Evidence For Clinical Effectiveness Research Articles

The clinical effects of pulsed electromagnetic field therapy for the management of chronic ankle instability: a study protocol for a double-blind randomized controlled trial

BackgroundChronic ankle instability is associated with long-term neuromuscular deficits involving poor postural control and peroneal muscular impairment. Symptoms of chronic ankle instability hinder engagement in physical activity and undermine the patient’s quality of life. Despite the existence of various treatment modalities, none has conclusively provided evidence of clinical effectiveness in counteracting neuromuscular deficits, such as arthrogenic muscle inhibition of the peroneal longus (PL). Pulse electromagnetic field therapy employed as an adjunct biophysical therapy can potentially improve stability by mitigating peroneal muscle weakness and by activating the peroneal muscle. We postulate that by combining standard care (muscle strengthening, balance training, and range of motion exercise) with pulse electromagnetic field therapy, postural control stability and peroneal muscle weakness will significantly improve.MethodsThis is a prospective, randomized, double-blind, placebo-controlled trial. A total of 48 adults with chronic ankle instability will be recruited and randomly allocated into either the intervention or control groups. The intervention group (n = 24) will receive active pulse electromagnetic field therapy and standard exercise training, while the control group (n = 24) will receive sham pulse electromagnetic field therapy and standard exercise training for 8 weeks. Primary and secondary outcomes will be evaluated at baseline, week 4, 8 as well as at 3-, 6-, and 12-month follow-up visits.DiscussionChronic ankle instability is a common debilitating condition without a curative conservative treatment. Investigating different treatment modalities will be essential for improving rehabilitation outcomes in this clinical population. This study will investigate the effectiveness of pulsed electromagnetic field therapy on the functional and clinical outcomes in the chronic ankle instability population. This trial may demonstrate this non-invasive biophysical therapy to be an effective measure to help patients with CAI.Trial registrationClinicalTrials.gov NCT05500885. Registered on August 13, 2022.

Integrated manual therapies: IASP taskforce viewpoint.

Manual therapy refers to a range of hands-on interventions used by various clinical professionals, such as osteopaths, osteopathic physicians, chiropractors, massage therapists, physiotherapists, and physical therapists, to treat patients experiencing pain. To present existing evidence of mechanisms and clinical effectiveness of manual therapy in pain. This Clinical Update focuses on the 2023 International Association for the Study of Pain Global Year for Integrative Pain Care. Current models of manual therapy and examples of integrative manual therapy are discussed. The evolution of concepts in recent years are presented and current gaps in knowledge to guide future research highlighted. Mechanisms of manual therapy are discussed, including specific and contextual effects. Findings from research on animal and humans in manual therapy are presented including on inflammatory markers, fibrosis, and behaviours. There is low to moderate levels of evidence that the effect sizes for manual therapy range from small to large for pain and function in tension headache, cervicogenic headache, fibromyalgia, low back pain, neck pain, knee pain, and hip pain. Manual therapies appear to be effective for a variety of conditions with minimal safety concerns. There are opportunities for manual therapies to integrate new evidence in its educational, clinical, and research models. Manual therapies are also well-suited to fostering a person-centred approach to care, requiring the clinician to relinquish some of their power to the person consulting. Integrated manual therapies have recently demonstrated a fascinating evolution illustrating their adaptability and capacity to address contemporary societal challenges.

Evaluation of a complex intervention: the Latch On randomized controlled trial of multicomponent breastfeeding support for women with a raised body mass index.

Latch On's objective was to achieve improved breastfeeding rates in women with raised body mass indices using a multicomponent breastfeeding support intervention. A hybrid type 1 implementation-effectiveness trial with mixed-methods process and health economics analyses were conducted. Data collection included stakeholder questionnaires, interviews, focus groups, fidelity data, participant and health system costs. The intervention was delivered with fidelity but the high breastfeeding rates at 3months were not different between intervention and usual care. Participants receiving the minimum intervention dose were more likely to initiate breastfeeding (P=0.045) and be breastfeeding at hospital discharge (P=0.01) compared with participants below the threshold. Participant exit interview themes highlighted the importance of improving breastfeeding support to women, the effect of COVID-19 on the breastfeeding experience, and found that the intervention improved the experience of establishing breastfeeding. The intervention cost €157 per participant, with no other cost difference between groups. Process analysis found that follow-up breastfeeding services continued in half of sites after study completion. This low-cost intervention resulted in a more enjoyable breastfeeding experience for participants and changed practice in some study sites. The intervention dose received may impact effectiveness, but further research is needed to provide definitive evidence of clinical and cost effectiveness.

Modernizing Medical Device Regulation: Challenges and Opportunities for the 510(k) Clearance Process.

Nearly all medical devices reviewed by the U.S. Food and Drug Administration (FDA) are authorized via the 510(k) clearance process. Established in 1976, this review pathway bases authorizations on the comparability of new devices to previously authorized devices ("predicates"). This evaluation usually does not require clinical evidence of safety and effectiveness. Advocates of the 510(k) clearance process tout its support for device innovation and rapid market access, and critics of the 510(k) clearance process express that it may inadequately protect patient safety. In September 2023, the FDA issued 3 guidance documents that, if finalized, would significantly change medical device regulation. This article provides clinical and regulatory context for the proposed guidance documents, which focus on predicate selection, clinical testing requirements, and implantable devices, and identifies opportunities for further reforms that promote transparency and patient safety.

Short-Cycle Autoclave Sterilization of Instruments in Same-Day Ophthalmic Surgeries

What Is the Issue? The volume of ophthalmic surgeries is increasingly high, with cataract surgery being 1 of the most performed surgeries in Canada. Infections following ophthalmic surgeries, while rare, can cause severe complications that may lead to irreversible vision loss. Reducing postsurgery infections is a high priority in clinical practice. Running a full wrapped, terminal steam sterilization cycle for ophthalmic instruments in autoclaves may be inefficient for ophthalmic surgeries and may cause unnecessary heavy economic and environmental burdens due to high surgical volumes. Using instruments sterilized on a short cycle between sequential same-day ophthalmic surgeries may help improve efficiency and reduce resources used. These instruments are generally processed using autoclaves (i.e., steam sterilizers); the effectiveness of a shorter-cycle method of sterilization is unclear. What Did We Do? To inform decisions regarding the use of autoclaves for short-cycle sterilization for sequential same-day instrument use in ophthalmic surgery, we sought to identify and summarize evidence comparing this method to full-cycle sterilization of wrapped instruments and identify any relevant recommendations. We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence published since 2012. One reviewer screened articles for inclusion based on predefined criteria. What Did We Find? In a laboratory setting to simulate sequential same-day procedures, short-cycle sterilization with interrupted dry time for unwrapped ophthalmic instruments is feasibly as effective as full-cycle sterilization for wrapped instruments using the STATIM autoclave. Similarly, short-cycle sterilization with interrupted dry time for contained ophthalmic instruments is feasibly as effective as full-cycle sterilization for contained instruments using the AMSCO autoclave. For sequential same-day ophthalmic procedures, wet instruments sterilized by a short-cycle process with an interrupted dry time can remain sterile for at least 3 minutes if kept in a covered sterilizer containment device. One guideline recommends that wrapped or unwrapped ophthalmic instruments sterilized by a short-cycle process without full drying should be stored in a covered containment device until retrieved by staff wearing sterile gloves and gowns in the operating room for the subsequent surgery after a short delay. Phaco handpieces should be immediately primed with a balanced salt solution and remain wet as they sit on the sterile instrument table. We did not identify any clinical setting evidence from studies or autoclave manufacturers. It is unclear if clinical outcomes differ between patients undergoing sequential same-day ophthalmic surgeries using short-cycle sterilized instruments and those undergoing surgery using full-cycle sterilized instruments. What Does This Mean? Preliminary laboratory evidence and guideline recommendations supporting the use of autoclaves for short-cycle sterilization of instruments for sequential same-day ophthalmic surgeries are available. However, there is no clinical effectiveness evidence available on this process in patient settings. Future research is necessary to understand the clinical safety of using instruments sterilized by short cycles for sequential same-day use for patients undergoing ophthalmic surgeries. In addition to the evidence and recommendations identified, other factors, such as environmental influence, may be useful considerations when making decisions about short-cycle sterilization for sequential same-day instrument use for ophthalmic surgery.

Debate: How much should nonspecialists be involved in mental health care when resources are limited? A perspective from low- and middle-income countries.

Millions of children and young people (CYP) in low- and middle-income countries (LMICs) have no access to mental health care. This huge treatment gap is primarily due to limited availability of trained mental health professionals. We propose task-sharing as a scalable strategy to expand access to child and adolescent mental health (CAMH) interventions in LMICs. Task-sharing involves using the few mental health specialists in LMICs to train and supervise nonspecialists to provided CAMH interventions. There is strong evidence of clinical and cost effectiveness of task-shared mental health interventions for adults in LMICs and promising evidence for CYP. To succeed, task-shared programmes need to be embedded in a balanced system-wide care setting that includes stakeholder involvement. The existing mental health specialists may require additional training in leadership, supervision, mentoring, service design and evaluation in order to meet the additional expectations of managing task-sharing programmes. The nonspecialists to be trained would need assurances about workload, ongoing supervision, clinical back up for cases that exceed their expertise, certification for their training and career progression. CAMH task-sharing offers good promise for increasing CYP's access to mental health interventions in LMICs. However, planners need to be aware of the important practical, ethical and contextual considerations necessary for success and sustainability.

Continuous Diffused Oxygen Therapy for Wound Healing

What Is the Issue? Wounds are prevalent across health care settings, costing Canada an estimated $12 billion per year in wound care. Chronic wounds (wounds that do not heal in the typical amount of time, which can depend on the size and type of wound) can have a significant impact on a patient’s quality of life and health. Healing tissue has a high need for oxygen. Oxygen can be delivered in several ways, including topical oxygen therapy, which delivers oxygen directly to the wound. One type of topical oxygen therapy is continuously diffused oxygen (CDO) therapy, which uses a device that takes oxygen from the air and then delivers pure, humidified oxygen to the wound. We previously completed a Rapid Review on CDO therapy for wounds in 2020. This review aimed to determine if new evidence has since been published on this topic. What Did We Do? To inform decisions about CDO therapy for wound healing, we sought to identify and summarize literature comparing the clinical effectiveness and cost-effectiveness of CDO therapy versus conventional wound care. We also attempted to identify evidence-based recommendations for the use of CDO therapy. We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence published since 2019. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? CDO therapy appears to be clinically effective for treating patients with diabetic foot ulcers, particularly chronic or hard-to-heal ulcers that have not responded to standard care. Rates of adverse events were comparable between patients receiving CDO and patients receiving standard care. Two cost-effectiveness studies reported that CDO is likely to be cost-effective compared to standard care for patients with chronic, hard-to-heal diabetic foot ulcers. We identified fewer studies for other types of wounds. Preliminary evidence suggests that CDO therapy may be helpful for patients with other types of wounds that are chronic or have not responded to standard care. Reporting on adverse events was limited. Limited evidence suggests that patients receiving CDO therapy had better outcomes if their wound was debrided more frequently as well as if they received CDO therapy for a longer time. The evidence-based guidelines recommend the use of topical oxygen therapy (of which CDO is a subtype) for treating diabetic foot ulcers that have failed to heal with standard care. One guideline suggested that topical oxygen therapy may be considered for other types of non-neoplastic, hard-to-heal wounds. We did not find cost-effectiveness evidence for wounds other than diabetic foot ulcers that met the inclusion criteria for our report. We also did not identify any clinical effectiveness or cost-effectiveness evidence, or any guidelines regarding the use of CDO to treat First Nations, Inuit, and Métis patients, that met the inclusion criteria for our report. What Does This Mean? CDO therapy may be beneficial and more cost-effective than standard care for patients with hard-to-heal, chronic diabetic foot ulcers that have not responded to standard care. Evidence-based guidelines also recommend the use of CDO therapy for this patient population. The clinical effectiveness and cost-effectiveness of CDO therapy for other types of wounds is still unclear. It is also unclear if there is an optimal way to provide CDO (e.g., oxygen flow rate, debridement, length of treatment). We identified limited evidence that reported on patient ethnicity. Considering that some groups, including First Nations, Inuit, and Métis Peoples, have higher rates of diabetes than the overall population in Canada — which may lead to higher rates of diabetic foot ulcers — decision-makers involved in implementing CDO therapy should consider ways to ensure equitable access for all patients who may need this treatment.

Clinical effectiveness of robotic versus laparoscopic and open surgery: an overview of systematic reviews

ObjectiveTo undertake a review of systematic reviews on the clinical outcomes of robotic-assisted surgery across a mix of intracavity procedures, using evidence mapping to inform the decision makers on the...

Lenvatinib plus pembrolizumab for untreated advanced renal cell carcinoma: a systematic review and cost-effectiveness analysis.

Renal cell carcinoma is the most common type of kidney cancer, comprising approximately 85% of all renal malignancies. Patients with advanced renal cell carcinoma are the focus of this National Institute for Health and Care Excellence multiple technology appraisal. A patient's risk of disease progression depends on a number of prognostic risk factors; patients are categorised as having intermediate/poor risk or favourable risk of disease progression. The objectives of this multiple technology appraisal were to appraise the clinical effectiveness and cost-effectiveness of lenvatinib plus pembrolizumab versus relevant comparators listed in the final scope issued by the National Institute for Health and Care Excellence: sunitinib, pazopanib, tivozanib, cabozantinib and nivolumab plus ipilimumab. The assessment group carried out clinical and economic systematic reviews and assessed the clinical and cost-effectiveness evidence submitted by Eisai, Hatfield, Hertfordshire, UK (the manufacturer of lenvatinib) and Merck Sharp & Dohme, Whitehouse Station, NJ, USA (the manufacturer of pembrolizumab). The assessment group carried out fixed-effects network meta-analyses using a Bayesian framework to generate evidence for clinical effectiveness. As convergence issues occurred due to sparse data, random-effects network meta-analysis results were unusable. The assessment group did not develop a de novo economic model, but instead modified the partitioned survival model provided by Merck Sharp & Dohme. The assessment group clinical systematic review identified one relevant randomised controlled trial (CLEAR trial). The CLEAR trial is a good-quality, phase III, multicentre, open-label trial that provided evidence for the efficacy and safety of lenvatinib plus pembrolizumab compared with sunitinib. The assessment group progression-free survival network meta-analysis results for all three risk groups should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons owing to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. The assessment group overall survival network meta-analysis results for the intermediate-/poor-risk subgroup suggested that there was a numerical, but not statistically significant, improvement in the overall survival for patients treated with lenvatinib plus pembrolizumab compared with patients treated with cabozantinib or nivolumab plus ipilimumab. Because of within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption, the assessment group overall survival network meta-analysis results for the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons. Only one cost-effectiveness study was included in the assessment group review of cost-effectiveness evidence. The study was limited to the all-risk population, undertaken from the perspective of the US healthcare system and included comparators that are not recommended by the National Institute for Health and Care Excellence for patients with untreated advanced renal cell carcinoma. Therefore, the extent to which resource use and results are generalisable to the NHS is unclear. The assessment group cost-effectiveness results from the modified partitioned survival model focused on the intermediate-/poor-risk and favourable-risk subgroups. The assessment group cost-effectiveness results, generated using list prices for all drugs, showed that, for all comparisons in the favourable-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated fewer benefits than all other treatments available to NHS patients. For the intermediate-/poor-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated more benefits than treatment with cabozantinib and nivolumab plus ipilimumab. Good-quality clinical effectiveness evidence for the comparison of lenvatinib plus pembrolizumab with sunitinib is available from the CLEAR trial. For most of the assessment group Bayesian hazard ratio network meta-analysis comparisons, it is difficult to reach conclusions due to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. However, the data (clinical effectiveness and cost-effectiveness) used to populate the economic model are relevant to NHS clinical practice and can be used to inform National Institute for Health and Care Excellence decision-making. The assessment group cost-effectiveness results, generated using list prices for all drugs, show that lenvatinib plus pembrolizumab is less cost-effective than all other treatment options. This study is registered as PROSPERO CRD4202128587. This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR134985) and is published in full in Health Technology Assessment; Vol. 28, No. 49. See the NIHR Funding and Awards website for further award information.

Neuromodulation Treatments Targeting Pathological Synchrony for Tinnitus in Adults: A Systematic Review.

(1) Background: Tinnitus involves the conscious awareness of a tonal or composite noise for which there is no identifiable corresponding external acoustic source. For many people, tinnitus is a disorder associated with symptoms of emotional distress, cognitive dysfunction, autonomic arousal, behavioural changes, and functional disability. Many symptoms can be addressed effectively using education or cognitive behavioural therapy. However, there is no treatment that effectively reduces or alters tinnitus-related neurophysiological activity and thus the tinnitus percept. In this systematic review, we evaluated the effectiveness of neuromodulation therapies for tinnitus that explicitly target pathological synchronous neural activity. (2) Methods: Multiple databases were searched for randomised controlled trials of neuromodulation interventions for tinnitus in adults, with 24 trials included. The risk of bias was assessed, and where appropriate, meta-analyses were performed. (3) Results: Few trials used acoustic, vagal nerve, or transcranial alternating current stimulation, or bimodal stimulation techniques, with limited evidence of neuromodulation or clinical effectiveness. Multiple trials of transcranial direct current stimulation (tDCS) were identified, and a synthesis demonstrated a significant improvement in tinnitus symptom severity in favour of tDCS versus control, although heterogeneity was high. (4) Discussion: Neuromodulation for tinnitus is an emerging but promising field. Electrical stimulation techniques are particularly interesting, given recent advances in current flow modelling that can be applied to future studies.

Key elements of Korean medicine treatment for idiopathic short-stature: A qualitative SWOT analysis based on Korean medicine doctors' views.

The objective of this study was to explore the key elements of Korean medicine (KM) treatment for idiopathic short stature (ISS) by analyzing the strengths, weaknesses, opportunities, and threats (SWOT). This was a qualitative study of interviews with 7 KM doctors who had at least 3 years of experience in KM treatment for ISS. Based on the content, a SWOT and a cross-SWOT analysis were conducted. A SWOT of KM treatment for ISS was derived as follows: Strengths included the additional positive health promotion effects and fewer possibilities of adverse effects. Weaknesses included insufficient long-term evidence on the effect and safety and difficulty in predicting prognosis for ISS treatment in KM. Opportunities included a growing interest in height growth in general and the need for parental involvement in children height growth. Threats included the limited use of diagnostic devices and relatively high medical costs due to non-coverage by national health insurance. This study suggests that the safety and clinical effectiveness evidence of KM treatment for height growth should be guaranteed through well-designed large-scale long-term studies. Various strategies are needed to promote the use of diagnostic and evaluation devices for ISS treatment in KM clinical settings.

Choline Supplementation for Infants, Children, and Pregnant People

What Is the Issue? Choline is an essential nutrient produced by humans and animals and is important during pregnancy, fetal growth, and the development of the brain and nervous system. Most people do not get enough choline from their diet. Fetal alcohol spectrum disorders (FASD) are a set of conditions where fetuses have been exposed to alcohol and this affects memory, learning, and development from early childhood to later life. Choline supplements are products used to complement choline-deficient diets. Given the role of choline in fetal development, choline supplements are a potential intervention to support pregnancy or to mitigate the developmental harms in children from prenatal exposure to alcohol if supported by evidence of their effectiveness for these purposes. What Did We Do? To inform decisions about the use and timing of choline supplementation to support health outcomes in infants and children, CADTH sought to identify and summarize the literature about the effectiveness and safety of choline supplementation given to any pregnant people or given to children with either prenatal alcohol exposure or FASD. We also attempted to identify evidence-based recommendations for using choline supplementation in these populations. We searched key resources and conducted a focused internet search for relevant evidence published since 2014. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? We found few publications investigating this topic, and several studies had low statistical power and imprecise results. The clinical evidence was mixed depending on whether choline was given to the pregnant person or child, which interventional groups were compared, what the clinical exposures or diagnoses were in the study population, the time point and duration of choline supplementation, which outcomes were measured, and how old children were during follow-up. For choline supplementation in healthy pregnant people, evidence was mixed for infant and child neurocognitive and neurodevelopmental outcomes or behavioural symptoms; there were little-to-no differences in safety outcomes. For choline supplementation in pregnant people exposed to alcohol, evidence was mixed for infant and child neurocognitive and neurodevelopmental outcomes, body size, and brain region sizes; some minor side effects were reported overall. For choline supplementation in children with FASD, most evidence showed little-to-no benefits for neurocognitive and neurodevelopmental outcomes, and brain structure; limited evidence showed higher fishy body odour and some other unspecified adverse symptoms for children given choline. Guidelines based mostly on low-quality evidence or expert opinion recommend that all pregnant people, including those with gestational diabetes mellitus or on vegan or vegetarian diets, increase their choline intake through diet or supplements. We did not find clinical effectiveness evidence for choline supplementation in infants with FASD, or guidelines regarding choline supplementation in either infants or children with FASD, that met inclusion criteria for our report. What Does it Mean? Health care professionals and decision-makers can use this evidence to inform decisions around applicability of choline supplementation for pregnant people, or for infants and children with FASD, in their practice. There may be a need to balance the knowledge that choline intake is low at the population level and important for fetal development with the identified clinical effectiveness evidence for choline supplementation, which was limited and mixed for all evaluated patient populations. Careful consideration of the following may also be important to inform decisions about the appropriateness of choline supplementation: the care plan and other intensive and concurrent interventions for children with FASD; stigma and challenges faced by pregnant people and children in the context of prenatal alcohol exposure; cultural dietary practices; and accessibility, cost, and availability of supplements.

HTA45 Comparison of the Use of Real-World Evidence for Clinical Effectiveness in HTA Pre- and Post- Introduction of the NICE Framework – an Update

HTA45 Comparison of the Use of Real-World Evidence for Clinical Effectiveness in HTA Pre- and Post- Introduction of the NICE Framework – an Update

Potential novel role of the human amniotic membrane as a sustainable hemostat.

Acute hemorrhage can cause significant morbidity and mortality arising from trauma, bleeding disorders, surgical procedures, or obstetric complications. Surgical hemostasis methods may fail to stop acute bleeding due to the complex bleeding dynamics of each bleeding type. Therefore, developing safe and effective topical hemostatic agents remains crucial. The human amniotic membrane (hAM) has established clinical evidence of effectiveness in promoting wound healing and tissue regeneration. Despite its unique biological and immunologic properties and its structural composition of established hemostatic elements, the hemostatic role of hAM has not been yet explored. The present study aimed to investigate this potential role and to describe the development protocol and characterization of hAM-derived topical hemostat. Surface electron microscope (SEM) imaging and Fourier transform infrared (FTIR) spectroscopy were used for characterization, and mouse models with induced peritoneal and tail wound bleeding were employed to evaluate the hemostatic effectiveness using physiological studies, in comparison to a chitosan-based combat-scale hemostat. The hAM hemostat showed a distinctive composition by SEM and FTIR. Applying equal masses of the hAM hemostat, the commercial hemostat, or a combination reduced peritoneal wound bleeding time to averages of 108.4, 86.2, and 76.8 s, respectively, compared to the control group (300 s). Tail wound bleeding times were similarly reduced with no significant difference between the hAM and the commercial hemostat (P values = 0.29, 0.34 in peritoneal and tail wounds, respectively). Neither hemostat affected coagulation time. This study describes a simple cost-effective preparation protocol for a hAM-based hemostatic agent. The long-recognized safety, sustainability, and immunotolerance advantages of hAM can establish superiority over commercial hemostats with reported safety concerns. Robust research validation in larger-scale bleeding models is required for wider applications and severe bleeding types.

Extended-Release Calcifediol: A Data Journey from Phase 3 Studies to Real-World Evidence Highlights the Importance of Early Treatment of Secondary Hyperparathyroidism.

Early secondary hyperparathyroidism (SHPT) diagnosis and treatment are crucial to delay the progression of SHPT and related complications, in particular, cardiovascular events and bone fractures. Extended-release calcifediol (ERC) has been developed for the treatment of SHPT in patients with stage 3/4 chronic kidney disease (CKD) and vitamin D insufficiency (VDI). This review compares baseline characteristics and treatment responses of SHPT patients receiving ERC in phase 3 studies with those treated with ERC in a real-world study. Mean ± standard deviation baseline parathyroid hormone (PTH) levels were 147 ± 56 pg/mL and 148 ± 64 pg/mL in the phase 3 ERC cohorts, and 181 ± 98 pg/mL in the real-world study. Other baseline laboratory parameters were consistent between the clinical and real-world studies. ERC treatment increased 25-hydroxyvitamin D (25(OH)D) and significantly reduced PTH levels, regardless of baseline CKD stage, in all studies. In the pooled phase 3 per-protocol populations, 74% of the ERC cohort were uptitrated to 60 μg/day after 12 weeks at 30 μg/day, 97% attained 25(OH)D levels ≥30 ng/mL, and 40% achieved ≥30% PTH reduction. Despite a much lower rate of uptitration in the real-world study, 70% of patients achieved 25(OH)D levels ≥30 ng/mL, and 40% had a ≥30% reduction in PTH. These data establish a "continuum" of clinical and real-world evidence of ERC effectiveness for treating SHPT, irrespective of CKD stage, baseline PTH levels, and ERC dose. This evidence supports early treatment initiation with ERC, following diagnosis of SHPT, VDI, and stage 3 CKD, to delay SHPT progression.

Challenges and Opportunities in Interdisciplinary Research and Real-World Data for Treatment Sequences in Health Technology Assessments.

With an ever-increasing number of treatment options, the assessment of treatment sequences has become crucial in health technology assessment (HTA). This review systematically explores the multifaceted challenges inherent in evaluating sequences, delving into their interplay and nuances that go beyond economic model structures. We synthesised a 'roadmap' of literature from key methodological studies, highlighting the evolution of recent advances and emerging research themes. These insights were compared against HTA guidelines to identify potential avenues for future research. Our findings reveal a spectrum of challenges in sequence evaluation, encompassing selecting appropriate decision-analytic modelling approaches and comparators, deriving appropriate clinical effectiveness evidence in the face of data scarcity, scrutinising effectiveness assumptions and statistical adjustments, considering treatment displacement, and optimising model computations. Integrating methodologies from diverse disciplines-statistics, epidemiology, causal inference, operational research and computer science-has demonstrated promise in addressing these challenges. An updated review of application studies is warranted to provide detailed insights into the extent and manner in which these methodologies have been implemented. Data scarcity on the effectiveness of treatment sequences emerged as a dominant concern, especially because treatment sequences are rarely compared in clinical trials. Real-world data (RWD) provide an alternative means for capturing evidence on effectivenessand future research should prioritise harnessing causal inference methods, particularly Target Trial Emulation, to evaluate treatment sequence effectiveness using RWD. This approach is also adaptable for analysing trials harbouring sequencing information and adjusting indirect comparisons when collating evidence from heterogeneous sources. Such investigative efforts could lend support to reviews of HTA recommendations and contribute to synthesising external control arms involving treatment sequences.

Anti-amyloid therapies: are they effective and safe?

Abstract After numerous unsuccessful attempts to create a therapy that could alter the course of Alzheimer’s disease, first monoclonal antibodies targeting amyloid-β in the brain have finally shown consistent evidence of clinical effectiveness. These therapies not only slow the progression of the disease, but also show positive results in secondary clinical outcomes and reduced amyloid-β levels on PET scans. This presentation will examine the main features of the previous failed trials and explore possible reasons for their lack of success in developing a treatment for early-stage Alzheimer’s disease. It will also compare the safety profiles of various antibodies and point out precautions that should be taken when using them in regular clinical practice. Furthermore, it will be discussed how blood-based biomarkers can revolutionize the clinical care pathway, making it easier to adopt antibody treatments. A comprehensive model that integrates case-finding and treatment across various healthcare sectors will be proposed. In conclusion, we may have made a significant breakthrough by demonstrating that reducing amyloid-β levels leads to clinical benefits, not just changes in biomarkers. As the new generation of drugs becomes more commonly used, we will see whether their statistical effectiveness translates into meaningful clinical changes. This could mark the start of a new phase in the development of drugs for Alzheimer’s disease.Disclosure of InterestNone Declared

Intra-Articular Hyaluronic Acid for Osteoarthritis of the Hip, Shoulder, and Ankle

What Is the Issue?
 
 Osteoarthritis (OA) is a chronic disease of the joints, such as the hip, shoulder, and ankle. OA causes the joints to be painful, unstable, and less functional. In adults 55 years and younger, joint trauma is a common cause of OA.
 Hyaluronic acid (HA) is a naturally occurring molecule found in human cells that provides lubrication when injected into the joint. HA injections are a less invasive option than surgery, with potentially fewer complications.
 To support decision-making about treating hip, shoulder, or ankle OA in adults 55 years and younger, it is important to understand the potential benefits and harms of using HA in this population.
 
 What Did We Do?
 
 We reviewed the clinical effectiveness of high molecular weight (MW) injection of HA in adults between the ages of 18 and 55 years with OA of the hip, shoulder, or ankle joints to guide decisions on the use of high MW HA injection.
 An information specialist searched for peer-reviewed and grey literature sources published on January 1, 2013 to December 12, 2023. One reviewer screened citations and selected and critically appraised the included studies.
 
 What Did We Find?
 
 The evidence for this report was based on observational before-and-after studies. We found no relevant comparative studies examining the effect of high MW HA versus placebo or no treatment.
 While most studies reported post-treatment outcome improvements, it is uncertain whether high MW injection of HA improves pain, function, and disability in adults 55 years and under with hip, shoulder, or ankle OA. This is due to the low-quality evidence, small sample sizes, and methodological problems. Serious side effects of high MW HA were not reported.
 
 What Does This Mean?
 
 Due to the uncertainty of the clinical effectiveness evidence, health care providers and decision-makers may consider other factors when considering high MW IA-HA for patients with hip, shoulder, or ankle OA; these factors could include acceptability, feasibility, costs, health equity, and patient values and preferences.
 Future research from randomized studies in large populations is needed to understand the effectiveness and safety of high MW HA injections for hip, shoulder, and ankle OA.

Deep brain stimulation for refractory major depressive disorder: a comprehensive review.

Deep brain stimulation (DBS) has emerged as a promising treatment for select patients with refractory major depressive disorder (MDD). The clinical effectiveness of DBS for MDD has been demonstrated in meta-analyses, open-label studies, and a few controlled studies. However, randomized controlled trials have yielded mixed outcomes, highlighting challenges that must be addressed prior to widespread adoption of DBS for MDD. These challenges include tracking MDD symptoms objectively to evaluate the clinical effectiveness of DBS with sensitivity and specificity, identifying the patient population that is most likely to benefit from DBS, selecting the optimal patient-specific surgical target and stimulation parameters, and understanding the mechanisms underpinning the therapeutic benefits of DBS in the context of MDD pathophysiology. In this review, we provide an overview of the latest clinical evidence of MDD DBS effectiveness and the recent technological advancements that could transform our understanding of MDD pathophysiology, improve the clinical outcomes for MDD DBS, and establish a path forward to develop more effective neuromodulation therapies to alleviate depressive symptoms.

Ketamine for Adults With Treatment-Resistant Depression or Posttraumatic Stress Disorder: A 2023 Update

What Is the Issue?
 
 Many drug treatments are available for depression, but 22% of people in Canada with the condition have treatment-resistant depression (TRD). For people with TRD, standard drug treatments do not improve their symptoms or do not work for long, and their depression persists.
 Posttraumatic stress disorder (PTSD) is a disabling mental health condition that affects about 9% of people in Canada in their lifetime. Few drugs are available for treating PTSD, none of which are considered effective.
 Ketamine is a hallucinogenic drug used primarily for anesthesia. Ketamine has also been explored for other indications, such as TRD and PTSD, generating questions about whether it could be a treatment option for these conditions.
 
 What Did We Do?
 
 We conducted a review of the clinical effectiveness, cost-effectiveness, and evidence-based guidelines on the use of ketamine in adults with TRD or PTSD, to help guide decisions on the use of ketamine for managing these conditions.
 An information specialist conducted a search of peer-reviewed and grey literature sources published in March 2022 or later. One reviewer screened citations and selected and critically appraised the included studies.
 CADTH engaged a patient with lived experience of TRD who shared their experiences and perspectives on ketamine-assisted psychotherapy. These perspectives helped us to contextualize the literature and appreciate nuances of the experience.
 
 What Did We Find?
 
 Ketamine could lead to an immediate improvement in depressive symptoms and suicidal ideation compared to placebo or midazolam in adults with TRD. The longest follow-up was 90 days, and the longest lasting effect after a dose was 28 days. Serious side effects of ketamine — such as dissociation — were rare and short-lived, lasting hours, in adults with TRD.
 It is uncertain if ketamine is an effective and safe treatment for symptoms of PTSD, due to little to no evidence suggesting its effectiveness or safety against placebo, midazolam, or opioids.
 Most studies evaluated ketamine given intravenously, and we found limited evidence on intramuscular (IM), subcutaneous, and intranasal routes of administration. We found no studies on oral or sublingual administration of ketamine and no studies comparing the different ways that ketamine can be given for TRD or PTSD.
 An economic evaluation found that IV ketamine was likely to be cost-effective compared to intranasal esketamine in adults with TRD from a health care perspective in the US. However, from a patient perspective, IV ketamine was unlikely to be cost-effective compared to esketamine, due to comparable levels of clinical effectiveness and lower costs of esketamine attributable to commercial insurance coverage and manufacturer assistance programs.
 A US guideline on TRD suggests ketamine as augmentation to antidepressants. A US guideline on PTSD does not suggest the use of ketamine as therapy.
 The patient contributor CADTH engaged for this review highlighted the benefits, stigma, and barriers of ketamine therapy, including financial implications.
 
 What Does This Mean?
 
 There is some clinical effectiveness and cost-effectiveness evidence and a guideline recommendation to support the short-term use of ketamine in adults with TRD.
 Clinical effectiveness evidence and a guideline recommendation do not support the use of ketamine in adults with PTSD.
 Future research is necessary to understand the effectiveness and safety of ketamine as therapy for TRD in larger populations over longer periods and for PTSD for any follow-up duration.
 Decision-makers should consider offering ketamine in an equitable manner.