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LL-D49194 alpha 1 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m2. One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D49194 alpha 1 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial. [ABSTRACT FROM AUTHOR]

A total of 15 patients with residual ovarian cancer confined to the peritoneal cavity after first-line systemic chemotherapy were treated with triethylene-thiophosphoramide (thioTEPA) in a phase I study. A total of 50 courses of thioTEPA were given intraperitoneally in doses ranging from 30 to 80 mg/m2. The dose limiting toxicity was myelosuppression, which occurred at 80 mg/m2 and was frequently prolonged. Short-lived nausea and vomiting was easily controlled, and there was no local toxicity. Three patients remain free of disease progression at 6, 6 and 12 months. ThioTEPA concentrations were measured by gas chromatography. Peritoneal fluid concentrations declined rapidly in a first-order fashion, with a half-life of 0.96 +/- 0.1 h. A mean of 93% of the drug was absorbed during the 4-h dwell time. Peak plasma levels were achieved 30-60 min after drug instillation and were substantially lower than corresponding peritoneal levels. A pharmacokinetic advantage for intraperitoneal delivery was detected for peak drug concentration (24.9 +/- 8.5) and AUC (9.2 +/- 4.8). Based on this study, the recommended dose for intraperitoneal thioTEPA is 60 mg/m2 every 3-4 weeks. However, the rapid absorption of this drug from the peritoneum, secondary to thioTEPA's small molecular weight and lipophilic nature, suggests that it has only a limited role in intraperitoneal therapy. [ABSTRACT FROM AUTHOR]

LY 195448 is a phenethanolamine that has shown anti-tumour activity in a range of murine tumour models, although its mechanism of action is unknown. Pre-clinical studies have indicated the absence of "standard" side effects such as myelosuppression and gastrointestinal toxicity. The present phase I trial was carried out in nine patients at doses ranging up to 133 mg/m2. The major toxicities up to that dose were mild, reversible hypotension, tachycardia and tremor. No haematological or biochemical toxicity was observed. Murine pharmacokinetics were assessed at a dose level that was effective in experimental tumours and compared with human pharmacokinetic parameters derived from this study. The results indicated the clinical possibility of reaching peak drug levels associated with experimental activity. However, no responses were seen at the doses used. This study was terminated prior to its completion due to an unexplained loss of activity against murine tumours since September 1987. No significant loss of the in vitro anti-mitotic activity originally reported by Boder et al. [3] was observed. Possible reasons for the apparent loss of in vivo activity have been intensively investigated, but no cause has been determined. Therefore, clinical trials with LY 195448 have been discontinued. [ABSTRACT FROM AUTHOR]

Se presenta un discurso del presidente del American Academy of Orthopaedic Surgeons, E. Anthony Rankin, MD. Empieza con la necesidad de la defensa en la configuración de la ayuda médica. Sigue con la importancia de la unidad profesional y la diversidad médica.

Back pain is a common problem in rheumatology clinics and has a wide differential diagnosis. Ten young patients are described with the syndrome of persistent back pain, severe enough to prevent sleep, and characteristically eased by sitting forwards, which accompanies malignant retroperitoneal lymphadenopathy. Spinal movements and x rays are typically normal. Repeated thorough examinations are required to detect superficial adenopathy or testicular swellings. Ultrasound scanning usually reveals the nodes, which can also be demonstrated by computed tomographic (CT) scanning. These young patients have a variety of cancers, many of which can be cured, so increased awareness of this syndrome could save lives. [ABSTRACT FROM PUBLISHER]

A combination of carboplatin, vincristine, methotrexate and bleomycin (COMB) was given to 29 patients with locally advanced, metastatic or recurrent cervical carcinoma. A total of 85 cycles of chemotherapy were given, with half of the patients receiving greater than 3 cycles. Both the response rate (32.1%) and the median duration of response (30 weeks) were relatively disappointing. Renal toxicity was minimal, but one-third of our patients experienced severe (WHO grades 3 and 4) nausea and vomiting. This combination showed little advantage over carboplatin used as a single agent. [ABSTRACT FROM AUTHOR]

Abstract Background Spontaneous reporting systems for adverse drug reactions (ADRs) are handicapped by under-reporting and limited detail on individual cases. We report an investigation from a local surveillance for serious adverse drug reactions associated with disease modifying anti-rheumatic drugs that was triggered by the occurrence of liver failure in two of our patients. Methods Serious ADR reports have been solicited from local clinicians by regular postcards over the past seven years. Patients', who had hepatotoxicity on sulfasalazine and met a definition of a serious ADR, were identified. Two clinicians reviewed structured case reports and assessed causality by consensus and by using a causality assessment instrument. The likely frequency of hepatotoxicity with sulfasalazine was estimated by making a series of conservative assumptions. Results Ten cases were identified: eight occurred during surveillance. Eight patients were hospitalised, two in hepatic failure – one died after a liver transplant. All but one event occurred within 6 weeks of treatment. Seven patients had a skin rash, three eosinophilia and one interstitial nephritis. Five patients were of Black British of African or Caribbean descent. Liver enzymes showed a hepatocellular pattern in four cases and a mixed pattern in six. Drug-related hepatotoxicity was judged probable or highly probable in 8 patients. The likely frequency of serious hepatotoxicity with sulfasalazine was estimated at 0.4% of treated patients. Conclusion Serious hepatotoxicity associated with sulfasalazine appears to be under-appreciated and intensive monitoring and vigilance in the first 6 weeks of treatment is especially important.

Presents a letter to the editor related to acute aseptic arthropathyon caused by Isotretinoin.

State water quality agencies are custodians of water quality management programs under the Clean Water Act of which the protection and restoration of biological integrity in surface waters is an integral goal. However, an inappropriate reliance on chemical/physical stressor and exposure data or administrative indicators in place of the directmeasurement of ecological response has led to an incomplete foundation for water resource management. As point sources have declined in significance, the consequences of this flawed foundation for dealing with the major limitations to biological integrity (nonpoint sources, habitat degradation) have become more apparent. The use of biocriteria in Ohio, for example, resulted in the identification of 50% more impairment than a water chemistry approach alone and other inconsistencies of a flawed monitoring foundation are illustrated in the national305(b) report statistics on waters monitored, aquatic life use attainment, and habitat degradation. Biological criteria (biocriteria) incorporates the broader concept of water resource integrity to supplement the roles of chemical and toxicological approaches and reduces thelikelihood of making overly optimistic estimates of aquatic life condition. A carefully conceived ambient monitoring approach comprised of biological, chemical, and physical measures ensures all relevant stressors to water resource integrity am identified and that the efficacy of administrative actions can be directly measured with environmental results. New multimetric indices, such as the IBI, ICI, and BIBI represent a significant advancement in aquatic resource characterization that have allowed the inclusion of biological information into many States water quality management programs. Ohio adopted numerical biocriteria in the Ohio water quality standards regulations in May 1990 and, through multiple aquatic life uses that reflect a continuum ofbiological condition, represents a tiered approach to water resourcemana [ABSTRACT FROM AUTHOR]

Objectives To examine the quality of transitional care in a paediatric and adult hospital by investigating (i) adherence to national transition guidance and (ii) whether implementation is associated with better patient/carer experiences. Methods A cross-sectional study was conducted in a UK paediatric hospital ( PH) and neighbouring adult hospital. Clinics completed a questionnaire to determine characteristics of their transitional care provision and invited patients aged 11-21 years and parents/carers to complete a questionnaire (' Mind the Gap') to assess their satisfaction. Results Twenty-three clinics participated. Fourteen (70%) reported delivering a transition programme, but only 5 (25%) indicated this was holistic (addressing medical, psychosocial and vocational issues). Participants included 457 young people and 330 parents, 71% and 88% respectively attending the PH. Ratings of current care were significantly lower than ratings of best care. These 'gap' scores were not excessive, although some participants were very dissatisfied. Better satisfaction was associated with attending clinics that provided transitional care, especially when defined as 'holistic' and youth-friendly. Conclusions Transition programmes that adhere to current guidance are associated with better satisfaction, but variations in provision suggest barriers to implementation. Attention is required to how youth-friendly transitional care is defined with particular reference to the specific clinic model. [ABSTRACT FROM AUTHOR]

A classical approach for evaluating normal tissue radiation response is to count the number of intestinal regenerating crypts in mouse histological images acquired after abdominal radiation. However, manual counting is time-consuming and subject to inter-observer variations. The goal of this study is to build a deep learning-based pipeline for automatically identifying intestinal regenerating crypts to facilitate high-throughput studies. Sixty-six healthy C57BL/6 female mice underwent 16 MeV whole abdominal electron irradiation. The small bowel was collected from each mouse 4 days post-irradiation, and 9 jejunal cross-sections from each were processed together in a single slide. The slides were stained with hematoxylin and eosin (H&E) and subsequently scanned (x20), providing one electronic histological image per mouse. Regenerating crypts, consisting of more than 10 basophilic crypt epithelial cells, were manually identified using point annotations in histological images. The pipeline was built to take the input of the image containing 9 cross sections and automatically identify the regenerating crypts on each cross section. It mainly consists of two components, cross section segmentation using intensity thresholding and morphological operations and crypt identification using a UNet. The dataset was randomly split into 46, 10, and 10 slide images for UNet training, validation, and testing. Each slide image was split into grid tiles with a voxel size of 200 × 200, and 40 × 40 square masks were placed with centers at manual point annotations on tiles with regenerating crypts. 5203/5198 tiles (w/wo crypt mask) were extracted to train UNet by minimizing dice loss. The mask probability map generated by the UNet was post-processed to identify the crypt position. Postprocessing hyperparameters were tuned using the validation dataset. The model accuracy was evaluated using the testing dataset by computing the mean absolute error (MAE) of the crypt number averaged across all cross sections. The number of regenerating crypts on testing cross sections ranges from 1 to 63. The testing cross-section-wise MAE achieved by the platform is 3.5±4.8 crypts. 81.25% of testing cross sections have absolute number differences less than or equal to 5 crypts. Our established deep learning-based pipeline can accurately count the number of regenerating crypts in mouse intestinal histological images. We have integrated it into an online platform that enables automatic crypt identification and allows users to interactively modify auto-identified crypt annotations. The acquired annotations from the platform will be used to finetune the deep learning model to achieve better identification performance. [ABSTRACT FROM AUTHOR]

Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression. [ABSTRACT FROM AUTHOR]

Objective: The objective of this review is to generate a national picture of the scope of nursing work and models of service delivery in Australian primary and secondary schools., Introduction: Schools are an important setting for providing health services to school-aged children and youth. Early intervention with identified health needs has the potential to improve health and educational outcomes across the life course. Additionally, many children and young people present with health issues requiring sophisticated management at school. Nurses have worked in Australian schools for more than a century, but there is a lack of clarity about the scope of nursing work and models of service delivery in Australian schools., Inclusion Criteria: The review will include papers describing the work of registered or enrolled nurses in primary and secondary Australian schools providing education to children aged 3-18 years, in urban, regional, and remote areas of all states and territories. Peer-reviewed, non-peer-reviewed, and gray literature, not limited by publication date or language, will be included., Methods: The review will be conducted in accordance with the JBI methodology for scoping reviews. Databases to be searched will include CINAHL, MEDLINE, PsycINFO (all via EBSCOhost), together with ERIC, Informit, and Google. Two authors will independently screen titles and abstracts, and extract data from included papers. Data will be analyzed by state/territory and by education sector (government/non-government) to generate a national picture. The findings will be reported in a narrative synthesis aligned with the review questions., Review Registration: Open Science Framework https://osf.io/6yqrm., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 JBI.)

Background: Rheumatoid arthritis (RA) is often preceded by symptomatic phases during which classification criteria are not fulfilled. The health burden of these "at-risk" stages is not well described. This study assessed health-related quality of life (HRQoL), function, fatigue and depression in newly presenting patients with clinically suspect arthralgia (CSA), unclassified arthritis (UA) or RA., Methods: Cross-sectional analysis of baseline Patient-Reported Outcome Measures (PROMs) was conducted in patients from the Birmingham Early Arthritis Cohort. HRQoL, function, depression and fatigue at presentation were assessed using EQ-5D, HAQ-DI, PHQ-9 and FACIT-F. PROMs were compared across CSA, UA and RA and with population averages from the HSE with descriptive statistics. Multivariate linear regression assessed associations between PROMs and clinical and sociodemographic variables., Results: Of 838 patients included in the analysis, 484 had RA, 200 had CSA and 154 had UA. Patients with RA reported worse outcomes for all PROMs than those with CSA or UA. However, "mean EQ-5D utilities were 0.65 (95%CI: 0.61 to 0.69) in CSA, 0.61 (0.56 to 0.66) in UA and 0.47 (0.44 to 0.50) in RA, which was lower than in general and older (≥ 65 years) background populations." In patients with CSA or UA, HRQoL was comparable to chronic conditions such as heart failure, severe COPD or mild angina. Higher BMI and older age (≥ 60 years) predicted worse depression (PHQ-9: -2.47 (-3.85 to -1.09), P < 0.001) and fatigue (FACIT-F: 5.05 (2.37 to 7.73), P < 0.001). Women were more likely to report worse function (HAQ-DI: 0.13 (0.03 to 0.21), P = 0.01) and fatigue (FACIT-F: -3.64 (-5.59 to -1.70), P < 0.001), and residents of more deprived areas experienced decreased function (HAQ-DI: 0.23 (0.10 to 0.36), P = 0.001), greater depression (PHQ-9: 1.89 (0.59 to 3.18), P = 0.004) and fatigue (FACIT-F: -2.60 (-5.11 to 0.09), P = 0.04). After adjustments for confounding factors, diagnostic category was not associated with PROMs, but disease activity and polypharmacy were associated with poorer performance across all PROMs., Conclusions: Patient-reported outcomes were associated with disease activity and sociodemographic characteristics. Patients presenting with RA reported a higher health burden than those with CSA or UA, however HRQoL in the pre-RA groups was significantly lower than population averages., (© 2024. The Author(s).)

Purpose: Volumetric-modulated arc therapy for total body irradiation (VMAT-TBI) is a novel radiotherapy technique that has been implemented at our institution. The purpose of this work is to investigate possible failure modes (FMs) in the treatment process and to develop a quality control (QC) program for VMAT-TBI following TG-100 guidelines., Methods: We formed a multidisciplinary team to map out the complete treatment process of VMAT-TBI following the AAPM TG-100 guidelines. This process map gives a visual representation of the VMAT-TBI workflow from the CT simulation, image processing, contouring, treatment planning, to treatment delivery. From the process map, potential FMs were identified. The occurrence (O), detectability (D), and severity of impact (S) of each FM were assigned according to scoring criteria (1-10) by the multidisciplinary team. A risk priority number (RPN) was calculated from average O, S, and D of each FM (RPN = O x S x D). High risk FMs were identified as 20% of the FMs having the highest RPN scores. After the FMEA analysis, fault-tree analysis (FTA) was performed for each major step of the treatment process to determine the effects of potential failures to the treatment outcome. Effective QC methods were identified to prevent the high risk failures and to improve the safety of the VMAT-TBI program., Results: We identified a total of 55 sub-processes and 128 FMs from the VMAT-TBI workflow. The top five high-risk FMs were: (1) Prescription and/or OAR constraints changed during planning and not communicated to the planner, (2) Patient moves or breathes too heavily during the upper body CT scan (3) Patient moves during the lower body CT scan, (4) Treatment planning system not calculating total body DVH metrics correctly for TBI, (5) Improper optimization criteria used or not sufficient optimization, resulting in suboptimal dose coverage, OAR sparing or excessive hotspots during treatment planning. Two FMs have average severity scores ≥8: Incorrect PTV subdivision/isocenter placement and Prescription and/or OAR constraints changed during planning and not communicated to the planner. Quality assurance and QC interventions including staff training, standard operating procedures, and quality checklists were implemented based on the FMEA and FTA., Conclusion: FM and effect analysis was performed to identify high-risk FMs of our VMAT-TBI program. FMEA and FTA were effective in identifying potential FMs and determining the best quality management (QM) measures to implement in the VMAT-TBI program., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Objectives: The value of US-defined tenosynovitis in predicting the persistence of inflammatory arthritis is not well described. In particular, the predictive utility of US-defined tenosynovitis of larger tendons is yet to be reported. We assessed the value of US-defined tenosynovitis alongside US-defined synovitis and clinical and serological variables in predicting persistent arthritis in an inception cohort of DMARD-naïve patients with early arthritis., Methods: One hundred and fifty DMARD-naïve patients with clinically apparent synovitis of one or more joints and a symptom duration of ≤3 months underwent baseline clinical, laboratory and US (of 19 bilateral joints and 16 bilateral tendon compartments) assessments. Outcomes were classified as persistent or resolving arthritis after 18 months' follow-up. The predictive value of US-defined tenosynovitis for persistent arthritis was compared with those of US-defined synovitis, and clinical and serological variables., Results: At 18 months, 99 patients (66%) had developed persistent arthritis and 51 patients (34%) had resolving disease. Multivariate logistic regression analysis showed that US-detected digit flexor tenosynovitis [odds ratio (OR): 6.6, 95% CI: 2.0 , 22.1, P = 0.002] provided independent predictive data for persistence over and above the presence of US-detected joint synovitis and RF antibodies. In the RF/ACPA-negative subcohort, US-defined digit flexor tenosynovitis remained a significant predictive variable (OR: 4.7, 95% CI: 1.4, 15.8, P = 0.012), even after adjusting for US-defined joint synovitis., Conclusion: US-defined tenosynovitis provided independent predictive data for the development of persistent arthritis. The predictive role of US-defined digit flexor tenosynovitis should be further assessed; investigators should consider including this tendon site as a candidate variable when designing imaging-based predictive algorithms for persistent inflammatory arthritis development., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

This study sought to assess the current state of screening for congenital cytomegalovirus infection in newborns among birth hospitals and newborn nurseries in the state of Massachusetts. A survey assessing hospital protocols for cytomegalovirus testing in newborns was distributed to all birth hospitals and newborn nurseries in Massachusetts from November 2020 to February 2021. 73.3% of hospitals responded to at least one survey question. Of these, fewer than half (48.5%) had any established approach for neonatal cytomegalovirus screening. Salivary polymerase chain reaction was the most common testing modality. Most hospitals did not perform confirmatory testing for positive test results. Most respondents (87.9%) did not know or did not answer how results of cCMV screening were reported to families and who was responsible for coordinating care for cCMV-infected infants. We conclude that congenital cytomegalovirus screening protocols are absent or incomplete in most Massachusetts birth hospitals and newborn nurseries. A cohesive strategy involving standardized education and screening guidelines is needed to reduce the incidence and burden of congenital cytomegalovirus disease on children and their families.