Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial.

OBJECTIVES: To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain. DESIGN: The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial. SETTING: 34 UK hospitals. PARTICIPANTS: 405 women of reproductive age undergoing conservative surgery for endometriosis. INTERVENTIONS: Participants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill. MAIN OUTCOME MEASURES: The primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment). RESULTS: 405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference -0.8, 95% confidence interval -5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). CONCLUSIONS: Postoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some. TRIAL REGISTRATION: ISRCTN registry ISRCTN97865475.

Circulating Monocytes Are Predictive and Responsive in Moderate-to-Severe Plaque Psoriasis Subjects Treated with Apremilast.

Monocytes play a critical role in the inflammation associated with psoriasis, and their abnormalities have been reported as biomarkers of cardiovascular event risk, a psoriasis comorbidity. Monocytic cells in chronic inflammatory disorders express elevated levels of cAMP phosphodiesterase. Restoring cAMP levels using the oral cAMP phosphodiesterase-4 inhibitor, apremilast, improves clinical outcomes for a subset of patients with psoriasis. We asked whether aberrant monocyte subsets or transcriptomic pathways can function as biomarkers of psoriasis endotypes that can predict enhanced clinical responses to cAMP phosphodiesterase inhibition. A 16-week open-label study of 22 patients with monocyte flow cytometric and transcriptomic analysis was performed. Subjects with elevated hyperadhesive monocyte doublets at baseline were more likely to be responders to apremilast (P < .0001); 82% of subjects with elevated hyperadhesive monocyte doublets achieved 50% reduction in PASI compared with 46% in those without elevated doublets. We observed a significant reduction in hyperadhesive monocyte-containing doublets and monocyte-platelet aggregates, suggesting an effect of apremilast on the adhesiveness of blood monocytes during chronic inflammation. Monocyte differentially expressed gene transcripts predictive of clinical response uncovered pharmacoendotypes with distinct patterns of nucleotide metabolism, energetics, and differentiation. Further study to understand the basis of drug responsiveness and to develop an apremilast psoriasis treatment algorithm using monocyte-refined gene expression is required to validate and become practical in clinical use, offering patients a test that personalizes their likelihood of clinical response.

LAparoscopic Versus Abdominal hysterectomy (LAVA): protocol of a randomised controlled trial.

INTRODUCTION: There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique. METHODS AND ANALYSIS: A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months' postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE. TRIAL REGISTRATION NUMBER: ISRCTN14566195.

Effectiveness of laparoscopic removal of isolated superficial peritoneal endometriosis for the management of chronic pelvic pain in women (ESPriT2): protocol for a multi-centre randomised controlled trial.

BACKGROUND: Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it is associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic laparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometriosis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically remove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the management of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to determine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain. METHODS: We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and cost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health Service Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected endometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or ovarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by excision or ablation or both, according to surgeons' preference) versus diagnostic laparoscopy alone. Randomisation with block-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they received until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to participants' preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, 6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Profile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard deviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are required to be randomised to detect an 8-point pain score difference. DISCUSSION: This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal of isolated SPE. TRIAL REGISTRATION: ISRCTN registry ISRCTN27244948. Registered 6 April 2021.

Abnormal thrombosis and neutrophil activation increase hospital-acquired sacral pressure injuries and morbidity in COVID-19 patients.

Hospitalized patients have an increased risk of developing hospital-acquired sacral pressure injury (HASPI). However, it is unknown whether SARS-CoV-2 infection affects HASPI development. To explore the role of SARS-CoV-2 infection in HASPI development, we conducted a single institution, multi-hospital, retrospective study of all patients hospitalized for ≥5 days from March 1, 2020 to December 31, 2020. Patient demographics, hospitalization information, ulcer characteristics, and 30-day-related morbidity were collected for all patients with HASPIs, and intact skin was collected from HASPI borders in a patient subset. We determined the incidence, disease course, and short-term morbidity of HASPIs in COVID-19(+) patients, and characterized the skin histopathology and tissue gene signatures associated with HASPIs in COVID-19 disease. COVID-19(+) patients had a 63% increased HASPI incidence rate, HASPIs of more severe ulcer stage (OR 2.0, p<0.001), and HASPIs more likely to require debridement (OR 3.1, p=0.04) compared to COVID-19(-) patients. Furthermore, COVID-19(+) patients with HASPIs had 2.2x increased odds of a more severe hospitalization course compared to COVID-19(+) patients without HASPIs. HASPI skin histology from COVID-19(+) patients predominantly showed thrombotic vasculopathy, with the number of thrombosed vessels being significantly greater than HASPIs from COVID-19(-) patients. Transcriptional signatures of a COVID-19(+) sample subset were enriched for innate immune responses, thrombosis, and neutrophil activation genes. Overall, our results suggest that immunologic dysregulation secondary to SARS-CoV-2 infection, including neutrophil dysfunction and abnormal thrombosis, may play a pathogenic role in development of HASPIs in patients with severe COVID-19.

Differential RNA Transcriptome in Ustekinumab Responders vs Non-Responders.

Despite numerous available psoriasis treatments, no "one size fits all" regimen provides complete disease control without side effects, logistical obstacles, and/or expense. Despite increasingly efficacious drugs, only 20-25% of patients treated with biologic therapies achieve completely clear skin (PASI 100) and even fewer achieve this if they have experienced failures of multiple biologics.

Vitamin D3 and deconvoluting a rash.

BACKGROUNDAdverse drug reactions are unpredictable immunologic events presenting frequent challenges to clinical management. Systemically administered cholecalciferol (vitamin D3) has immunomodulatory properties. In this randomized, double-blinded, placebo-controlled interventional trial of healthy human adults, we investigated the clinical and molecular immunomodulatory effects of a single high dose of oral vitamin D3 on an experimentally induced chemical rash.METHODSSkin inflammation was induced with topical nitrogen mustard (NM) in 28 participants. Participant-specific inflammatory responses to NM alone were characterized using clinical measures, serum studies, and skin tissue analysis over the next week. All participants underwent repeat NM exposure to the opposite arm and then received placebo or 200,000 IU cholecalciferol intervention. The complete rash reaction was followed by multi-omic analysis, clinical measures, and serum studies over 6 weeks.RESULTSCholecalciferol mitigated acute inflammation in all participants and achieved 6 weeks of durable responses. Integrative analysis of skin and blood identified an unexpected divergence in response severity to NM, corroborated by systemic neutrophilia and significant histopathologic and clinical differences. Multi-omic and pathway analyses revealed a 3-biomarker signature (CCL20, CCL2, CXCL8) unique to exaggerated responders that is suppressed by cholecalciferol and implicates IL-17 signaling involvement.CONCLUSIONHigh-dose systemic cholecalciferol may be an effective treatment for severe reactions to topical chemotherapy. Our findings have broad implications for cholecalciferol as an antiinflammatory intervention against the development of exaggerated immune responses.TRIAL REGISTRATIONclinicaltrials.gov (NCT02968446).FUNDINGNIH and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; grants U01AR064144, U01AR071168, P30 AR075049, U54 AR079795, and P30 AR039750 (CWRU)).

PROSPECT: 4- and 6-year follow-up of a randomised trial of surgery for vaginal prolapse.

INTRODUCTION AND HYPOTHESIS: Our aim was to compare the mid-term results of native tissue, biological xenograft and polypropylene mesh surgery for women with vaginal wall prolapse. METHODS: A total of 1348 women undergoing primary transvaginal repair of an anterior and/or posterior prolapse were recruited between January 2010 and August 2013 from 35 UK centres. They were randomised by remote allocation to native tissue surgery, biological xenograft or polypropylene mesh. We performed both 4- and 6-year follow-up using validated patient-reported outcome measures. RESULTS: At 4 and 6 years post-operation, there was no clinically important difference in Pelvic Organ Prolapse Symptom Score for any of the treatments. Using a strict composite outcome to assess functional cure at 6 years, we found no difference in cure among the three types of surgery. Half the women were cured at 6 years but only 10.3 to 12% of women had undergone further surgery for prolapse. However, 8.4% of women in the mesh group had undergone further surgery for mesh complications. There was no difference in the incidence of chronic pain or dyspareunia between groups. CONCLUSIONS: At the mid-term outcome of 6 years, there is no benefit from augmenting primary prolapse repairs with polypropylene mesh inlays or biological xenografts. There was no evidence that polypropylene mesh inlays caused greater pain or dyspareunia than native tissue repairs.

An Educational Video Demonstration of How to Prone a Critically Ill Intubated Patient.

Early in the coronavirus disease 2019 (COVID-19) pandemic, it was reported that prone position was beneficial for mechanically ventilated COVID-19 patients with acute respiratory distress syndrome (ARDS). However, for staff in some small and large hospitals, experience with this intervention was low. Select hospitals were able to assemble proning teams; but, as facilities began to experience staffing shortages, they found proning teams unsustainable, and less specialized staff needed to learn how to safely prone patients. Proning is a high-risk procedure-a lack of a standard approach can result in staff confusion and poor patient outcomes, including unintentional endotracheal tube (ET) loss, vascular access dislodgement, and skin breakdown. Given the acuity and high patient volume, translating a complex procedure into written policy may not be entirely effective. Critical care nurses, respiratory therapists, physical therapists, wound nurses, nurse practitioners, physician assistants, and medical doctors need to be prepared to safely perform this procedure for an acutely ill COVID-19 patient. Communication, teamwork, and multidisciplinary collaboration are critical for complication avoidance. Interventions to prevent tube and vascular access dislodgement, skin breakdown, and brachial plexus and soft tissue injury must be implemented during the procedure. Repositioning the patient in the prone position, as well as returning the patient to supine positioning, should be components of a comprehensive proning plan.

Cognition/Psychological Burden and Resilience in Cutaneous T-Cell Lymphoma and Psoriasis Patients: Real-Life Data and Implications for the Treatment.

Background: Psoriasis and cutaneous T-cell lymphoma (CTCL) expose patients to chronic inflammation as well as physical and psychological disabilities, but the impact of such alterations on cognitive function is unknown. Objective: This study is aimed at determining if CTCL and psoriasis impact cognitive functioning in relation to psychological and health-related quality of life (HR-QOL) status. Methods: A cross-sectional study was performed in an outpatient dermatology clinic of a university teaching hospital. Thirty-nine subjects with CTCL (N = 20) or psoriasis (N = 19) who met eligibility criteria were included. The cognitive domains of memory, attention and processing speed, and executive function were assessed with standard neuropsychological tests. Subjects were assessed for depression, anxiety, and HR-QOL (using the SKINDEX-29 questionnaire). Results: Study participants were CTCL and psoriasis subjects; cognitive impairment was found in the domain of memory in 17.9% subjects with CTCL or psoriasis. Lower scores on executive function tests were predicted by higher (worse HR-QOL) SKINDEX-29 functioning scores (p = 0.01). A higher estimated baseline intellectual functioning predicted lower scores (better HR-QOL) on the symptoms and functioning domains of SKINDEX-29 (p = 0.01 and 0.02, respectively) and a statistical trend (p = 0.07) for the emotion domain. Memory and acute anxiety were adversely impacted by shorter disease duration (p = 0.01 for both). Conclusions: Memory impairment may be associated comorbidity in CTCL and psoriasis. Subjects with stronger cognitive resources appear to cope better with health-related quality of life (HR-QOL) challenges.

Range-wide persistence of the endangered arroyo toad (Anaxyrus californicus) for 20+ years following a prolonged drought.

Prolonged drought due to climate change has negatively impacted amphibians in southern California, U.S.A. Due to the severity and length of the current drought, agencies and researchers had growing concern for the persistence of the arroyo toad (Anaxyrus californicus), an endangered endemic amphibian in this region. Range-wide surveys for this species had not been conducted for at least 20 years. In 2017-2020, we conducted collaborative surveys for arroyo toads at historical locations. We surveyed 88 of the 115 total sites having historical records and confirmed that the arroyo toad is currently extant in at least 61 of 88 sites and 20 of 25 historically occupied watersheds. We did not detect toads at almost a third of the surveyed sites but did detect toads at 18 of 19 specific sites delineated in the 1999 Recovery Plan to meet one of four downlisting criteria. Arroyo toads are estimated to live 7-8 years, making populations susceptible to prolonged drought. Drought is estimated to increase in frequency and duration with climate change. Mitigation strategies for drought impacts, invasive aquatic species, altered flow regimes, and other anthropogenic effects could be the most beneficial strategies for toad conservation and may also provide simultaneous benefits to several other native species that share the same habitat.

A Retrospective Characterization of Dexmedetomidine-Suspected Fever and Its Consequences in Adult Critically Ill Patients.

BACKGROUND: Current evidence for dexmedetomidine-suspected fever (DSF) is limited. Lack of recognition may lead to costly or potentially harmful interventions for critically ill patients. OBJECTIVE: The primary objective was to characterize escalations of care related to DSF. Secondary objectives were to describe the incidence, severity, and consequences associated with DSF. METHODS: A retrospective review was conducted in critically ill adults who developed fever ≥39°C within 12 h from initiation of dexmedetomidine, with resolution of fever to <39°C within 12 h after discontinuation. The primary outcome was percentage of patients who received an escalation of care due to fever. Secondary outcomes included the percentage of patients who developed a multidrug-resistant organism or Clostridium difficile infection. RESULTS: Eighteen of 3943 patients screened in 4099 encounters met criteria for DSF (0.4%). The majority were white (83.3%), male (66.7%), and underwent cardiac surgery (61.1%). Median (interquartile range [IQR]) time to fever onset and resolution were 5.5 (3.6-7.6) and 1.3 (1.0-2.9) h. Nine patients (50%) underwent infectious workup including antimicrobial initiation (n = 1, 5.6%), broadening of antimicrobials (n = 4, 22.2%), or culture collection (n = 9, 50%). Eleven patients (61.1%) underwent attempted temperature reduction. Twelve patients (66.7%) underwent diagnostic imaging. Incidence of multidrug-resistant organism and C. difficile infection were low (11.1 and 16.7% of fever patients, respectively). CONCLUSION AND RELEVANCE: Incidence of DSF was low and more common in cardiac surgery patients. Unrecognized DSF led to an escalation of care in most patients. Dexmedetomidine exposure should be considered as a potential cause of fever in critically ill adults.

Healthy myeloid-derived suppressor cells express the surface ectoenzyme Vanin-2 (VNN2).

Study of human monocytic Myeloid-Derived Suppressor cells Mo-MDSC (CD14+ HLA-DRneg/low) has been hampered by the lack of positive cell-surface markers. In order to identify positive markers for Mo-MDSC, we performed microarray analysis comparing Mo-MDSC cells from healthy subjects versus CD14+ HLA-DRhigh monocytes. We have identified the surface ectoenzyme Vanin-2(VNN2) protein as a novel biomarker highly-enriched in healthy subjects Mo-MDSC. Indeed, healthy subjects Mo-MDSC cells expressed 68 % VNN2, whereas only 9% VNN2 expression was observed on CD14+ HLA-DRhigh cells (n = 4 p < 0.01). The top 10 percent positive VNN2 monocytes expressed CD33 and CD11b while being negative for HLA-DR, CD3, CD15, CD19 and CD56, consistent with a Mo-MDSC phenotype. CD14+VNN2high monocytes were able to inhibit CD8 T cell proliferation comparably to traditional Mo-MDSC at 51 % and 48 % respectively. However, VNN2 expression on CD14+ monocytes from glioma patients was inversely correlated to their grade. CD14+VNN2high monocytes thus appear to mark a monocytic population similar to Mo-MDSC only in healthy subjects, which may be useful for tumor diagnoses.

Fabrication and Validation of an Economical, Programmable, Dual-Channel, Electronic Cigarette Aerosol Generator.

Vaping (inhalation of electronic cigarette-generated aerosol) is a public health concern. Due to recent spikes in adolescent use of electronic cigarettes (ECIGs) and vaping-induced illnesses, demand for scientific inquiry into the physiological effects of electronic cigarette (ECIG) aerosol has increased. For such studies, standardized and consistent aerosol production is required. Many labs generate aerosol by manually activating peristaltic pumps and ECIG devices simultaneously in a predefined manner. The tedium involved with this process (large puff number over time) and risk of error in keeping with puff topography (puff number, duration, interval) are less than optimal. Furthermore, excess puffing on an ECIG device results in battery depletion, reducing aerosol production, and ultimately, its chemical and physical nature. While commercial vaping machines are available, the cost of these machines is prohibitive to many labs. For these reasons, an economical and programmable ECIG aerosol generator, capable of generating aerosol from two atomizers simultaneously, was fabricated, and subsequently validated. Validation determinants include measurements of atomizer temperatures (inside and outside), electrical parameters (current, resistance and power) of the circuitry, aerosol particle distribution (particle counts and mass concentrations) and aerosol delivery (indexed by nicotine recovery), all during stressed conditions of four puffs/minute for 75 min (i.e., 300 puffs). Validation results indicate that the ECIG aerosol generator is better suited for experiments involving ≤100 puffs. Over 100 puffs, the amount of variation in the parameters measured tends to increase. Variations between channels are generally higher than variations within a channel. Despite significant variations in temperatures, electrical parameters, and aerosol particle distributions, both within and between channels, aerosol delivery remains remarkably stable for up to 300 puffs, yielding over 25% nicotine recovery for both channels. In conclusion, this programmable, dual-channel ECIG aerosol generator is not only affordable, but also allows the user to control puff topography and eliminate battery drain of ECIG devices. Consequently, this aerosol generator is valid, reliable, economical, capable of using a variety of E-liquids and amenable for use in a vast number of studies investigating the effects of ECIG-generated aerosol while utilizing a multitude of puffing regimens in a standardized manner.