Trial Forge Guidance 4: a guideline for reporting the results of randomised Studies Within A Trial (SWATs).

BACKGROUND: Evidence to support decisions on trial processes is minimal. One way to generate this evidence is to use a Study Within A Trial (SWAT) to test trial processes or explore methodological uncertainties. SWAT evidence relies on replication to ensure sufficient power and broad applicability of findings. Prompt reporting is therefore essential; however, SWAT publications are often the first to be abandoned in the face of other time pressures. Reporting guidance for embedded methodology trials does exist but is not widely used. We sought therefore to build on these guidelines to develop a straightforward, concise reporting standard, which remains adherent to the CONSORT guideline. METHODS: An iterative process was used to develop the guideline. This included initial meetings with key stakeholders, development of an initial guideline, pilot testing of draft guidelines, further iteration and pilot testing, and finalisation of the guideline. RESULTS: We developed a reporting guideline applicable to randomised SWATs, including replications of previous evaluations. The guideline follows the Consolidated Standards for Reporting Trials (CONSORT) statement and provides example text to ensure ease and clarity of reporting across all domains. CONCLUSIONS: The SWAT reporting guideline will aid authors, reviewers, and journal editors to produce and review clear, structured reports of randomised SWATs, whilst also adhering to the CONSORT guideline. TRIAL REGISTRATION: EQUATOR Network - Guidelines Under Development ( https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-clinical-trials/#SWAT ). Registered on 25 March 2021.

Expression of TRPM8 in sheep reproductive tissues and brain areas important for the expression of reproductive behavior.

The Transient Receptor Potential Melastatin 8 (TRPM8) channel is a temperature-sensitive, calcium permeable ion channel and purported testosterone receptor. To determine how the hormone environment influences the expression of TRPM8 in gonadal tissue and areas of the brain important for reproduction, tissue from western white-faced cross-bred ewes, rams, and gonadectomized males (wethers; n = 6 per group) approximately 6 mo of age were collected. TRPM8 mRNA expression was greater (P = 0.01) in prostate of rams than wethers. Testes had greater (P = 0.004) expression of TRPM8 mRNA than the ovary. Differences in protein expression was similar with the testes having greater (P = 0.007) TRPM8 protein than the ovary. Protein expression did not differ (P = 0.6) in the prostate due to presence (ram) or absence (wether) of the testes. In the brain, TRPM8 varied in the amygdala with rams tending (P = 0.07) to express more mRNA which was reflected in greater (P = 0.04) number of neurons staining positive for TRPM8 in the central amygdala. Differences among ewes and wethers were not detected. This pattern was not observed (P ≥ 0.16) in the hypothalamus or olfactory bulb. To determine if TRPM8 was associated with the expression of ram sexual behavior, brains from rams categorized as high (n = 4) or low (n = 3) sexual activity were collected and blocked. Presence of TRPM8 channels was verified in the amygdala and hypothalamus of rams but was absent in the ventral tegmental area. Numbers of neurons staining positive for TRPM8 did not differ by expression of sexual behavior (P ≥ 0.2) in any area quantified. While expression of TRPM8 is more robust in tissues from intact males, expression of the channel does not appear to be important in the expression of sexual behavior.

Prophylaxis is the new standard of care in patients with haemophilia.

Randomised controlled clinical trial evidence on prophylaxis as optimal care for patients with haemophilia was generated more than a decade ago. However, this knowledge has not translated into clinical practice in South Africa (SA) owing to many barriers to prophylaxis. These include the high treatment burden imposed by prophylaxis (frequent injections two to four times a week), the need for intravenous access to administer replacement clotting factor therapies, and the higher volume of clotting factor required compared with episodic treatment. The recently introduced non-factor therapies in haemophilia care have addressed many of these barriers. For example, emicizumab, which is currently the only globally approved non-factor therapy, can be administered subcutaneously less frequently (weekly, fortnightly or every 4 weeks) and has led to global adoption of prophylaxis as the standard of care in haemophilia by the bleeding disorders community. Haemophilia A is the most prevalent clotting factor deficiency in SA, with >2 000 people diagnosed to date. However, only a few of these patients are currently on prophylaxis. In this 'In Practice' article, we review the rationale for prophylaxis, outline its goals and benefits, and provide evidence-based guidance on which haemophilia patients should be prioritised for emicizumab prophylaxis. This consensus guidance facilitates the adoption of prophylaxis as a national policy and the new standard of care in haemophilia in SA.

Fetal heart rate mirrors maternal temperature during posterior fossa craniotomy: a case report.

While it is well known that maternal temperature affects fetal heart rate, the exact relationship is not well described. The circumstances accompanying most cases of maternal hypothermia and rewarming (e.g. a drowning event) have precluded a precise quantitative description of this relationship. We describe hypothermia and controlled rewarming during resection of a maternal brain stem tumor in the early third trimester. Continuous electronic fetal heart rate and core temperature monitoring demonstrated a near linear relationship during the development of hypothermia and rewarming. Recognition of the close relationship between maternal temperature and fetal heart rate can help safeguard maternal and fetal health, and prevent unnecessary delivery during non-obstetric surgery in pregnancy.

Determining sample size for progression criteria for pragmatic pilot RCTs: the hypothesis test strikes back!

BACKGROUND: The current CONSORT guidelines for reporting pilot trials do not recommend hypothesis testing of clinical outcomes on the basis that a pilot trial is under-powered to detect such differences and this is the aim of the main trial. It states that primary evaluation should focus on descriptive analysis of feasibility/process outcomes (e.g. recruitment, adherence, treatment fidelity). Whilst the argument for not testing clinical outcomes is justifiable, the same does not necessarily apply to feasibility/process outcomes, where differences may be large and detectable with small samples. Moreover, there remains much ambiguity around sample size for pilot trials. METHODS: Many pilot trials adopt a 'traffic light' system for evaluating progression to the main trial determined by a set of criteria set up a priori. We construct a hypothesis testing approach for binary feasibility outcomes focused around this system that tests against being in the RED zone (unacceptable outcome) based on an expectation of being in the GREEN zone (acceptable outcome) and choose the sample size to give high power to reject being in the RED zone if the GREEN zone holds true. Pilot point estimates falling in the RED zone will be statistically non-significant and in the GREEN zone will be significant; the AMBER zone designates potentially acceptable outcome and statistical tests may be significant or non-significant. RESULTS: For example, in relation to treatment fidelity, if we assume the upper boundary of the RED zone is 50% and the lower boundary of the GREEN zone is 75% (designating unacceptable and acceptable treatment fidelity, respectively), the sample size required for analysis given 90% power and one-sided 5% alpha would be around n = 34 (intervention group alone). Observed treatment fidelity in the range of 0-17 participants (0-50%) will fall into the RED zone and be statistically non-significant, 18-25 (51-74%) fall into AMBER and may or may not be significant and 26-34 (75-100%) fall into GREEN and will be significant indicating acceptable fidelity. DISCUSSION: In general, several key process outcomes are assessed for progression to a main trial; a composite approach would require appraising the rules of progression across all these outcomes. This methodology provides a formal framework for hypothesis testing and sample size indication around process outcome evaluation for pilot RCTs.

Understanding the complexities of unexplained stillbirth in sub-Saharan Africa: a mixed-methods study.

OBJECTIVE: To understand the complexities surrounding unexplained stillbirth for the development and implementation of culturally acceptable interventions to underpin care in Tanzania and Zambia. DESIGN: Mixed-methods study. SETTING: Tertiary, secondary and primary care facilities in Mansa, Zambia, and Mwanza, Tanzania. SAMPLE: Quantitative: 1997 women giving birth at two tertiary care facilities (one in each country). Qualitative: 48 women and 19 partners from tertiary, secondary and primary care facilities. METHODS: Case review using data from a target of 2000 consecutive case records. Qualitative interviews with a purposive sample of women and partners, using a grounded theory approach. RESULTS: A total of 261 stillbirths were recorded, with a rate of 16% in Tanzania and 10% in Zambia, which is higher than the previous estimates of 2.24 and 2.09%, respectively, for those countries. Women in both countries who reported a previous stillbirth were more likely to have stillbirth (RR 1.86, 95% CI 1.23-2.81). The cause of death was unexplained in 28% of cases. Qualitative findings indicated that not knowing what caused the baby to be stillborn prevented women from grieving. This was compounded by the poor communication skills of health professionals, who displayed little empathy and skill when counselling bereaved families. CONCLUSIONS: The stillbirth risk in both facilities was far higher than the risk recorded from national data, with women reporting a previous stillbirth being at higher risk. Women want to know the cause of stillbirth and an exploration of appropriate investigations in this setting is required. Providing health professionals with support and continuing training is key to improving the experiences of women and future care. TWEETABLE ABSTRACT: Stillbirths receive little investigation and are often unexplained. Communication with women about the death of their baby is limited.

Efficacy and safety of HAT1 compared with calcipotriol in the treatment of patients with mild to moderate chronic plaque psoriasis: results from an open-label randomized comparative pilot clinical study.

Psoriasis is commonly treated with topical corticosteroids, oral cytotoxic drugs and biologic agents, which can be associated with significant adverse effects (AEs), high cost and response attenuation. Additionally, patients often use alternative therapies ad hoc, which can be challenging to integrate into a treatment regimen, owing to a lack of adequately powered controlled trials assessing efficacy and safety. We developed a novel topical botanical complex, herbal anti-inflammatory treatment (HAT1), through extensive preclinical in vitro and in vivo modelling to define key mechanisms of action and clinical potential. To assess the efficacy and safety of HAT1 in psoriasis, we performed a 10-week, open-label, pilot clinical trial comparing topical treatment of HAT1 with calcipotriol 0.005% in adult patients with mild to moderate psoriasis. Primary and secondary endpoints included the percentage of patients obtaining improvement of ≥ 75% in Psoriasis Area and Severity Index (PASI 75), Physician's Global Assessment (PGA) response, and evaluation of tolerability and safety of HAT1. In the HAT1 arm, 85.7% of study patients reached PASI 75 compared with 21.4% in the calcipotriol comparator group. Additionally, 78.6% of patients in the HAT1 arm achieved a 'clear' or 'minimal' PGA response. HAT1 was well tolerated, with no AEs observed throughout the trial. These results suggest that HAT1 reduces psoriasis disease activity in a clinically relevant manner. Ongoing studies, including well-powered, double-blind, randomized controlled trials will be required to assess the potential of HAT1 in psoriasis.

Author Correction: LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Home therapy for inherited bleeding disorders in South Africa: Results of a modified Delphi consensus process.

BACKGROUND: Optimal care of patients with inherited bleeding disorders requires that bleeding episodes are treated early, or still better prevented, through extension of patient care beyond hospital-based treatment to home-based therapy. In South Africa (SA), adoption of home therapy is variable, in part owing to lack of consensus among healthcare providers on what constitutes home therapy, which patients should be candidates for it, how it should be monitored, and what the barriers to home therapy are. OBJECTIVES: To conduct a modified Delphi process in order to establish consensus on home therapy among haemophilia healthcare providers in SA. METHODS: Treaters experienced in haemophilia care were invited to participate in a consensus-seeking process conducted in three rounds. In round 1, provisional statements around home therapy were formulated as questions and collated in a structured list. In rounds 2 and 3, evolving versions of the questionnaire were administered to participants. Consensus was defined as ≥70% agreement among the participants. RESULTS: The panel composition included an equal number of physicians and non-physicians. The participation rate was 100% through all three consensus rounds. The group reached consensus for 92% of the statements. Consensus of 100% was reached on starting home therapy in paediatric patients, requiring all patients on home therapy to sign informed consent and indemnity, and providing round-the-clock support for patients on home therapy. CONCLUSIONS: The home therapy consensus statements in this report have the potential to translate to policy on home therapy and to guide the initiation, practice and evaluation of home therapy programmes in SA.

LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer.

Complex regulatory networks control epithelial-to-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs. LSD1 phosphorylation at serine-111 (LSD1-s111p) by chromatin anchored protein kinase C-theta (PKC-θ), is critical for its demethylase and EMT promoting activity and LSD1-s111p is enriched in chemoresistant cells in vivo. LSD1 couples to PKC-θ on the mesenchymal gene epigenetic template promotes LSD1-mediated gene induction. In vivo, chemotherapy reduced tumour volume, and when combined with an LSD1 inhibitor, abrogated the mesenchymal signature and promoted an innate, M1 macrophage-like tumouricidal immune response. Circulating tumour cells (CTCs) from metastatic breast cancer (MBC) patients were enriched with LSD1 and pharmacological blockade of LSD1 suppressed the mesenchymal and stem-like signature in these patient-derived CTCs. Overall, LSD1 inhibition may serve as a promising epigenetic adjuvant therapy to subvert its pleiotropic roles in breast cancer progression and treatment resistance.

The effects of supervised exercise training 12-24 months after bariatric surgery on physical function and body composition: a randomised controlled trial.

BACKGROUND: Bariatric surgery is effective for the treatment of stage II and III obesity and its related diseases, although increasing evidence is showing weight regain ~12-24 months postsurgery. Weight regain increases the risk of physical function decline, which negatively affects an individual's ability to undertake activities of daily living. The study assessed the effects of a 12-week supervised exercise intervention on physical function and body composition in patients between 12 and 24 months post bariatric surgery. METHODS: Twenty-four inactive adult bariatric surgery patients whose body mass index remained ⩾30 kg m2 12 to 24 months post surgery were randomised to an exercise intervention (n=12) or control group (n=12). Supervised exercise consisted of three 60-min gym sessions per week of moderate intensity aerobic and resistance training for 12 weeks. Control participants received usual care. The incremental shuttle walk test (ISWT) was used to assess functional walking performance after the 12-week exercise intervention, and at 24 weeks follow-up. Measures of anthropometric, physical activity, cardiovascular and psychological outcomes were also examined. Using an intention-to-treat protocol, independent t-tests were used to compare outcome measures between groups. RESULTS: Significant improvements in the exercise group were observed for the ISWT, body composition, physical function, cardiovascular and self-efficacy measures from baseline to 12 weeks. A large baseline to 12-week change was observed for the ISWT (exercise: 325.00±117.28 m; control: 355.00±80.62 m, P<0.001). The exercise group at 24 weeks recorded an overall mean improvement of 143.3±86.6 m and the control group recorded a reduction of -32.50±75.93 m. Findings show a 5.6 kg difference between groups in body mass change from baseline to 24 weeks favouring the exercise group. CONCLUSIONS: A 12-week supervised exercise intervention led to significant improvements in body mass and functional walking ability post intervention, with further improvements at the 24-week follow-up.

What's trending now? An analysis of trends in internet searches for labor epidurals.

BACKGROUND: The study aim was to investigate internet use for obtaining information about epidurals for labor and delivery. METHODS: Google Trends for US data was queried from 2004 to 2015 to find the most common searches and determine temporal trends. The Google Trends query used the term [epidural] and evaluated changes in search trends over time. Search comparisons were made for each year from 2004 to 2015, and three equal time epochs during the study period (2004-07, 2008-11, 2012-15) were compared. We also compared searches for epidurals with commonly searched birth-related terms. RESULTS: Internet searches are increasing; there were 726000 searches for [epidural] in 2015. Search terms with the most significant growth in the past 4years (2012-15) were "birth with epidural," "pain after epidural," "labor without epidural," "epidural birth video," and "epidural vs natural". Searches for epidural side effects, risks, and pain on insertion were among the most common and were increasing most rapidly. Searches related to epidurals were more common than searches related to "natural births", "home births", and "labor pain", but were less common than searches for "midwives" or "doulas". CONCLUSION: The findings provide an insight into internet use by those seeking information about labor analgesic options. Identifying the most common and rapidly increasing online search queries may guide physician-parturient interactions and online content creation, to address labor analgesic topics that most interest users.

Seroprevalence of Toxoplasma gondii in American Black Bears ( Ursus americanus ) of the Central Appalachians, USA.

We assessed Toxoplasma gondii seroprevalence in 53 free-ranging American black bears ( Ursus americanus ) in the Central Appalachian Mountains, US. Seroprevalence was 62% with no difference between males and females or between juvenile and adult bears. Wildlife agencies should consider warnings in hunter education programs to reduce the chances for human infection from this source.

Comparing hospital and telephone follow-up for patients treated for stage-I endometrial cancer (ENDCAT trial): a randomised, multicentre, non-inferiority trial.

OBJECTIVE: To evaluate the effectiveness of nurse-led telephone follow-up (TFU) for patients with stage-I endometrial cancer. DESIGN: Multicentre, randomised, non-inferiority trial. SETTING: Five centres in the North West of England. SAMPLE: A cohort of 259 women treated for stage-I endometrial cancer attending hospital outpatient clinics for routine follow-up. METHODS: Participants were randomly allocated to receive traditional hospital based follow-up (HFU) or nurse-led TFU. MAIN OUTCOME MEASURES: Primary outcomes were psychological morbidity (State Trait Anxiety Inventory, STAI-S) and patient satisfaction with the information provided. Secondary outcomes included patient satisfaction with service, quality of life, and time to detection of recurrence. RESULTS: The STAI-S scores post-randomisation were similar between groups [mean (SD): TFU 33.0 (11.0); HFU 35.5 (13.0)]. The estimated between-group difference in STAI-S was 0.7 (95% confidence interval, 95% CI -1.9 to 3.3); the confidence interval lies above the non-inferiority limit (-3.5), indicating the non-inferiority of TFU. There was no significant difference between groups in reported satisfaction with information (odds ratio, OR 0.9; 95% CI 0.4-2.1; P = 0.83). Women in the HFU group were more likely to report being kept waiting for their appointment (P = 0.001), that they did not need any information (P = 0.003), and were less likely to report that the nurse knew about their particular case and situation (P = 0.005). CONCLUSIONS: The TFU provides an effective alternative to HFU for patients with stage-I endometrial cancer, with no reported physical or psychological detriment. Patient satisfaction with information was high, with similar levels between groups. TWEETABLE ABSTRACT: ENDCAT trial shows effectiveness of nurse-led telephone follow-up for patients with stage-I endometrial cancer.

Identification of chromatin accessibility domains in human breast cancer stem cells.

Epithelial-to-mesenchymal transition (EMT) is physiological in embryogenesis and wound healing but also associated with the formation of cancer stem cells (CSCs). Many EMT signaling pathways are implicated in CSC formation, but the precise underlying mechanisms of CSC formation remain elusive. We have previously demonstrated that PKC is critical for EMT induction and CSC formation in inducible breast EMT/CSC models. Here, we used formaldehyde-assisted isolation of regulatory elements-sequencing (FAIRE-seq) to investigate DNA accessibility changes after PKC activation and determine how they influence EMT and CSC formation. During EMT, DNA accessibility principally increased in regions distant from transcription start sites, low in CpG content, and enriched with chromatin enhancer marks. ChIP-sequencing revealed that a subset of these regions changed from poised to active enhancers upon stimulation, with some even more acteylated in CSCs. While regions with increased accessibility were enriched for FOX, AP-1, TEAD, and TFAP2 motifs, those containing FOX and AP-1 motif were associated with increased expression of CSC-associated genes, while those with TFAP2 were associated with genes with increased expression in non-CSCs. Silencing of 2 members of the FOX family, FOXN2 and FOXQ1, repressed CSCs and the mesenchymal phenotype and inhibited the CSC gene signature. These novel, PKC-induced DNA accessibility regions help explain how the epigenomic plasticity of cells undergoing EMT leads to CSC gene activation.