific gait and autonomic nervous system (ANS) measures (i.e., heart rate, HR, r-r interval, R-R, HR variability, HRV) in trait-PF and state-PF., Methods: Forty-eight pwMS [42 ± 1.9 years, 65% female, EDSS 2 (IQR: 0-5.5)] completed the Timed Up and Go test (simple and with dual task, TUG-DT) and the 6-min walk test (6MWT). ANS measures were measured via a POLAR H10 strap. Gait was measured using inertial-measurement units (OPALs, APDM Inc). Trait-PF was evaluated via the Modified Fatigue Impact Scale (MFIS) motor component. State-PF was evaluated via a Visual Analog Scale (VAS) scale before and after the completion of the 6MWT. Multiple linear regression models identified trait-PF and state-PF predictors., Results: Both HR and gait metrics were associated with trait-PF and state-PF. HRV at rest was associated only with state-PF. In models based on the first 3 min of the 6MWT, double support (%) and cadence explained 47% of the trait-PF variance; % change in R-R explained 43% of the state-PF variance. Models based on resting R-R and TUG-DT explained 39% of the state-PF., Discussion: These findings demonstrate that specific gait measures better capture trait-PF, while ANS metrics better capture state-PF. To capture both physical fatigue aspects, the first 3 min of the 6MWT are sufficient. Alternatively, TUG-DT and ANS rest metrics can be used for state-PF prediction in pwMS when the 6MWT is not feasible., (© 2024. The Author(s).)

Severe respiratory failure caused by COVID-19 often requires mechanical ventilation, including extracorporeal membrane oxygenation (ECMO). In rare cases, lung transplantation (LTx) may be considered as a last resort. However, uncertainties remain about patient selection and optimal timing for referral and listing. This retrospective study analyzed patients with severe COVID-19 who were supported by veno-venous ECMO and listed for LTx between July 2020 and June 2022. Out of the 20 patients in the study population, four who underwent LTx were excluded. The clinical characteristics of the remaining 16 patients were compared, including nine who recovered and seven who died while awaiting LTx. The median duration from hospitalization to listing was 85.5 days, and the median duration on the waitlist was 25.5 days. Younger age was significantly associated with a higher likelihood of recovery without LTx after a median of 59 days on ECMO, compared to those who died at a median of 99 days. In patients with severe COVID-19-induced lung damage supported by ECMO, referral to LTx should be delayed for 8-10 weeks after ECMO initiation, particularly for younger patients who have a higher probability of spontaneous recovery and may not require LTx.

Background: Physical activity is lower in people with multiple sclerosis (pwMS) compared to healthy controls. Previous work focused on studying activity levels or activity volume, but studies of daily-living rest-activity fragmentation patterns, circadian rhythms, and fractal regulation in pwMS are limited. Based on findings in other cohorts, one could suggest that these aspects of daily-living physical activity will provide additional information about the health and well-being of pwMS. Therefore, here, we aimed to (1) identify which fragmentation, fractal, and circadian amplitude measures differ between pwMS and healthy controls, (2) evaluate the relationship between fragmentation, fractal, and circadian amplitude measures and disease severity, and (3) begin to evaluate the added value of those measures, as compared to more conventional measures of physical activity (e.g., mean signal vector magnitude (SVM). A global measure of the overall volume of physical activity)., Methods: 132 people with relapsing-remitting MS (47±11 yrs, 69.7% female, Expanded Disability Status Scale, EDSS, median (IQR): 3 (2-4)) and 90 healthy controls (46±11 yrs, 47.8% female) were asked to wear a 3D accelerometer on their lower back for 7 days. Rest-activity fragmentation, circadian amplitude, fractal regulation, and mean SVM metrics were extracted. PwMS and healthy controls were compared using independent samples t-tests and linear regression, including comparisons adjusted for mean SVM to control for the effect of physical activity volume. Spearman correlations between measures and logistic regressions were used to identify the clinical condition based on the measures that differed significantly after adjusting for SVM. All analyses included adjustments for demographic and clinical parameters (e.g., age, sex)., Results: Multiple measures of activity fragmentation significantly differed between pwMS and healthy controls, reflecting a more fragmented active behavior in pwMS. PwMS had a lower circadian rhythm amplitude, indicating a smaller amplitude in the circadian changes of daily activity, and weaker temporal correlations as based on the fractal analysis. When taking into account physical activity volume, one circadian amplitude measure and one fractal measure remained significantly different in pwMS and controls. Fragmentation measures and circadian amplitude measures were significantly associated with disability level as measured by the EDSS; the association with circadian amplitude remained significant, even after adjusting for the mean SVM., Conclusion: The physical activity patterns of pwMS differ from those of healthy individuals in rest-activity fragmentation, the amplitude of the circadian rhythm, and fractal regulation. Measures describing these aspects of activity provide information that is not captured in the total volume of physical activity and could, perhaps, augment the monitoring of disease progression and evaluation of the response to interventions., Competing Interests: Declaration of Competing Interest RT and NS are employees of Owlytics Healthcare Ltd., a company that develops and delivers patient monitoring tools. All of the other authors declare that they have no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Context: Buprenorphine is medication-assisted treatment for opioid use disorder. It is a controlled substance and most states limit the dispensing to a 30-day supply. Patients with opioid use disorder often have social determinants of health barriers that make it difficult to engage with the health system to obtain a new supply of buprenorphine every month. Telehealth can be used to reduce barriers to accessing care and improve continuity of care for patients receiving buprenorphine treatment., Objective: To assess the rates of patient continuity for patients receiving buprenorphine treatment via tele-health versus in-person in a primary care outpatient setting., Study Design: Review of patients receiving buprenorphine treatment for opioid use disorder and rates of continuity by visit type during a 2-year time period May 2019-May 2021., Dataset: EPIC electronic medical records from an urban university-affiliated ambulatory primary care practice in New Jersey., Population Studied: Patients scheduled for a visit in the outpatient primary care clinic. Approximately 69% were African American, 22% Hispanic, and 9% other. The majority were enrolled in Medicaid. 80% of patients faced one or more barriers to social determinants of health including transportation, housing, and economic stability., Intervention: Establishment and implementation of HIPAA compliant tele-health following approved state guidelines for buprenorphine prescribing via tele-health. Appointments were scheduled in-person or tele-health by patients' preference., Outcome Measures: Rates of continuity by visit type for patients receiving buprenorphine treatment during the study time period compared by chi-square., Results: Of the 487 patients seen via tele-health, 297 (61%) continued to receive follow up care. Of the 811 patients seen in-person, 400 (49.3%) continued to receive follow up care, p<.0001. The patients who did not continue to receive follow up care were lost to follow up despite attempts to reach patients to re-engage in care., Conclusions: Our study shows that rates of continuity of care are higher using tele-health for patients receiving medication assisted therapy for opioid use disorder. In an urban underserved population, tele-health can result in improved continuity of care for patients with opioid use disorder. Telehealth may reduce barriers to accessing care including transportation, work schedule, childcare, and other competing demands., Competing Interests: Authors report none., (2021, Annals of Family Medicine, Inc.)

Background: Mechanical shunting of cerebrospinal fluid is an effective treatment for hydrocephalus. Some studies suggest that bradycardia without hypertension may also be observed in ventriculoperitoneal (VP) shunt malfunction; however, in our experience, this is not a common presenting sign., Objective: The aim of this study was to evaluate whether bradycardia without hypertension was a common sign in patients presenting to the pediatric emergency department (ED) with a VP shunt malfunction., Methods: A retrospective observational study, from May 2006 to April 2015, which included a random sample of children admitted to the ED with clinical features suggestive of possible VP shunt malfunction. Control patients were defined as those who arrived at our ED with suspected VP shunt malfunction that was later ruled out on further workup., Results: A total of 65 patients were included in this study. A significantly greater number of patients with a confirmed shunt pathology presented with vomiting (P = 0.01) and lethargy/apathy (P = 0.01). In the control group, a significantly greater number of patients presented with fever (P = 0.004) and seizures (P = 0.02). The number of patients presenting with bradycardia was not significantly different between the shunt pathology and control groups (P > 0.05)., Conclusions: Bradycardia is not a common presentation in patients with VP shunt malfunction. Bradycardia is often recognized as a significant sign; however, it is one of the last presenting signs. Educating patients about the early signs must be considered as part of the treatment for VP shunt malfunction., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The use of a nation-wide, pediatricians online (PO) after-hours telemedicine service has been offered in Israel for more than a decade. We sought to compare PO visits with those to the primary care pediatrician (PCP)., Methods: This is a retrospective cross-sectional study using Israel's largest health care provider database. We included children aged 0 to 18 years using either PO or PCP between 2015 and 2018. We compared the baseline characteristics, matching by socioeconomic status, chronic illness, and diagnosis, and compared their admission rates, laboratory testing, and medication prescription., Results: During this study period there were 262,541 PO visits and a random 10% sample of PCP visits which yielded 1,813,103 visits. Users of PO were more likely to have a higher socioeconomic status (43% vs 28.9%), fever (13.3% vs 4.4%) and less likely to have acute respiratory conditions (8.8% vs 16.7%). Users of PO had higher rates of emergency department admissions (2.9% vs 0.4%), hospital admissions (0.9% vs 0.2%), and lower rates of laboratory testing (3.7% vs 7.4%) and medication prescription (42.0% vs 52.0%) within 24 hours. All differences were statistically significant (P < .005)., Conclusions: Our pediatric telemedicine service operating after-hours has been found to be feasible, and widely used, for a myriad of clinical conditions. Significant differences exist between PO and PCP visit characteristics and outcomes. However, it remained unclear whether these differences reflect the difference in the patient population or whether they are the result of the different clinical services. Further research is warranted to clarify this matter., (Copyright © 2021 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Researchers and clinicians use text messages to collect data with the advantage of real time capture when compared with standard data collection methods. This article reviews project setup and management for successfully collecting patient-reported data through text messages., Methods: We review our experience enrolling over 2600 participants in six clinical trials that used text messages to relay information or collect data. We also reviewed the literature on text messages used for repeated data collection. We classify recommendations according to common themes: the text message, the data submitted and the phone used., Results: We present lessons learned and discuss how to create text message content, select a data collection platform with practical features, manage the data thoughtfully and consistently, and work with patients, participants and their phones to protect privacy. Researchers and clinicians should design text messages to include short, simple prompts and answer choices. They should decide whether and when to send reminders if participants do not respond and set parameters regarding when and how often to contact patients for missing data. Data collection platforms send, receive, and store messages. They can validate responses and send error messages. Researchers should develop a protocol to append and correct data in order to improve consistency with data handling. At the time of enrollment, researchers should ensure that participants can receive and respond to messages. Researchers should address privacy concerns and plan for service interruptions by obtaining alternate participant contact information and providing participants with a backup data collection method., Conclusions: Careful planning and execution can reward clinicians and investigators with complete, timely and accurate data sets.

Background: The objective of the study is to determine whether higher pain thresholds are associated with better performance in long-distance runners., Methods: Seventy participants, divided into groups of fast and non-fast runners according to peak results in a 10km run. Main Outcome Measures, Cold pressor test., Results: Of the 70 participants, 28 were in the fastest group (less than 39 minutes in a 10km run) and 42 in the non-fast group. The faster group was characterized with older age (34.0±8.5 vs. 29.5±5.7, P=0.01), greater mean weekly running time (5.5 [0-17]) vs. 2 [0-10], P<0.001), and more years of running (10 [1.5-34.0] vs. 7 [0-20, P=0.05]). In a multivariable analysis longer cold pressor time was associated with faster 10Km run (OR 1.01, 95% CI 1.00-1.01)., Conclusions: It seems that higher pain thresholds play an important role in the superior ability of long distance runners.

Objective: To assess the impact of early versus late menstrual cycle insertion on bleeding/spotting in the 90 days following levonorgestrel (LNG) 13.5 mg intrauterine system (IUS) insertion., Study Design: In this observational study, participants received a LNG 13.5 mg IUS and provided 90 days of bleeding/spotting data by answering the following daily text: "Have you had no flow (0), spotting (1), or bleeding (2) today?" We dichotomized insertion timing as early (days 1-7 from last menstrual period) and late (remainder of menstrual cycle) and compared bleeding/spotting between the two groups in the 90- and 30-day reference periods. We used multivariate regression methods to study associations between cycle day at insertion, parity, historical bleeding, recent hormonal contraceptive use and bleeding/spotting., Results: In the 90-day dichotomous analysis (n=125), we found no differences in the number of days of bleeding/spotting, bleeding or spotting between the early and late insertion groups. In the 30-day dichotomous analysis (n=131), early insertion was associated with fewer days of bleeding than late insertion (5±3 vs. 7±4 days, p<.01). Recent hormonal contraceptive users experienced fewer days of bleeding than new users (5±4 vs. 7±3 days, p<.01). In the 90- and 30-day regression models, earlier insertion was associated with fewer days of bleeding (p=.02, p=.02). Recent contraceptive use was associated with fewer days of bleeding/spotting (90-day, p=.03) and fewer days of bleeding (30-day, p<.01). Nulliparity was associated with spotting (30-day, p=.04)., Conclusions: Early cycle insertion does not impact 90-day bleeding/spotting. Early cycle insertion and recent hormonal contraceptive use decrease 30-day bleeding., Implications: The LNG 13.5 mg IUS may be inserted throughout the menstrual cycle with small differences in bleeding patterns in the 30 but not the 90 days following insertion. Shared decision making should determine timing of insertion., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Hantavirus pulmonary syndrome (HPS) is a rare and sometimes fatal respiratory disease in humans. The infection is acquired mainly through inhalation of aerosolized rodent secretions which serves as the reservoir for the virus. HPS cases are mostly reported from the American continent. In this article we describe a case of fulminant HPS in a 47 years old man who had traveled with his family on vacation to the southwestern region of the United States. The patient was hospitalized one month after his return to Israel and the diagnosis of hantavirus infection (species Sin Nombre Virus), was performed on samples sent to the CDC's Viral Special Pathogens Branch. Clinicians should be aware of this special entity and consider HPS in the differential diagnosis of patients with respiratory failure and fever, when there is a history of travel to the endemic area.

Objectives: Our randomized trial compared early and delayed intrauterine device (IUD) insertion following medical abortion. In this planned substudy, we explore if endometrial thickness and initial IUD position were associated with IUD expulsion. We also describe IUD movement within the uterus during the 6 months after insertion., Study Design: We recruited women undergoing medical abortion and choosing the copper IUD for contraception (n=156). Participants were randomly assigned to early insertion 1 week after mifepristone or delayed insertion 4-6 weeks later. We measured endometrial thickness by transvaginal sonogram 1 week after abortion and IUD distance from the fundal aspect of the endometrial cavity three times: at insertion, 6-8 weeks later and at 6 months., Results: We analyzed endometrial thickness in 113 women, baseline IUD position in 114 women and IUD movement in 65 women. Women who expelled IUDs (n=15) had slightly thicker endometria (p=.007) and slightly lower baseline IUD positions (p=.03) than those who retained IUDs, but no clear cutoffs emerged in the receiver operating characteristic curve analysis. Retained IUDs commonly moved up and down throughout the 6 months (from 14 mm towards the fundus to 32 mm towards the cervix). Overall, retained IUDs moved a median of 2mm towards the cervix between insertion and exit (p<.0001)., Conclusions: After medical abortion, the risk of IUD expulsion increases with thicker endometria and lower baseline position. Since no clear cutoffs emerged in the analysis and expulsion remained uncommon even with thicker endometria, we do not recommend restricting IUD insertion based on ultrasound data., Implication: Copper T IUDs often move within the uterus without expelling. Expulsion is uncommon, and we do not recommend restricting IUD insertion based on ultrasound data., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This article reviews the two intrauterine devices (IUDs) available in the United States: the TCu380A, marketed as ParaGard (Duramed Pharmaceuticals, Inc. Pomona, NY), and the levonorgestrel-releasing intrauterine system (LNG-IUS), marketed as Mirena (Bayer HealthCare Pharmaceuticals, Inc., Wayne, NJ). The properties of the two devices are detailed, as well as noncontraceptive indications and appropriate candidates for use. Studies consistently demonstrate that the devices are safe, effective, and provide cost savings when compared with other reversible methods. The TCu380A may be used as postcoital contraception with close to 100% effectiveness. Menstrual blood loss is likely to increase with the TCu380A and decrease with the LNG-IUS. Reduction in menstrual blood loss and endometrial suppression make the LNG-IUS an increasingly popular treatment for menorrhagia, endometriosis, adenomyosis, and as an adjunct to estrogen therapy. IUDs may be inserted immediately after a first- or second-trimester abortion, immediately postpartum, and >or=4 weeks postpartum. Candidacy for IUDs has expanded, and includes nulliparous women, adolescents, and women with immunocompromised conditions including HIV., (Thieme Medical Publishers.)

Background: Increased levels of high density lipoprotein (over 60 mg/dl) are considered to be a negative risk factor for ischemic heart disease. However, some patients with high HDL still develop cardiovascular diseases., Objective: To explore why patients with very high HDL still suffer from cardiovascular diseases., Methods: We analyzed several risk factors, such as increased lipid peroxidation, hyperhomocysteinemia and increased release of inflammatory molecules, that could be related to the development of vascular disease in patients with high serum HDL levels. Patients with HDL cholesterol levels above 75 mg/dl were selected for this study and were separated into two groups based on the presence of atherosclerotic vascular disease, i.e., those with vascular disease (patients) and those without (controls)., Results: Plasma isolated from the patient group exhibited significantly increased lipid peroxidation by 21% and decreased total antioxidant status by 17%, but there were no differences regarding their serum or their paraoxonase activity. Moreover, both groups exhibited similar levels of serum C-reactive protein, fibrinogen and homocysteine, enabling us to eliminate these risk factors in the etiology of cardiovascular disease in the patient group., Conclusion: Increased oxidative stress could be one of the factors leading to cardiovascular diseases in patients with high serum HDL levels.

Objective: to report on prophylaxis provided to victims of sexual assault seen at hospital emergency departments in the United States., Methods: Secondary analysis was performed on data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) for 1994 to 1999. NHAMCS is a national probability sample of patient visits to US hospital emergency departments. Cases of sexual assault were identified using reason for visit, diagnostic, and injury codes. The medications provided for each case were examined., Results: We identified 160 cases of sexual assault from 137 822 emergency department visits. None of these victims received the full regimen of antibiotics for sexually transmitted infections (STIs) recommended by the Centers for Disease Control and Prevention. Antibiotics for gonorrhea and chlamydia, 2 of the more frequently diagnosed STIs, were provided for only 24.8% of adults and adolescents. No antibiotics were ordered in 62.5% of all cases or in 51.3% of cases of patients 12 years and older. Twenty-one percent of those eligible received emergency contraception. Human immunodeficiency virus prophylaxis was amongthe medications ordered in one 1999 case. Roughly estimated, more than 60000 victims of sexual assault who visit US emergency departments annually may not be offered antibiotic treatment for the prevention of STIs., Conclusion: Even when data limitations are taken into account, our results suggest that emergency department staff may not be routinely providing antibiotic therapy for the prevention of STIs or emergency contraception to victims of sexual assault. A comprehensive national standard of care is needed for the medical treatment of victims of sexual assault along with more training for health care providers.

We detected a strong correlation between the constitutive expression of IL-1 alpha and reduced tumorigenicity, using fibrosarcomas which produce the cytokine spontaneously (as an aberration of the transformation process) or upon gene transfer. In fibroblasts intracellular or membrane-associated IL-1 alpha is expressed, whereas the secreted form of the cytokine (IL-1 beta) is absent. Studies on the mechanisms of tumour regression of the IL-1 alpha producing fibroblastoid cell lines indicated that IL-1 alpha potentiates the development of tumour cell-specific CTLs, which are of importance for tumour eradication. It also appears that IL-1 alpha-induced enhanced helper T-cell activity provides auxiliary signals for the growth/development of CTLs. In addition, we observed a massive lymphocytic infiltrate in IL-1 alpha producing regressing tumours which ultimately replaces the tumour's mass. Non-adaptive effector cells, activated locally by IL-1 alpha expressing fibrosarcoma cells, were also shown to contribute, to some extent, to the eradication of IL-1 alpha expressing fibrosarcomas. Local IL-1 alpha expression potentiated antigen presentation, by the malignant fibroblasts as well as by tissue-resident antigen-presenting cells, and by this anti-tumour immune responses were further potentiated. Mice, in which IL-1 alpha producing tumours regressed, developed systemic immunity and rejected a challenge with a non IL-1 producing violent tumour cell line. It appears that endogenous IL-1 alpha, being a strong inducer of cytokine production, operates a whole cytokine cascade (such as IL-6, CSFs and prostaglandins). However, studies using clonal populations have indicated that IL-1 alpha is essential for fibrosarcoma eradication, whereas the other cytokines possibly amplify and sustain its action. We assume that most naturally occurring tumours are not constitutive IL-1 alpha producers, as it would be disadvantageous for the tumour to express a cytokine which increases its immunogenicity. However, IL-1 non-producing fibrosarcomas can be induced easily to express IL-1 transiently, by treatment with cytokines/LPS, and upon the induction of the cytokine they shift from progressor to regressor tumours. We also obtained positive immunotherapeutical effects when treating mice bearing IL-1 non-producing fibrosarcomas with cells from the same line induced in vitro to express IL-1 alpha. The results may shed light on a novel parameter affecting tumour-host interactions, namely cytokine expression by the tumorous cells, and may provide the basis for new immunotherapy protocols for fibrosarcoma management.

A direct correlation between the constitutive expression of IL-1 alpha and reduced tumorigenicity of fibrosarcomas was observed. This was established in fibrosarcoma cell lines which produce IL-1 alpha 'spontaneously', possibly as an aberration of oncogene-mediated transformation or upon IL-1 alpha gene transfer. In fibroblasts intracellular or membrane-associated IL-1 alpha is expressed, whereas the secreted form of the cytokine (IL-1 beta) is absent. Studies on the mechanisms of tumor regression of the IL-1 alpha-positive fibroblastoid cell lines indicated that IL-1 alpha potentiates the development of tumor cell-specific CTLs, which are of importance for tumor eradication. Thus, IL-1 alpha induces enhanced helper T cell activity which provides auxiliary signals for the growth/development of CTLs. Non-adaptive effector cells, activated locally by IL-1 alpha-expressing fibrosarcoma cells, also contribute to the eradication of IL-1 alpha-expressing fibrosarcomas. Local IL-1 alpha expression potentiated antigen presentation, by the malignant fibroblasts as well as by tissue-resident antigen-presenting cells, thus further potentiating anti-tumor immune responses. Mice, in which IL-1 alpha-producing tumors were regressed, developed an immune memory and rejected a challenge with an IL-1 non-producing violent tumor cell line. Endogenous IL-1 alpha activates a cytokine cascade (i.e., IL-6, CSF), produced by the malignant cells and possibly also by stromal cells. However, IL-1 alpha expression is essential for fibrosarcoma eradication, while other cytokines possibly amplify and sustain its action.(ABSTRACT TRUNCATED AT 250 WORDS)

In the present study we report on novel immunoregulatory functions lately attributed to fibroblasts, namely participation in cellular immune responses in connective tissues, by generation of pro-inflammatory cytokines and by presenting antigens to proliferating T cells. In order to execute immunoregulatory functions, the fibroblast has to be activated by signals abundant at inflammatory sites, i.e., cytokines and bacterial products. It was demonstrated that such immune-activated fibroblasts are able to generate a variety of cytokines such as interleukin-1 (IL-1), IL-6, colony stimulating factors (CSFs) as well as prostaglandins. The array of cytokines generated by immune-activated fibroblasts is determined by the stimulant and is controlled at multiple regulatory levels, such as transcription, translation, post-translational modifications, compartmentalization within the producing cell as well as the timing of expression. Some oncogene-transformed fibroblastoid cells lines were shown to constitutively generate IL-1 (and not IL-1 beta), as evidenced by the continuous expression of specific mRNA and biological activity of the cytokine, associated to the cell membrane or located in the cytosol. When these IL-2 producing cell lines were injected into mice, they failed to generate established tumors or regressed following initial growth, possibly due to mounting the host anti-tumor specific immune responses in which cytotoxic lymphocytes (CTLs) predominate. In contrast, IL-1 non-producing tumor cell lines induced progressive tumors which ultimately killed the animals. However, IL-1 non-producing fibroblastoid cell lines shifted from an in vivo progressive to a regressive phenotype, following immune activation of the malignant cells in vitro with cytokines/LPS. Similarly, primary immune-activated fibroblasts also induced tumor regression, mediated by anti-tumor specific immune responses, when the fibroblasts were injected into the vicinity of the tumor. Thus, the importance of activated stromal cells on tumor development was emphasized. This situation is relevant to the development of malignancies, as tumor growth is often accompanied by a local inflammatory response. Thus, the induction of IL-1 and other pro-inflammatory cytokines expression by the malignant cells or by stromal cells, in the vicinity of the tumor, might be efficient for tumor eradication. These findings should serve as a basis for development of novel immunotherapeutical strategies for the eradication of solid tumors.