Development of a core outcome set and outcome definitions for studies on uterus-sparing treatments of adenomyosis (COSAR): an international multistakeholder-modified Delphi consensus study.

STUDY QUESTION: What outcomes should be reported in all studies investigating uterus-sparing interventions for treating uterine adenomyosis? SUMMARY ANSWER: We identified 24 specific and 26 generic core outcomes in nine domains. WHAT IS KNOWN ALREADY: Research reporting adenomyosis treatment is not patient-centred and shows wide variation in outcome selection, definition, reporting and measurement of quality. STUDY DESIGN, SIZE, DURATION: An international consensus development process was performed between March and December 2021. Participants in round one were 150 healthcare professionals, 17 researchers and 334 individuals or partners with lived experience of adenomyosis from 48 high-, middle- and low-income countries. There were 291 participants in the second round. PARTICIPANTS/MATERIALS, SETTING, METHODS: Stakeholders included active researchers in the field, healthcare professionals involved in diagnosis and treatment, and people and their partners with lived experience of adenomyosis. The core component of the process was a 2-step modified Delphi electronic survey. The Steering Committee analysed the results and created the final core outcome set (COS) in a semi-structured meeting. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 241 outcomes was identified and distilled into a 'long list' of 71 potential outcomes. The final COS comprises 24 specific and 26 generic core outcomes across nine domains, including pain, uterine bleeding, reproductive outcomes, haematology, urinary system, life impact, delivery of care, adverse events and reporting items, all with definitions provided by the Steering Committee. Nineteen of these outcomes will apply only to certain study types. Although not included in the COS, the Steering Committee recommended that three health economic outcomes should be recorded. LIMITATIONS, REASONS FOR CAUTION: Patients from continents other than Europe were under-represented in this survey. A lack of translation of the survey might have limited the active participation of people in non-English speaking countries. Only 58% of participants returned to round two, but analysis did not indicate attrition bias. There is a significant lack of scientific evidence regarding which symptoms are caused by adenomyosis and when they are related to other co-existent disorders such as endometriosis. As future research provides more clarity, the appropriate review and revision of the COS will be necessary. WIDER IMPLICATIONS OF THE FINDINGS: Implementing this COS in future studies on the treatment of adenomyosis will improve the quality of reporting and aid evidence synthesis. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was received for this work. T.T. received a grant (grant number 2020083) from the South Eastern Norwegian Health Authority during the course of this work. T.T. receives personal fees from General Electrics and Medtronic for lectures on ultrasound. E.R.L. is the chairman of the Norwegian Endometriosis Association. M.G.M. is a consultant for Abbvie Inc and Myovant, receives research funding from AbbVie and is Chair of the Women's Health Research Collaborative. S.-W.G. is a board member of the Asian Society of Endometriosis and Adenomyosis, on the scientific advisory board of the endometriosis foundation of America, previous congress chair for the World Endometriosis Society, for none of which he received personal fees. E.S. received outside of this work grants for two multicentre trials on endometriosis from the National Institute for Health Research UK, the Rosetrees Trust, and the Barts and the London Charity, he is a member of the Medicines and Healthcare Products Regulatory Agency (MHRA), Medicines for Women's Health Expert Advisory Group, he is an ambassador for the World Endometriosis Society, and he received personal fees for lectures from Hologic, Olympus, Medtronic, Johnson & Johnson, Intuitive and Karl Storz. M.H. is member of the British Society for Gynaecological Endoscopy subcommittee. No other conflict of interest was declared. TRIAL REGISTRATION NUMBER: N/A.

Activation of RyR2 by class I kinase inhibitors.

BACKGROUND AND PURPOSE: Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP-binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload-induced Ca2+ release (SOICR), is a common mechanism underlying arrhythmia. We explored whether class I kinase inhibitors could modify the activity of RyR2 and trigger SOICR to determine if this contributes to the cardiotoxic nature of these compounds. EXPERIMENTAL APPROACH: The impact of class I and II kinase inhibitors on SOICR was studied in HEK293 cells and ventricular myocytes using single-cell Ca2+ imaging. A specific effect on RyR2 was confirmed using single channel recordings. Ventricular myocytes were also used to determine if drug-induced changes in SOICR could be reversed using anti-SOICR agents. KEY RESULTS: Class I kinase inhibitors increased the propensity of SOICR. Single channel recording showed that this was due to a specific effect on RyR2. Class II kinase inhibitors decreased the activity of RyR2 at the single channel level but had little effect on SOICR. The promotion of SOICR mediated by class I kinase inhibitors could be reversed using the anti-SOICR agent VK-II-86. CONCLUSIONS AND IMPLICATIONS: Part of the cardiotoxicity of class I kinase inhibitors can be assigned to their effect on RyR2 and increase in SOICR. Compounds with anti-SOICR activity may represent an improved treatment option for patients.

The SAGES Fundamental Use of Surgical Energy program (FUSE): history, development, and purpose.

BACKGROUND: Adverse events due to energy device use in surgical operating rooms are a daily occurrence. These occur at a rate of approximately 1-2 per 1000 operations. Hundreds of operating room fires occur each year in the United States, some causing severe injury and even mortality. The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) therefore created the first comprehensive educational curriculum on the safe use of surgical energy devices, called Fundamental Use of Surgical Energy (FUSE). This paper describes the history, development, and purpose of this important training program for all members of the operating room team. METHODS: The databases of SAGES and the FUSE committee as well as personal photographs and documents of members of the FUSE task force were used to establish a brief history of the FUSE program from its inception to its current status. RESULTS: The authors were able to detail all aspects of the history, development, and national as well as global implementation of the third SAGES Fundamentals Program FUSE. CONCLUSIONS: The written documentation of the making of FUSE is an important contribution to the history and mission of SAGES and allows the reader to understand the idea, concept, realization, and implementation of the only free online educational tool for physicians on energy devices available today. FUSE is the culmination of the SAGES efforts to recognize gaps in patient safety and develop state-of-the-art educational programs to address those gaps. It is the goal of the FUSE task force to ensure that general FUSE implementation becomes multinational, involving as many countries as possible.

The evidence base for healthcare related decision-making in Regional Health Authorities

OBJECTIVES: To evaluate the evidence base used in policy and healthcare decision making by the Regional Health Authorities in Trinidad. DESIGN AND METHODS: The study focused on the five Regional Health Authorities (RHAs) in Trinidad where senior administrative employees at each Regional Health Authority were purposively sampled and interviewed using a structured questionnaire. Responses were initially reviewed individually to determine types of evidence used within each RHA. All responses were secondly compared between the various RHAs. RESULTS: All RHAs participated; each had an observatory type unit which was responsible for data collection, collation and production of reports on an annual basis. Reports focused on the number of patients accessing services (e.g. specialist clinics and surgical procedures), patient demographics and patient access to health services. All RHAs had annual service agreements with the Ministry of Health which acted as a guide with targets and as a check on accountability of money spent. Decision making in each RHA was tiered by financial cap; most decisions were made by the Chief Executive Officer and/or Board of Directors within their caps; decisions requiring monetary investment over the RHA limit had to be approved by the Ministry of Health. CONCLUSION: This study revealed that RHAs had systems in place whereby they engaged in evidence-based practice utilising the Authority’s observatory data plus other information sources, ran trial periods and economic analyses for healthcare related decision making.

Hysteroscopic sterilization: 10-year retrospective analysis of worldwide pregnancy reports.

STUDY OBJECTIVE: To identify factors that might contribute to pregnancies reported after hysteroscopic sterilization worldwide. DESIGN: Retrospective review of commercial data compiled from the MAUDE database, medical literature, and manufacturer reports received during commercial distribution of hysteroscopic sterilization micro-inserts from 2001 through 2010 (Canadian Taskforce classification III descriptive study). MEASUREMENTS AND MAIN RESULTS: From 2001 through 2010, 497 305 hysteroscopic sterilization kits were distributed worldwide, and 748 pregnancies were reported, i.e., 0.15% of the estimated user population based on the number of distributed kits. The data were sufficient to enable analysis of 508 pregnancies for potential contributing factors and showed most to be associated with patient or physician noncompliance (n = 264) or misinterpreted confirmation tests (n = 212). Conceptions deemed to have occurred within 2 weeks of the procedure and therefore too early for detection were identified in 32 cases. CONCLUSION: Although there are limitations to the dataset and the study design is retrospective, it represents the largest body of cumulative hysteroscopic sterilization data available to date. Of the 748 pregnancies reported, it is apparent that some might have been prevented with greater patient and clinician attention to interim contraceptive use and counseling and with more rigorous evaluation and informed interpretation of the procedure confirmation tests. Although the estimated pregnancy rate based on such a dataset is likely an underestimation, it does suggest that the evaluable field performance of hysteroscopic sterilization micro-inserts is consistent with the labeled age-adjusted effectiveness of 99.74% at 5 years.

Swelling in the upper arm: the presentation and management of an isolated brachial artery aneurysm.

True aneurysms of the brachial artery are uncommon. We describe the presentation and surgical management of an isolated, brachial artery aneurysm in a 64-year-old woman. Excision of the aneurysm and long saphenous venous interposition grafting was performed with no postoperative complications and histology demonstrated true aneurysmal degeneration.

Healthcare issues of detainees in police custody in London, UK.

Little is known about the general healthcare needs of detainees in police custody. The aims of this study were to: determine the level of general health issues, diseases and/or pathology for detainees in police custody, and to determine how well those general health issues, diseases and/or pathology are being managed. This was done by a detailed analysis of healthcare issues of a cohort of detainees and reviewing intended and prescribed medication needs with current medication availability. In August 2007, a prospective detailed, anonymised, structured questionnaire survey was undertaken of 201 detainees in police custody in London, UK. Of these 83.6% consented to participate in the study. 85.1% of subjects were male; mean age was 33.9 years; 70.8% had English as a first language; 13.7% were of no fixed abode; 70.2% were registered with a general practitioner (primary care physician); 25% were already in contact with other healthcare teams; 7.1% had previously been sectioned under the Mental Health Act 1983; 16.7% had previously intentionally self-injured; 33.9% were dependent on heroin, 33.9% on crack cocaine; 25% on alcohol, 16.6% on benzodiazepines and 63.1% on cigarettes. 56% of subjects had active medical conditions; of those with active medical conditions 74% were prescribed medication for those medical conditions; only 3/70 had their medication available. 28/70 were not taking medication regularly, and many were not taking it at all. Three subjects who had deep vein thromboses were not taking their prescribed anticoagulants and six subjects with severe mental health issues were not taking their anti-psychotic medication. Mental health issues and depression predominated, but there was a very large range of mixed diseases and pathology. Asthma, epilepsy, diabetes, deep vein thrombosis, pulmonary embolism, hepatitis, and hypertension were all represented. The study has achieved its aims and has also shown that--in part because of the chaotic lifestyle of many detainees--appropriate care was not being rendered, thereby, putting both detainee, and potentially others coming into contact with them, at risk.

Pseudosclerodermatous triad of perniosis, pulp atrophy and 'parrot-beaked' clawing of the nails--a newly recognized syndrome of chronic crack cocaine use.

The number of people dependent on crack-cocaine in the UK has increased substantially in recent years. Some crack-cocaine users develop coarsening changes in the appearance of their hands after prolonged use of the drug. These changes have most often been recognized in females and include: (i) Perniosis with cold, numb hands, sometimes with perniotic hyperkeratosis over the knuckles.(ii) Finger pulp atrophy of the distal part of the pulps of some digits, especially the thumbs and index fingers.(iii) Claw-like curvature of the nails. As the distal pulp is lost, it can no longer splint the nail straight and so the nail curves, claw-like, and reminiscent of a parrot's beak as it clings to the new contour. As the pulp atrophy progresses, the nail eventually also becomes smaller.This triad may be due to ischemia consequent upon peripheral vasoconstriction induced by crack-cocaine. Early changes may resolve with abstinence. In the patients described the syndrome does not appear to be to related to intravenous drug usage. It may occur without concomitant use of heroin, whether smoked or via the intravenous route. The syndrome does not occur in all crack-cocaine users. It is hypothesized that those with a vasoreactive circulation (i.e., those with vasomotor instability/perniosis) are more susceptible to this reaction pattern. The syndrome consisting of the triad of perniosis, pulp atrophy and parrot-beaked clawing of the nails should alert the clinician to the possibility of prolonged crack-cocaine misuse.

Can we achieve international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding?

BACKGROUND: There is considerable worldwide confusion in the use of terminologies and definitions around the symptom of abnormal uterine bleeding (AUB), and these are leading increasingly to difficulties in setting up multinational clinical trials and in interpreting the results of studies undertaken in single centres. An international initiative was established to develop an agreement process to recommend clear, simple terminologies and definitions with the potential for wide acceptance. METHODS: After widespread consultation with relevant international and national organizations, journal editors and individuals, a modified Delphi process was developed to assess the current use of terminologies followed by a structured face-to-face meeting of 35 clinicians (mostly gynaecologists) and scientists in Washington. Focused small group discussions led to plenary assessment of concepts and recommendations using an electronic keypad voting system. RESULTS: There was almost universal agreement that poorly defined terms of classical origin used in differing ways in the English medical language should be discarded and that these should be replaced by simple, descriptive terms with clear definitions which have the potential to be understood by health professional and patient alike and which can be translated into most languages. The major recommendations were to replace terms such as menorrhagia, metrorrhagia, hypermenorrhoea and dysfunctional uterine bleeding. Suggestions for potentially suitable replacement terms and definitions are made. CONCLUSIONS: A simple terminology has been recommended for the description and definition of symptoms and signs of AUB. This manuscript should be a living document and should be part of an ongoing process with international medical and community debate. Classification of causes, investigations and cultural and quality of life issues should be part of the ongoing process.

Bilateral congenital diaphragmatic hernia.

Bilateral congenital diaphragmatic hernia (CDH) is a rare condition, with the literature suggesting a bleak prognosis. We describe a case of bilateral CDH that, despite confirming the challenges of diagnosis, demonstrates that the condition can have a favourable outcome.

Measurement of the flux of ultrahigh energy cosmic rays from monocular observations by the High Resolution Fly's Eye experiment.

We have measured the cosmic ray spectrum above 10(17.2) eV using the two air-fluorescence detectors of the High Resolution Fly's Eye observatory operating in monocular mode. We describe the detector, phototube, and atmospheric calibrations, as well as the analysis techniques for the two detectors. We fit the spectrum to a model consisting of galactic and extragalactic sources.

Antenatal counselling, resuscitation practices and attitudes among Australian neonatologists towards life support in extreme prematurity.

A questionnaire survey of Australian neonatologists was conducted to ascertain their antenatal counselling and resuscitation practices, and attitudes towards life support in the extremely preterm infant. This study showed that in antenatal parental counselling, whether a paediatrician was given the opportunity to participate depends on the gestation at the time of the threatened preterm delivery The counselling employed almost invariably covered mortality and morbidity. The obstetrician's opinion was considered to be of utmost importance. Both financial and moral obligations were found to be of little importance in counselling and resuscitation. Only one-third of institutions had guidelines for limiting resuscitation. The onus remained on the neonatologists concerning which infant to resuscitate, and the level of the resuscitation to be conducted. In Australia, resuscitation at birth was restricted to infants of 23 weeks' gestation or above, and neonatologists did not believe the legal system has a role to play in limiting or mandating resuscitation of extremely preterm infants. Neither were they concerned with the threat of litigation when they decide to limit resuscitation. The majority of neonatologists agreed with their institution's approach to life support in extremely preterm infants. One grey area was the question of withholding assisted feeding in an infant for which the decision to withdraw life support has been made. Australia lacked a current consensus policy on selective non-treatment. The establishment of national guidelines would be helpful to aid Australian obstetricians and neonatologists in their clinical practice.

Gas and air embolization during hysteroscopic electrosurgical vaporization: comparison of gas generation using bipolar and monopolar electrodes in an experimental model.

STUDY OBJECTIVE: To compare the composition of gases generated by bipolar hysteroscopic vaporizing electrodes using electrolyte-rich medium (normal saline) with those of monopolar vaporizing electrodes using nonelectrolytic medium (1.5% glycine). DESIGN: In vitro study (Canadian Task Force classification II-1). SETTING: Laboratory. INTERVENTION: Fresh morbid bovine cardiac muscle was fully immersed in normal saline for the bipolar vaporizing electrode and 1.5% glycine for the monopolar vaporizing electrode. Standard hysteroscopic electrodes were activated at usual and maximum power outputs from radiofrequency electrosurgical generators appropriate for each system. The gases generated were captured and analyzed by gas chromatography and fast Fourier transform. MEASUREMENTS AND MAIN RESULTS: Gaseous by-products of electrosurgical vaporization of test tissues largely consisted of hydrogen, carbon monoxide, and carbon dioxide. The composition of gases generated by hysteroscopic monopolar and bipolar electrodes in this laboratory model appear to be similar. CONCLUSION: These gases are all highly soluble in serum. This observation suggests that emboli of gaseous by-products of electrosurgery are unlikely to have an adverse impact on patients. On the other hand, air emboli, largely composed of relatively insoluble nitrogen, are more likely to result in clinically significant cardiopulmonary events.

Dysfunctional uterine bleeding: advances in diagnosis and treatment.

Dysfunctional uterine bleeding occurs during the reproductive years unrelated to structural uterine abnormalities. Ovulatory dysfunctional uterine bleeding occurs secondary to defects in local endometrial hemostasis; while anovulatory dysfunctional uterine bleeding is a systemic disorder, occurring secondary to endocrinologic, neurochemical, or pharmacologic mechanisms. Evaluation of patients with abnormal uterine bleeding and identifying those with dysfunctional uterine bleeding is achieved with a combination of the following: history; physical examination; and judicious use of laboratory evaluation, endometrial sampling and uterine imaging, with sonographic techniques and/or hysteroscopy. Coagulopathies should be considered as should the notion that intramural and subserosal myomas are unlikely to contribute to AUB. High-quality evidence suggests that medical therapy is frequently successful, and newer approaches, such as local delivery of progestins via intrauterine devices, appear to be particularly promising and devoid of systemic side effects. For those intolerant of medical therapy, and/or for whom fertility is no longer desired, a number of minimally invasive surgical options for hysterectomy now exist and are collectively termed endometrial ablation. Endometrial ablation may be performed with or without hysteroscopic guidance. There is an increasing body of evidence that suggests that nonhysteroscopic endometrial ablation may be at least as effective as hysteroscopic endometrial ablation, even when the hysteroscopic procedure is performed by experts.