Crossover Trial Research Articles

Acute response to resistance exercise and later development of arm lymphedema in breast cancer survivors: An exploratory follow-up of a randomized cross-over trial

BackgroundIn breast cancer survivors at risk for lymphedema, variation in lymphatic function and arm volume has been observed related to a bout of exercise, with potential for prediction of breast cancer-related arm lymphedema (BCRaL). This novel, exploratory study examined the acute lymphatic response to resistance exercise and later development of BCRaL in women at high risk for BCRaL. MethodsOne year after participation in a cross-over trial evaluating the acute lymphatic response to upper-extremity resistance exercise (low-and heavy-load), participants were assessed for BCRaL (n ​= ​16). The response to exercise was assessed before and after (post, 24- and 72-hrs) each exercise bout as extracellular fluid (L-Dex; bioimpedance spectroscopy (BIS)), interarm volume % difference (IVD; Dual-energy x-ray absorptiometry (DXA)) and symptoms (Numeric rating scale, 0–10 (NRS)). BCRaL at follow-up was defined as presence of one objective indicator (L-Dex >10, change ≥+6.5, IVD >5%) plus one objective or subjective indicator (interarm symptom ≥1 or visual inspection). Descriptive statistics were used to compare the acute response between participants with and without BCRaL at follow-up. ResultsNo trends indicating a similar acute response to exercise was observed in participants who later developed BCRaL (n ​= ​5). There were no observable differences in acute lymphatic response between participants that developed BCRaL and those who did not, both at an individual and group level. ConclusionsFindings from this exploratory study showed no evidence to suggest that the acute response to resistance exercise can predict BCRaL development.

Switching people who smoke to unfiltered cigarettes: Effects on smoking topography

IntroductionSmoking topography (ST) describes smoking behavior and patterns. Removal of the cigarette filter and subsequent impact on ST has not been investigated. This is the first clinical trial comparing ST for filtered and unfiltered cigarettes in a naturalistic experiment. MethodsWe conducted a crossover clinical trial following established people who smoke cigarettes (n = 32) for two weeks under filtered and unfiltered smoking experimental conditions. Participants (50 % female, mean age 38.3 yr.) smoked in each experimental condition followed by a 3-week post-washout period. ST (puff count, volume, duration, peak and average flow) was measured at six time-points. Statistical analysis included a linear repeated mixed-effects model of smoking experimental conditions by visit number and sex. ResultsAverage flow (ml/sec) was significantly less for filtered smoking (−6.92 lower (95 % CI: −13.44 to −0.39), p < 0.05), thus demonstrating more resistance on inhalation. No significant differences were found between filtered or unfiltered experimental conditions for other ST variables. However, average volume and average peak flow were somewhat higher in unfiltered smoking, and lower mean puff counts/cigarette were observed for unfiltered compared to filtered smoking. ConclusionLower average flow rates were associated with filtered cigarette smoking. No significant differences were found for other ST variables between smoking experimental conditions. ST measurements comparing cigarette smoking conditions may determine if product regulatory changes, such as removing the cigarette filter could impact smoking behavioral patterns among people who smoke. This proof-of-principle study measuring ST may be replicated in larger trials to determine potential behavioral changes in smoking unfiltered cigarettes.

A randomised controlled crossover trial comparing polymeric and semi-elemental oral nutritional supplements (ONS) in patients with short bowel

A randomised controlled crossover trial comparing polymeric and semi-elemental oral nutritional supplements (ONS) in patients with short bowel

A Pilot Study of Ketotifen in Patients Aged 8-17 Years with Functional Dyspepsia Associated with Mucosal Eosinophilia.

Mast cells have been implicated in abdominal pain-associated disorders of gut-brain interaction, such as functional dyspepsia. As such, ketotifen, a second-generation antihistamine and mast cell stabilizer, could represent a viable treatment option in these conditions. The primary aim of the current pilot study was to assess clinical response to ketotifen and assess pharmacokinetics in youth with functional dyspepsia. We conducted a pilot randomized, double-blind, placebo-controlled, cross-over trial of ketotifen in 11 youth with functional dyspepsia and duodenal mucosal eosinophilia with 4 weeks of active treatment at a dose of 1 mg twice daily. Global clinical response was graded on a 5-point Likert Scale. A single plasma sample was obtained at steady state for pharmacokinetic analysis. Ketotifen was not superior to placebo with regard to global clinical response. Only 18% of patients demonstrated a complete or near-complete clinical response. The estimated half-life was 3.3 h. While ketotifen was not superior to placebo, this study highlights several important challenges for developing drug trials for youth with chronic abdominal pain. Recommendations are made for designing a larger treatment trial for ketotifen in this patient group. This study was registered at ClinicalTrials.gov: NCT02484248.

Impact of nocturnal hypoxia on glycaemic control, appetite, gut microbiota and inflammation in adults with type 2 diabetes mellitus: A single-blind cross-over trial.

High altitude residents have a lower incidence of type 2 diabetes mellitus (T2DM). Therefore, we examined the effect of repeated overnight normobaric hypoxic exposure on glycaemic control, appetite, gut microbiota and inflammation in adults with T2DM. Thirteen adults with T2DM [glycated haemoglobin (HbA1c): 61.1±14.1mmolmol-1; aged 64.2±9.4years; four female] completed a single-blind, randomised, sham-controlled, cross-over study for 10 nights, sleeping when exposed to hypoxia (fractional inspired O2 [ ]=0.155; ∼2500m simulated altitude) or normoxic conditions ( =0.209) in a randomised order. Outcome measures included: fasted plasma [glucose]; [hypoxia inducible factor-1α]; [interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]; [heat shock protein 70]; [butyric acid]; peak plasma [glucose] and insulin sensitivity following a 2h oral glucose tolerance test; body composition; appetite indices ([leptin], [acyl ghrelin], [peptide YY], [glucagon-like peptide-1]); and gut microbiota diversity and abundance [16S rRNA amplicon sequencing]. During intervention periods, accelerometers measured physical activity, sleep duration and efficiency, whereas continuous glucose monitors were used to assess estimated HbA1c and glucose management indicator and time in target range. Overnight hypoxia was not associated with changes in any outcome measure (P>0.05 with small effect sizes) except fasting insulin sensitivity and gut microbiota alpha diversity, which exhibited trends (P=0.10; P=0.08 respectively) for a medium beneficial effect (d=0.49; d=0.59 respectively). Ten nights of overnight moderate hypoxic exposure did not significantly affect glycaemic control, gut microbiome, appetite, or inflammation in adults with T2DM. However, the intervention was well tolerated and a medium effect-size for improved insulin sensitivity and reduced alpha diversity warrants further investigation. KEY POINTS: Living at altitude lowers the incidence of type 2 diabetes mellitus (T2DM). Animal studies suggest that exposure to hypoxia may lead to weight loss and suppressed appetite. In a single-blind, randomised sham-controlled, cross-over trial, we assessed the effects of 10 nights of hypoxia (fractional inspired O2 ∼0.155) on glucose homeostasis, appetite, gut microbiota, inflammatory stress ([interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]) and hypoxic stress ([hypoxia inducible factor 1α]; heat shock protein 70]) in 13 adults with T2DM. Appetite and inflammatory markers were unchanged following hypoxic exposure, but an increased insulin sensitivity and reduced gut microbiota alpha diversity were associated with a medium effect-size and statistical trends, which warrant further investigation using a definitive large randomised controlled trial. Hypoxic exposure may represent a viable therapeutic intervention in people with T2DM and particularly those unable or unwilling to exercise because barriers to uptake and adherence may be lower than for other lifestyle interventions (e.g. diet and exercise).

Percutaneous bone marrow concentrate and platelet products versus exercise therapy for the treatment of rotator cuff tears: a randomized controlled, crossover trial with 2-year follow-up

BackgroundSurgical repair is recommended for the treatment of high-grade partial and full thickness rotator cuff tears, although evidence shows surgery is not necessarily superior to non-surgical therapy. The purpose of this study was to compare percutaneous orthobiologic treatment to a home exercise therapy program for supraspinatus tears.MethodsIn this randomized-controlled, crossover design, participants with a torn supraspinatus tendon received either ‘BMC treatment’, consisting of a combination of autologous bone marrow concentrate (BMC) and platelet products, or underwent a home exercise therapy program. After three months, patients randomized to exercise therapy could crossover to receive BMC treatment if not satisfied with shoulder progression. Patient-reported outcomes of Numeric Pain Scale (NPS), Disabilities of the Arm, Shoulder, and Hand, (DASH), and a modified Single Assessment Numeric Evaluation (SANE) were collected at 1, 3, 6, 12, and 24 months. Pre- and post-treatment MRI were assessed using the Snyder Classification system.ResultsFifty-one patients were enrolled and randomized to the BMC treatment group (n = 34) or the exercise therapy group (n = 17). Significantly greater improvement in median ΔDASH, ΔNPS, and SANE scores were reported by the BMC treatment group compared to the exercise therapy group (-11.7 vs -3.8, P = 0.01; -2.0 vs 0.5, P = 0.004; and 50.0 vs 0.0, P < 0.001; respectively) after three months. Patient-reported outcomes continued to progress through the study’s two-year follow-up period without a serious adverse event. Of patients with both pre- and post-treatment MRIs, a majority (73%) showed evidence of healing post-BMC treatment.ConclusionsPatients reported significantly greater changes in function, pain, and overall improvement following BMC treatment compared to exercise therapy for high grade partial and full thickness supraspinatus tears.Trial registrationThis protocol was registered with www.clinicaltrials.gov (NCT01788683; 11/02/2013).

Comparison of subarachnoid administration of low-dose bupivacaine and lidocaine in healthy goats.

This study aimed to compare the effects of low-dose subarachnoid injections of 2% lidocaine (LIDO) and 0.5% bupivacaine (BUPI) in goats. 6 healthy, privately owned female goats. In this randomized blind crossover clinical trial, each goat received 0.05 mL/kg-1 of LIDO, BUPI, or sterile saline solution into the lumbosacral subarachnoid space, with a seven-day washout. Cardiorespiratory variables, rectal temperature, and somatosensory (pinprick) and motor (ataxia) functions were recorded at baseline (time 0) and 2, 5, 10, 15, and 30 minutes after injection, then every 20 minutes until the goat was standing and able to walk. Time to regain somatosensory and motor functions was compared between treatments using Kaplan-Meier survival curves and the Cox proportional hazards model. Linear mixed-effects models were used to compare cardiorespiratory variables between treatments and over time. A P value ≤ .05 was considered significant. Somatosensory recovery was longer with BUPI, though not statistically significant. The median time to stand was 50 (50, 67) minutes after LIDO injection and 104 (101, 156) minutes after BUPI injection (P = .031). The median time to walk was 72 (54, 85) minutes after LIDO versus 225 (220, 245) minutes after BUPI injection (P = .031). Cardiovascular and respiratory variables showed no significant differences between treatments. Despite prolonged ataxia with BUPI, pinprick sensation recovery did not differ. At reduced doses, both LIDO and BUPI are deemed acceptable for short procedures of the flank, pelvic limb, or tail in healthy goats.

A single-dose, randomized, open-label, four-period, crossover equivalence trial comparing the clinical similarity of the proposed biosimilar rupatadine fumarate to reference Wystamm® in healthy Chinese subjects

PurposeThe aim of this study was to evaluate the bioequivalence of two formulations of rupatadine (10-mg tablets) under fasting and fed conditions in healthy Chinese subjects.MethodsA total of 72 subjects were randomly assigned to the fasting cohort (n = 36) and fed cohort (n = 36). Each cohort includes four single-dose observation periods and 7-day washout intervals. Blood samples were collected at several timepoints for up to 72 h post-dose. The plasma concentration of rupatadine and the major active metabolites (desloratadine and 3-hydroxydesloratadine) were analyzed by a validated HPLC–MS/MS method. The non-compartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation of the reference formulation, a reference-scaled average bioequivalence or average bioequivalence method was used to evaluate the bioequivalence of the two formulations.ResultsFor the fasting status, the reference-scaled average bioequivalence method was used to evaluate the bioequivalence of the maximum observed rupatadine concentration (Cmax; subject standard deviation &amp;gt; 0.294), while the average bioequivalence method was used to evaluate the bioequivalence of the area under the rupatadine concentration–time curve from time 0 to the last detectable concentration (AUC0-t) and from time 0 to infinity (AUC0-∞). The geometric mean ratio (GMR) of the test/reference for Cmax was 95.91%, and the upper bound of the 95% confidence interval was 95.91%. For AUC0-t and AUC0-∞ comparisons, the GMR and 90% confidence interval (CI) were 98.76% (93.88%–103.90%) and 98.71% (93.93%–103.75%), respectively. For the fed status, the subject standard deviation values of Cmax, AUC0-t, and AUC0-∞ were all &amp;lt;0.294; therefore, the average bioequivalence method was used. The GMR and 90% CI for Cmax, AUC0-t, and AUC0-∞ were 101.19% (91.64%–111.74%), 98.80% (94.47%–103.33%), and 98.63% (94.42%–103.03%), respectively. The two-sided 90% CI of the GMR for primary pharmacokinetic endpoints of desloratadine and 3-hydroxydesloratadine was also within 80%–125% for each cohort. These results met the bioequivalence criteria for highly variable drugs. All adverse events (AEs) were mild and transient.ConclusionThe test drug rupatadine fumarate showed a similar safety profile to the reference drug Wystamm® (J. Uriach y Compañía, S.A., Spain), and its pharmacokinetic bioequivalence was confirmed in healthy Chinese subjects based on fasting and postprandial status.Clinical trial registration:http://www.chinadrugtrials.org.cn/index.html, identifier CTR20213217

Evaluating possible 'next day' impairment in insomnia patients administered an oral medicinal cannabis product by night: a pilot randomized controlled trial.

Cannabis and its major constituents, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are being widely used to treat sleep disturbances. However, THC can cause acute cognitive and psychomotor impairment and there are concerns that driving and workplace safety might be compromised the day after evening use.Here, weexamined possible 'next day' impairment following evening administration of a typical medicinal cannabis oil in adults with insomnia disorder, compared to matched placebo. This paper describes the secondary outcomes of a larger study investigating the effects of THC/CBD on insomnia disorder.Twenty adults [16 female; mean (SD) age, 46.1 (8.6) y] with physician-diagnosed insomnia who infrequently use cannabis completed two 24 h in-laboratory visits involving acute oral administration of combined 10 mg THC and 200 mg CBD ('THC/CBD') or placebo in a randomised, double-blind, crossover trial design. Outcome measures included 'next day' (≥9 h post-treatment) performance on cognitive and psychomotor function tasks, simulated driving performance, subjective drug effects, and mood.We foundno differences in 'next day' performance on 27 out of 28 tests of cognitive and psychomotor function and simulated driving performance relative to placebo. THC/CBD produced a small decrease (-1.4%, p=.016, d=-0.6) in accuracy on the Stroop-Colour Task (easy/congruent) but not the Stroop-Word Task (hard/incongruent). THC/CBD also produced a small increase (+8.6, p=.042, d=0.3) in self-ratings of Sedated at 10 h post-treatment, but with no accompanying changes in subjective ratings of Alert or Sleepy (p's>0.05).In conclusion, we found a lack of notable 'next day' impairment to cognitive and psychomotor function and simulated driving performance following evening use of 10 mg oral THC, in combination with 200 mg CBD, in an insomnia population who infrequently use cannabis.

Effects of traditional and dry bed baths on patients admitted in intensive units: A randomized crossover clinical trial.

The bed bath is an important part of nursing care. There are few studies evaluating the effects of traditional and dry bed baths on patients. This study was performed with the aim of investigating the effect of traditional and dry bed baths given to intensive care unit patients on the patients' hemodynamic parameters, the duration of the bathing procedure and the cost of consumable items. This was a randomized crossover clinical trial and a prospective study. The study was conducted in a General Surgery Intensive Care Unit with 22 intensive care patients aged 18 and over, who had a nursing diagnosis of bathing personal care deficiency. Each patient was given two types of bed baths at an interval of 24 h: a traditional bed bath and a dry bed bath performed with single-use tissues. Immediately before each bath, in the 5th, 10th and 15th minute of bathing, immediately after bathing and 30 min after bathing, body temperature, heart rate, blood pressure, breathing rate and peripheral oxygen saturation measurement changes over time were compared within the group using the Friedman test. The Wilcoxon signed ranks test was used to compare the variables of bathing duration and bathing consumable item costs between the bathing procedures. It was found that at the completion of traditional and dry bed bathing, the participants' body temperature, blood pressure, heart rate and breathing rate parameters were statistically significantly lower than before bathing, whereas peripheral oxygen saturation values showed a significant increase (p < 0.05). It was found that the dry bed bath took a statistically significantly shorter time than the traditional bed bath and that the cost of consumable bathing materials was less (p < 0.05). It was concluded that traditional and dry bed baths given to intensive care patients affected their hemodynamic parameters and that the dry bed bath was superior to the traditional bed bath in that it took less time and that it cost less.

Assessment of subjective well-being of healthcare workers in response to heat and personal protective equipment under controlled conditions using a standardized protocol

BackgroundDue to climate change, the increasing frequency of hot summer days and heat waves can result in occupational heat strain, especially in non-air-conditioned workplaces. Healthcare workers (HCW) engaged in patient care are particularly affected, as they are additionally exposed to physical stress. The use of personal protective equipment (PPE) can aggravate heat strain in HCW. This study aimed to examine the subjective well-being of HCW when exposed to heat and PPE under controlled conditions.MethodsThis study was designed as a randomized crossover trial. Participants performed standardized healthcare tasks in a climatic chamber for approximately 3.5 h at different indoor temperatures (22 °C and 27 °C) and varied working conditions (with or without PPE). The effects on participants’ subjective well-being, encompassing thermal, physiological and psychological stress were assessed using a customized questionnaire.ResultsHeat had a greater effect than PPE on thermal, physical and psychological stress. Conversely, PPE had a greater effect on physical demand and effort. For the majority of outcomes, combined exposure to heat and PPE resulted in the highest perceived discomfort. Furthermore, the participants reported increased sweating and other discomforts when working at elevated temperatures or with PPE.ConclusionsIn this study, heat and PPE, but particularly the combination of both factors, were identified as unfavorable working environments. Although the trials were conducted in a controlled environment, the outcomes provide valuable information about the effect of heat and PPE on HCW in a real-life setting. Furthermore, the design used in this study can be beneficial in evaluating the effect of mitigation strategies.

Senolytic effects of exercise in human muscles require acute inflammation.

Higher intensity exercise, despite causing more tissue damage, improved aging conditions. We previously observed decreased p16INK4a mRNA in human skeletal muscle after high-intensity interval exercise (HIIE), with no change following equivalent work in moderate-intensity continuous exercise. This raises the question of whether the observed senolytic effect of exercise is mediated by inflammation, an immune response induced by muscle damage. In this study, inflammation was blocked using a multiple dose of ibuprofen (total dose: 1200 mg), a commonly consumed nonsteroidal anti-inflammatory drug (NSAID), in a placebo-controlled, counterbalanced crossover trial. Twelve men aged 20-26 consumed ibuprofen or placebo before and after HIIE at 120% maximum aerobic power. Multiple muscle biopsies were taken for tissue analysis before and after HIIE. p16INK4a+ cells were located surrounding myofibers in muscle tissues. The maximum decrease in p16INK4a mRNA levels within muscle tissues occurred at 3 h post-exercise (-82%, p < 0.01), gradually recovering over the next 3-24 h. A concurrent reduction pattern in CD11b mRNA (-87%, p < 0.01) was also found within the same time frame. Ibuprofen treatment attenuated the post-exercise reduction in both p16INK4a mRNA and CD11b mRNA. The strong correlation (r = 0.88, p < 0.01) between p16INK4a mRNA and CD11b mRNA in muscle tissues suggests a connection between the markers of tissue aging and pro-inflammatory myeloid differentiation. In conclusion, our results suggest that the senolytic effect of high-intensity exercise on human skeletal muscle is mediated by acute inflammation.

The effects of melatonin and magnesium in a novel supplement delivery system on sleep scores, body composition and metabolism in otherwise healthy individuals with sleep disturbances.

The purpose of this study was to investigate the effects of a novel dietary supplement, including melatonin and magnesium, delivered via coffee pods on sleep quality, resting metabolic rate (RMR), and body composition in individuals with poor sleep quality disturbances. Using a double-blinded, randomized, crossover trial, we recruited 35 participants to a 4-week intervention with both supplements (1.9 mg melatonin + 200 mg elemental magnesium before sleep) and placebo conditions, considering a 7d washout period between treatments. The Pittsburgh Sleep Quality Index (PSQI) questionnaire was applied, RMR (kcal) was measured using indirect calorimetry (canopy ventilated open-circuit system) and body composition was assessed using dual-energy X-ray absorptiometry. Decreases in PSQI and anger - hostility scores, as well as in energy intake and fat mass, were observed (p < 0.05) for both conditions, from baseline to the end of each 4-week intervention. Differences between conditions were also observed for these parameters along with energy spent in activity, number of sedentary breaks, sleep efficiency, latency time, time in bed, total sleep time, awakening time, and movement index (p < 0.05) favouring the supplement condition. However, the final PSQI questionnaire scores still indicated poor sleep quality on average (PSQI > 5), in both conditions, with no changes regarding RMR. A melatonin-magnesium supplement, in a coffee pod format, showed improvements in sleep quality in otherwise healthy individuals with sleep disturbances, however PSQI questionnaire scores still indicated poor quality on average (PSQI > 5).

Lowering the Acquisition of Multi-drug Resistant Organism (MDROs) with Pulsed-xenon (LAMP) Study: a cluster randomized controlled, double-blinded, interventional crossover trial.

Environmental disinfection is essential for reducing spread of healthcare associated infections (HAIs). Previous studies report conflicting results regarding the effects of ultraviolet light (UV) in reducing infections. This trial evaluated the impact of adding pulsed xenon UV (PX-UV) to standard terminal cleaning in reducing environmentally-implicated HAIs (eiHAIs). The LAMP trial was conducted in 2 hospitals (15 inpatient wards) utilizing a cluster randomized controlled, double-blinded, interventional crossover trial comparing standard terminal cleaning followed by either pulsed xenon ultraviolet (PX-UV) disinfection (intervention arm) or sham disinfection (control arm). The primary outcome was incidence of eiHAIs from clinical microbiology tests on the 4th day of stay or later or within 3 days after discharge from the study unit. EiHAIs included clinical cultures positive for vancomycin-resistant enterococci (VRE), extended spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumonia, methicillin-resistant Staphylococcus aureus (MRSA), and Acinetobacter baumannii, and stool PCR positive for Clostridiodes difficile. Between May 18, 2017 to Jan 7, 2020, 25,732 patients were included, with an incidence of 601 eiHAI and 180,954 patient days. There was no difference in the rate of eiHAIs in the intervention and sham arms (3.49 vs 3.17 infections/1000 patient days respectively, RR 1.10 CI (0.94, 1.29, p= 0.23)). Study results were similar when stratified by eiHAI type, hospital, and unit type. The LAMP study failed to demonstrate an effect of the addition of UV light disinfection following terminal cleaning on reductions in rates of eiHAIs. Further investigations targeting hospital environmental surfaces and the role of no touch technology to reduce HAIs are needed.

The efficacy of ball blankets on insomnia in depression in outpatient clinics: A randomised crossover multicentre trial.

Many patients with depression report insomnia symptoms that profoundly affect their health and well-being. Non-pharmacological treatments of insomnia may be preferable for some patients. In this randomised crossover trial, we investigated the efficacy of the Protac Ball Blanket® on insomnia among patients with depression. Included patients (n = 45) were diagnosed with unipolar depression, and with subjective insomnia and poor sleep quality (Pittsburgh Sleep Quality Index Score > 5). Each patient slept 2 weeks with a Protac Ball Blanket® and 2 weeks with a control duvet. Randomisation defined the order of the 2-week sleep periods. Patients served as their own control in this design. The primary outcome was changes in total night-time sleep. Secondary outcomes were sleep-onset latency, number of awakenings, wake after sleep onset, daily use of pro necessitate sedatives and hypnotics, subjective sleep quality (Pittsburgh Sleep Quality Index), insomnia severity (Insomnia Severity Index), symptoms of depression (Hamilton Depression Rating Scale, Major Depression Inventory), symptoms of anxiety (Beck Anxiety Index), and patient-reported outcomes concerning interpersonal sensitivity, neurasthenia, anxiety and depression (Self-Reported Symptom State Scale). Paired two-sided t-tests were used to compare the means of the differences of the outcomes. Protac Ball Blanket® increased total night-time sleep by 12.9 min (95% confidence interval: 1.21-24.63, p = 0.031). Among the secondary outcomes, Protac Ball Blanket® decreased Hamilton Depression Rating Scale by 2.78 (95% confidence interval: -5.44; -0.11, p = 0.042) and Insomnia Severity Index by 2.98 (95% confidence interval: -5.45; -0.50, p = 0.020). No changes were observed in sleep-onset latency, number of awakenings, wake after sleep onset, Pittsburgh Sleep Quality Index, Major Depression Inventory, Beck Anxiety Index, Self-Reported Symptom State Scale, and medication use. The results suggest that some patients may benefit from Protac Ball Blanket® as an add-on non-pharmacological treatment to improve sleep in depression.

A randomised, crossover trial exploring the patient perspective and effectiveness of biosimilar adalimumab transition: IBD reference and biosimilar adalimumab cross over study (iBaSS).

Patient satisfaction has been positively associated with adherence which is expected to impact outcomes. Although vital for successful implementation of biosimilar medicines, little is known about the patient perspective of transition. The aim of this study was to investigate clinical outcomes and patient experience of transitioning between reference adalimumab and a biosimilar (SB5). iBaSS is a phase IV single-centre, prospective, randomised, single-blind, cross-over study in adult subjects with Crohn's disease. Participants, stable on adalimumab before consent, received 24weeks of treatment with both reference adalimumab and SB5. The primary outcome was the proportion of patients maintaining baseline clinical status throughout each treatment period, with patients' perspective of disease control and treatment satisfaction assessed as secondary outcomes. A total of 112 participants, representative of the heterogeneous patient populations encountered in routine clinical practice, were enrolled. A similar proportion of participants maintained baseline clinical status through each treatment period: 81.8% with reference adalimumab and 79.5% with SB5. Patient reported outcomes (IBD-Control questionnaire (SB5: 15.5; reference adalimumab 15) and TSQM), adverse events and therapeutic drug monitoring remained consistent through both treatment periods, although a higher median injection pain VAS score was noted with SB5 (53/100 versus 6/100 with reference adalimumab). The number of switches undertaken in the study did not impact serum drug concentration or immunogenicity. This study, mimicking real world adalimumab transition, demonstrates that patients undertaking brand transition can be expected to have consistent clinical and satisfaction outcomes. Number 2018-004967-30.

Influence of acute dietary nitrate supplementation on oxygen delivery/consumption and critical impulse during maximal effort forearm exercise in males: a randomized crossover trial.

Beetroot juice supplementation (BRJ) increases nitric oxide bioavailability under conditions of hypoxia and acidosis, characteristics of maximal effort exercise, which is required to identify forearm critical impulse. We hypothesized BRJ would improve oxygen delivery:demand matching and forearm critical impulse performance. Healthy males (20.8±2.4 years) participated in a randomized crossover trial between October 2017-May 2018 (Queen's University, Kingston, ON). Participants completed 10-minutes of rhythmic maximal effort forearm handgrip exercise 2.5 hours post placebo (PL) vs. BRJ (9 completed PL/BRJ vs. 4 completed BRJ/PL) within a 2 week period. Data are presented as mean±SD. There was a main effect of drink (PL > BRJ) for oxygen extraction (P=0.033,ηp2=0.351) and oxygen consumption/force (P=0.017,ηp2=0.417). There was a drink x time interaction (PL > BRJ) for oxygen consumption/force (P=0.035,ηp2=0.216) between 75-360s (1.25-6 min) from exercise onset. BRJ did not influence oxygen delivery (P=0.953,ηp2=0.000), oxygen consumption (P=0.064,ηp2=0.278), metabolites [[lactate] (P=0.196,ηp2=0.135), pH (P=0.759,ηp2=0.008)] or power-duration performance parameters [critical impulse (P=0.379,d=0.253), W' (P=0.733,d=0.097)]. BRJ during all-out handgrip exercise does not influence oxygen delivery or exercise performance. Oxygen cost of contraction with BRJ is reduced as contraction impulse is declining during maximal effort exercise resulting in less oxygen extraction. https://osf.io/pga37/registrations.

Oral preparation of hyaluronic acid, chondroitin sulfate, N-acetylglucosamine, and vitamin C improves sexual and urinary symptoms in participants with recurrent urinary tract infections: a randomized crossover trial.

Intravesical instillation of hyaluronic acid (HA) has been associated with reduced sexual dysfunction in participants with recurrent urinary tract infections (rUTIs), but the efficacy of an oral treatment has never been investigated. To investigate the efficacy of an oral preparation of HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C in improving sexual and urinary symptoms in a cohort of reproductive-age participants with rUTI. In a monocentric randomized crossover pilot trial, participants with rUTI who were referred to our institute between March 2022 and April 2023 were randomized 1:1 in 2 groups: intervention vs control. All participants had an oral preparation of cranberry, D-mannose, propolis extract, turmeric, and Boswellia twice a day for 3 months. The intervention group also included an oral preparation of HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C once a day for 3 months. Crossover of treatment occurred at 3 months for an additional 3 months. At baseline and 3 and 6 months, participants were evaluated clinically and with the International Prostate Symptom Score (IPSS) and Female Sexual Function Index (FSFI). Descriptive statistics and logistic regression models tested the impact of the intervention on urinary and sexual symptoms at each follow-up assessment. Improvement in sexual and urinary symptoms as measured by the FSFI and IPSS. Overall, 27 (54%) participants had an FSFI score <26.5 at enrollment. At 3 months, FSFI scores were higher in the intervention group vs control (P < .001), but IPSS scores were lower (P = .03). After crossover of treatment, FSFI and IPSS scores remained stable in the intervention group. However, after crossover, the control group showed a significant improvement in IPSS and FSFI scores (all P < .01) vs the 3-month assessment. At last follow-up, urinary and sexual symptoms were comparable between groups. In logistic regression analyses, the intervention group was associated with early improvement in sexual symptoms (odds ratio, 3.9; P = .04) and urinary symptoms (odds ratio, 5.1; P = .01) after accounting for clinical confounders. Combination treatment with HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C is effective if started immediately or even after a few months from symptoms in participants with rUTI. The main limitation is the lack of long-term follow-up. The oral formulation of HA, chondroitin sulfate, N-acetylglucosamine, and vitamin C could be an effective therapy against urinary and sexual distress in participants with rUTI (NCT06268483; ClinicalTrials.gov).

Transient brain structure changes after high phenylalanine exposure in adults with phenylketonuria.

Phenylketonuria is a rare metabolic disease resulting from a deficiency of the enzyme phenylalanine hydroxylase. Recent cross-sectional evidence suggests that early-treated adults with phenylketonuria exhibit alterations in cortical grey matter compared to healthy peers. However, the effects of high phenylalanine exposure on brain structure in adulthood need to be further elucidated. In this double-blind, randomised, placebo-controlled crossover trial, we investigated the impact of a four-week high phenylalanine exposure on the brain structure and its relationship to cognitive performance and metabolic parameters in early-treated adults with phenylketonuria. Twenty-eight adult patients with early-treated classical phenylketonuria (19-48 years) underwent magnetic resonance imaging before and after the four-week phenylalanine and placebo interventions (four timepoints). Structural T1-weighted images were preprocessed and evaluated using DL+DiReCT, a deep-learning-based tool for brain morphometric analysis. Cortical thickness, white matter volume, and ventricular volume were compared between the phenylalanine and placebo periods. Brain phenylalanine levels were measured using 1H spectroscopy. Blood levels of phenylalanine, tyrosine, and tryptophan were assessed at each of the four timepoints, along with performance in executive functions and attention. Blood phenylalanine levels were significantly higher after the phenylalanine period (1441µmol/L) than after the placebo period (873µmol/L, P<0.001). Morphometric analyses revealed a statistically significant decrease in cortical thickness in 17 out of 60 brain regions after the phenylalanine period compared to placebo. The largest decreases were observed in the right pars orbitalis (point estimate=-0.095mm, P<0.001) and the left lingual gyrus (point estimate=-0.070mm, P<0.001). Bilateral white matter and ventricular volumes were significantly increased after the phenylalanine period. However, the structural alterations in the Phe-placebo group returned to baseline measures following the washout and placebo period. Additionally, elevated blood and brain phenylalanine levels were related to increased bilateral white matter volume (rs=0.43 to 0.51, P≤0.036) and decreased cortical thickness (rs=-0.62 to -0.39, not surviving FDR correction) after the phenylalanine and placebo periods. Moreover, decreased cortical thickness was correlated with worse cognitive performance after both periods (rs=-0.54 to -0.40, not surviving FDR correction). These findings provide evidence that a four-week high phenylalanine exposure in adults with phenylketonuria results in transient reductions of the cortical grey matter and increases in white matter volume. Further research is needed to determine the potential long-term impact of high phenylalanine levels on brain structure and function in adults with phenylketonuria.

Comparing the posture and comfort of anaesthesiologists during laryngoscopy and tracheal intubation in the head-elevated laryngoscopy position in supine position and with a 25° backup: A randomised clinical crossover trial

Background and Aims: The head-elevated laryngoscopy position (HELP) and a 25° backup have been proposed to enhance glottic visualisation, yet concerns about ergonomic discomfort hinder their widespread adoption. This study compares the comfort and posture adopted by anaesthesiologists while performing laryngoscopy and tracheal intubation with patients in HELP while in a supine position or with 25° backup. Methods: The study included 48 patients aged 18–60 years with normal airways and 12 experienced anaesthesiologists. Patients were randomised into two groups using permuted block randomisation. Anaesthesiologists performed laryngoscopy and intubation in supine HELP and 25° backup HELP positions. Anaesthesiologist’s posture was determined by measuring the angles of neck, wrist, elbow, back and knee joints, which were compared using Student’s t-test, and subjective comfort assessed on a Likert scale was compared using the Chi-square test. As mentioned by the anaesthesiologist, Cormack- Lehane grading was also noted and compared using a Chi-square test between groups, taking a P value &lt;0.05 as significant. Results: Both positions demonstrated comparable anaesthesiologist posture (P = 0.919) and comfort (P = 0.644). However, the 25° backup HELP positions significantly improved Cormack–Lehane grades, with 68% achieving grade 1 compared to 31% in the supine HELP group (P = 0.012). Haemodynamic stability and tracheal intubation time showed no significant differences between the groups (P = 0.475 and 0.117, respectively), and no complications were reported in either group. Conclusion: Anaesthesiologists’ posture and comfort during laryngoscopy and tracheal intubation are similar between supine and 25° backup in patients with easy airways.