Non-pharmacological interventions to manage psychological distress in patients living with cancer: a systematic review.

BACKGROUND: Psychological distress is common in patients with cancer; interfering with physical and psychological wellbeing, and hindering management of physical symptoms. Our aim was to systematically review published evidence on non-pharmacological interventions for cancer-related psychological distress, at all stages of the disease. METHODS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review was registered on PROSPERO (CRD42022311729). Searches were made using eight online databases to identify studies meeting our inclusion criteria. Data were collected on outcome measures, modes of delivery, resources and evidence of efficacy. A meta-analysis was planned if data allowed. Quality was assessed using the Mixed Methods Appraisal Tool (MMAT). RESULTS: Fifty-nine studies with 17,628 participants were included. One third of studies included mindfulness, talking or group therapies. Half of all studies reported statistically significant improvements in distress. Statistically significant intervention effects on distress were most prevalent for mindfulness techniques. Four of these mindfulness studies had moderate effect sizes (d = -0.71[95% CI: -1.04, -0.37] p < 0.001) (d = -0.60 [95% CI: -3.44, -0.89] p < 0.001) (d = -0.77 [CI: -0.146, -1.954] p < 0.01) (d = -0.69 [CI: -0.18, -1.19] p = 0.008) and one had a large effect size (d = -1.03 [95% CI: -1.51, -0.54] p < 0.001). Heterogeneity of studies precluded meta-analysis. Study quality was variable and some had a high risk of bias. CONCLUSIONS: The majority of studies using a mindfulness intervention in this review are efficacious at alleviating distress. Mindfulness-including brief, self-administered interventions-merits further investigation, using adequately powered, high-quality studies. SYSTEMATIC REVIEW REGISTRATION: This systematic review is registered on PROSPERO, number CRD42022311729.

Characterising the Features of 381 Clinical Studies Evaluating Transcutaneous Electrical Nerve Stimulation (TENS) for Pain Relief: A Secondary Analysis of the Meta-TENS Study to Improve Future Research.

Background and Objectives: Characterising the features of methodologies, clinical attributes and intervention protocols, of studies is valuable to advise directions for research and practice. This article reports the findings of a secondary analysis of the features from studies screened as part of a large systematic review of TENS (the meta-TENS study). Materials and Methods: A descriptive analysis was performed on information associated with methodology, sample populations and intervention protocols from 381 randomised controlled trials (24,532 participants) evaluating TENS delivered at a strong comfortable intensity at the painful site in adults with pain, irrespective of diagnosis. Results: Studies were conducted in 43 countries commonly using parallel group design (n = 334) and one comparator group (n = 231). Mean ± standard deviation (SD) study sample size (64.05 ± 58.29 participants) and TENS group size (27.67 ± 21.90 participants) were small, with only 13 of 381 studies having 100 participants or more in the TENS group. Most TENS interventions were 'high frequency' (>10 pps, n = 276) and using 100 Hz (109/353 reports that stated a pulse frequency value). Of 476 comparator groups, 54.2% were active treatments (i.e., analgesic medication(s), exercise, manual therapies and electrophysical agents). Of 202 placebo comparator groups, 155 used a TENS device that did not deliver currents. At least 216 of 383 study groups were able to access other treatments whilst receiving TENS. Only 136 out of 381 reports included a statement about adverse events. Conclusions: Clinical studies on TENS are dominated by small parallel group evaluations of high frequency TENS that are often contaminated by concurrent treatment(s). Study reports tended focus on physiological and clinical implications rather than the veracity of methodology and findings. Previously published criteria for designing and reporting TENS studies were neglected and this should be corrected in future research using insights gleaned from this analysis.

Comparing the safety and efficacy of ruxolitinib in patients with Dynamic International Prognostic Scoring System low-, intermediate-1-, intermediate-2-, and high-risk myelofibrosis in JUMP, a Phase 3b, expanded-access study.

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, has demonstrated durable improvements in patients with myelofibrosis. In this analysis of the Phase 3b JUMP study, which included patients aged ≥18 years with a diagnosis of primary or secondary myelofibrosis, we assessed the safety and efficacy of ruxolitinib in patients stratified by Dynamic International Prognostic Scoring System (DIPSS) risk categories. Baseline characteristic data were available to assess DIPSS status for 1844 of the 2233 enrolled patients; 60, 835, 755, and 194 in the low-, intermediate (Int)-1-, Int-2-, and high-risk groups, respectively. Ruxolitinib was generally well tolerated across all risk groups, with an adverse-event (AE) profile consistent with previous reports. The most common hematologic AEs were thrombocytopenia and anemia, with highest rates of Grade ≥3 events in high-risk patients. Approximately, 73% of patients experienced ≥50% reductions in palpable spleen length at any point in the ≤24-month treatment period, with highest rates in lower-risk categories (low, 82.1%; Int-1, 79.3%; Int-2, 67.1%; high risk, 61.6%). Median time to spleen length reduction was 5.1 weeks and was shortest in lower-risk patients. Across measures, 40%-57% of patients showed clinically meaningful symptom improvements, which were observed from 4 weeks after treatment initiation and maintained throughout the study. Overall survival (OS) was 92% at Week 72 and 75% at Week 240 (4.6 years). Median OS was longer for Int-2-risk than high-risk patients (253.6 vs. 147.3 weeks), but not evaluable in low-/Int-1-risk patients. By Week 240, progression-free survival (PFS) and leukemia-free survival (LFS) rates were higher in lower-risk patients (PFS: low, 90%; Int-1, 82%; Int-2, 46%; high risk, 15%; LFS: low, 92%; Int-1, 86%; Int-2, 58%; high risk, 19%). Clinical benefit was seen across risk groups, with more rapid improvements in lower risk patients. Overall, this analysis indicates that ruxolitinib benefits lower-risk DIPSS patients in addition to higher risk.

Does TENS Reduce the Intensity of Acute and Chronic Pain? A Comprehensive Appraisal of the Characteristics and Outcomes of 169 Reviews and 49 Meta-Analyses.

Background and Objectives: Uncertainty about the clinical efficacy of transcutaneous electric nerve stimulation (TENS) to alleviate pain spans half a century. There has been no attempt to synthesise the entire body of systematic review evidence. The aim of this comprehensive review was to critically appraise the characteristics and outcomes of systematic reviews evaluating the clinical efficacy of TENS for any type of acute and chronic pain in adults. Materials and Methods: We searched electronic databases for full reports of systematic reviews of studies, overviews of systematic reviews, and hybrid reviews that evaluated the efficacy of TENS for any type of clinical pain in adults. We screened reports against eligibility criteria and extracted data related to the characteristics and outcomes of the review, including effect size estimates. We conducted a descriptive analysis of extracted data. Results: We included 169 reviews consisting of eight overviews, seven hybrid reviews and 154 systematic reviews with 49 meta-analyses. A tally of authors' conclusions found a tendency toward benefits from TENS in 69/169 reviews, no benefits in 13/169 reviews, and inconclusive evidence in 87/169 reviews. Only three meta-analyses pooled sufficient data to have confidence in the effect size estimate (i.e., pooled analysis of >500 events). Lower pain intensity was found during TENS compared with control for chronic musculoskeletal pain and labour pain, and lower analgesic consumption was found post-surgery during TENS. The appraisal revealed repeated shortcomings in RCTs that have hindered confident judgements about efficacy, resulting in stagnation of evidence. Conclusions: Our appraisal reveals examples of meta-analyses with 'sufficient data' demonstrating benefit. There were no examples of meta-analyses with 'sufficient data' demonstrating no benefit. Therefore, we recommend that TENS should be considered as a treatment option. The considerable quantity of reviews with 'insufficient data' and meaningless findings have clouded the issue of efficacy. We offer solutions to these issues going forward.

Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts.

Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF). Ruxolitinib was assessed in JUMP, a large (N = 2233), phase 3b, expanded-access study in MF in countries without access to ruxolitinib outside a clinical trial, which included patients with low platelet counts (<100 × 109 /l) and patients without splenomegaly - populations that have not been extensively studied. The most common adverse events (AEs) were anaemia and thrombocytopenia, but they rarely led to discontinuation (overall, 5·4%; low-platelet cohort, 12·3%). As expected, rates of worsening thrombocytopenia were higher in the low-platelet cohort (all grades, 73·2% vs. 53·5% overall); rates of anaemia were similar (all grades, 52·9% vs. 59·5%). Non-haematologic AEs, including infections, were mainly grade 1/2. Overall, ruxolitinib led to meaningful reductions in spleen length and symptoms, including in patients with low platelet counts, and symptom improvements in patients without splenomegaly. In this trial, the largest study of ruxolitinib in patients with MF to date, the safety profile was consistent with previous reports, with no new safety concerns identified. This study confirms findings from the COMFORT studies and supports the use of ruxolitinib in patients with platelet counts of 50-100 × 109 /l. (ClinicalTrials.gov identifier NCT01493414).

Acupuncture for the Relief of Chronic Pain: A Synthesis of Systematic Reviews.

Background and Objectives: It is estimated that 28 million people in the UK live with chronic pain. A biopsychosocial approach to chronic pain is recommended which combines pharmacological interventions with behavioural and non-pharmacological treatments. Acupuncture represents one of a number of non-pharmacological interventions for pain. In the current climate of difficult commissioning decisions and constantly changing national guidance, the quest for strong supporting evidence has never been more important. Although hundreds of systematic reviews (SRs) and meta-analyses have been conducted, most have been inconclusive, and this has created uncertainty in clinical policy and practice. There is a need to bring all the evidence together for different pain conditions. The aim of this review is to synthesise SRs of RCTs evaluating the clinical efficacy of acupuncture to alleviate chronic pain and to consider the quality and adequacy of the evidence, including RCT design. Materials and Methods: Electronic databases were searched for English language SRs and meta-analyses on acupuncture for chronic pain. The SRs were scrutinised for methodology, risk of bias and judgement of efficacy. Results: A total of 177 reviews of acupuncture from 1989 to 2019 met our eligibility criteria. The majority of SRs found that RCTs of acupuncture had methodological shortcomings, including inadequate statistical power with a high risk of bias. Heterogeneity between RCTs was such that meta-analysis was often inappropriate. Conclusions: The large quantity of RCTs on acupuncture for chronic pain contained within systematic reviews provide evidence that is conflicting and inconclusive, due in part to recurring methodological shortcomings of RCTs. We suggest that an enriched enrolment with randomised withdrawal design may overcome some of these methodological shortcomings. It is essential that the quality of evidence is improved so that healthcare providers and commissioners can make informed choices on the interventions which can legitimately be provided to patients living with chronic pain.

Epidemiologic and clinical characteristics of nontransfusion-dependent thalassemia in the United States.

BACKGROUND: Nontransfusion-dependent thalassemia (NTDT) refers to a diverse group of thalassemia mutations and clinical phenotypes that do not require chronic transfusions. It is increasingly prevalent in the United States. PROCEDURE: This study reviews the epidemiology and clinical characteristics of 138 patients with NTDT treated at four US thalassemia centers from 1997 to 2014. Data on laboratory results, transfusions, and clinical complications were collected from patient charts. RESULTS: Overall, 84 patients with α-thalassemia (62 deletional hemoglobin H; 22 nondeletional hemoglobin H), 39 with ß-thalassemia (26 with homozygous or double heterozygous ß mutations; 13 with single ß mutations with or without α triplication), and 15 with E/ß-thalassemia (12 E/ß0 ; three E/ß+ ) were identified. At study entry, the median age for patients with α-thalassemia was 2.3 years; 9.2 years for patients with ß-thalassemia and 2.2 years for patients with E/ß-thalassemia. Most patients with α-thalassemia were Asian. Patients with ß-thalassemia were predominantly Caucasian (46%) or of African descent (36%). Twenty percent of patients were born outside the United States and 5% were transfused before immigration. Complications varied by genotype and age. Individuals with nondeletional hemoglobin H were severely affected and, despite their young age, had many complications. Iron overload increased with age and was more common in patients who received transfusions. CONCLUSIONS: NTDT in the United States is a multi-ethnic disease with different genotypic mutations and phenotypic manifestations. A higher than expected proportion of patients was Black/African American. NTDT-related complications are common and increase with age, supporting a need for early diagnosis.

Transcutaneous electrical nerve stimulation (TENS) for fibromyalgia in adults.

BACKGROUND: Fibromyalgia is characterised by persistent, widespread pain; sleep problems; and fatigue. Transcutaneous electrical nerve stimulation (TENS) is the delivery of pulsed electrical currents across the intact surface of the skin to stimulate peripheral nerves and is used extensively to manage painful conditions. TENS is inexpensive, safe, and can be self-administered. TENS reduces pain during movement in some people so it may be a useful adjunct to assist participation in exercise and activities of daily living. To date, there has been only one systematic review in 2012 which included TENS, amongst other treatments, for fibromyalgia, and the authors concluded that TENS was not effective. OBJECTIVES: To assess the analgesic efficacy and adverse events of TENS alone or added to usual care (including exercise) compared with placebo (sham) TENS; no treatment; exercise alone; or other treatment including medication, electroacupuncture, warmth therapy, or hydrotherapy for fibromyalgia in adults. SEARCH METHODS: We searched the following electronic databases up to 18 January 2017: CENTRAL (CRSO); MEDLINE (Ovid); Embase (Ovid); CINAHL (EBSCO); PsycINFO (Ovid); LILACS; PEDRO; Web of Science (ISI); AMED (Ovid); and SPORTDiscus (EBSCO). We also searched three trial registries. There were no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-randomised trials of TENS treatment for pain associated with fibromyalgia in adults. We included cross-over and parallel-group trial designs. We included studies that evaluated TENS administered using non-invasive techniques at intensities that produced perceptible TENS sensations during stimulation at either the site of pain or over nerve bundles proximal (or near) to the site of pain. We included TENS administered as a sole treatment or TENS in combination with other treatments, and TENS given as a single treatment or as a course of treatments. DATA COLLECTION AND ANALYSIS: Two review authors independently determined study eligibility by assessing each record and reaching agreement by discussion. A third review author acted as arbiter. We did not anonymise the records of studies before assessment. Two review authors independently extracted data and assessed risk of bias of included studies before entering information into a 'Characteristics of included studies' table. Primary outcomes were participant-reported pain relief from baseline of 30% or greater or 50% or greater, and Patient Global Impression of Change (PGIC). We assessed the evidence using GRADE and added 'Summary of findings' tables. MAIN RESULTS: We included eight studies (seven RCTs, one quasi-RCT, 315 adults (299 women), aged 18 to 75 years): six used a parallel-group design and two used a cross-over design. Sample sizes of intervention arms were five to 43 participants.Two studies, one of which was a cross-over design, compared TENS with placebo TENS (82 participants), one study compared TENS with no treatment (43 participants), and four studies compared TENS with other treatments (medication (two studies, 74 participants), electroacupuncture (one study, 44 participants), superficial warmth (one cross-over study, 32 participants), and hydrotherapy (one study, 10 participants)). Two studies compared TENS plus exercise with exercise alone (98 participants, 49 per treatment arm). None of the studies measured participant-reported pain relief of 50% or greater or PGIC. Overall, the studies were at unclear or high risk of bias, and in particular all were at high risk of bias for sample size.Only one study (14 participants) measured the primary outcome participant-reported pain relief of 30% or greater. Thirty percent achieved 30% or greater reduction in pain with TENS and exercise compared with 13% with exercise alone. One study found 10/28 participants reported pain relief of 25% or greater with TENS compared with 10/24 participants using superficial warmth (42 °C). We judged that statistical pooling was not possible because there were insufficient data and outcomes were not homogeneous.There were no data for the primary outcomes participant-reported pain relief from baseline of 50% or greater and PGIC.There was a paucity of data for secondary outcomes. One pilot cross-over study of 43 participants found that the mean (95% confidence intervals (CI)) decrease in pain intensity on movement (100-mm visual analogue scale (VAS)) during one 30-minute treatment was 11.1 mm (95% CI 5.9 to 16.3) for TENS and 2.3 mm (95% CI 2.4 to 7.7) for placebo TENS. There were no significant differences between TENS and placebo for pain at rest. One parallel group study of 39 participants found that mean ± standard deviation (SD) pain intensity (100-mm VAS) decreased from 85 ± 20 mm at baseline to 43 ± 20 mm after one week of dual-site TENS; decreased from 85 ± 10 mm at baseline to 60 ± 10 mm after single-site TENS; and decreased from 82 ± 20 mm at baseline to 80 ± 20 mm after one week of placebo TENS. The authors of seven studies concluded that TENS relieved pain but the findings of single small studies are unlikely to be correct.One study found clinically important improvements in Fibromyalgia Impact Questionnaire (FIQ) subscales for work performance, fatigue, stiffness, anxiety, and depression for TENS with exercise compared with exercise alone. One study found no additional improvements in FIQ scores when TENS was added to the first three weeks of a 12-week supervised exercise programme.No serious adverse events were reported in any of the studies although there were reports of TENS causing minor discomfort in a total of 3 participants.The quality of evidence was very low. We downgraded the GRADE rating mostly due to a lack of data; therefore, we have little confidence in the effect estimates where available. AUTHORS' CONCLUSIONS: There was insufficient high-quality evidence to support or refute the use of TENS for fibromyalgia. We found a small number of inadequately powered studies with incomplete reporting of methodologies and treatment interventions.

PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma.

Panobinostat is an oral pan-deacetylase inhibitor that synergizes with bortezomib to inhibit both the aggresome and proteasome pathways in preclinical studies. PANORAMA 2 is a phase 2 trial of panobinostat in combination with bortezomib and dexamethasone to treat patients with relapsed and bortezomib-refractory multiple myeloma (with ≥2 prior lines of therapy, including an immunomodulatory drug, and patients who had progressed on or within 60 days of the last bortezomib-based therapy). Fifty-five heavily pretreated patients were enrolled (median, 4 prior regimens, including a median of 2 prior bortezomib-containing regimens). The overall response rate was 34.5% (1 near-complete response and 18 partial responses). An additional 10 patients achieved minimal response, for a clinical benefit rate of 52.7%. Median exposure and progression-free survival were 4.6 and 5.4 months, respectively. In patients who achieved a response, median time to response was 1.4 months, and median duration of response was 6.0 months. Common grade 3/4 adverse events, regardless of study drug relationship, included thrombocytopenia (63.6%), fatigue (20.0%), and diarrhea (20.0%). Only 1 patient had grade 3 peripheral neuropathy. Panobinostat, when combined with bortezomib and dexamethasone, can recapture responses in heavily pretreated, bortezomib-refractory multiple myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT01083602.

Acupuncture for cancer pain in adults.

BACKGROUND: Forty per cent of individuals with early or intermediate stage cancer and 90% with advanced cancer have moderate to severe pain and up to 70% of patients with cancer pain do not receive adequate pain relief. It has been claimed that acupuncture has a role in management of cancer pain and guidelines exist for treatment of cancer pain with acupuncture. This is an updated version of a Cochrane Review published in Issue 1, 2011, on acupuncture for cancer pain in adults. OBJECTIVES: To evaluate efficacy of acupuncture for relief of cancer-related pain in adults. SEARCH METHODS: For this update CENTRAL, MEDLINE, EMBASE, PsycINFO, AMED, and SPORTDiscus were searched up to July 2015 including non-English language papers. SELECTION CRITERIA: Randomised controlled trials (RCTs) that evaluated any type of invasive acupuncture for pain directly related to cancer in adults aged 18 years or over. DATA COLLECTION AND ANALYSIS: We planned to pool data to provide an overall measure of effect and to calculate the number needed to treat to benefit, but this was not possible due to heterogeneity. Two review authors (CP, OT) independently extracted data adding it to data extraction sheets. Data sheets were compared and discussed with a third review author (MJ) who acted as arbiter. Data analysis was conducted by CP, OT and MJ. MAIN RESULTS: We included five RCTs (285 participants). Three studies were included in the original review and two more in the update. The authors of the included studies reported benefits of acupuncture in managing pancreatic cancer pain; no difference between real and sham electroacupuncture for pain associated with ovarian cancer; benefits of acupuncture over conventional medication for late stage unspecified cancer; benefits for auricular (ear) acupuncture over placebo for chronic neuropathic pain related to cancer; and no differences between conventional analgesia and acupuncture within the first 10 days of treatment for stomach carcinoma. All studies had a high risk of bias from inadequate sample size and a low risk of bias associated with random sequence generation. Only three studies had low risk of bias associated with incomplete outcome data, while two studies had low risk of bias associated with allocation concealment and one study had low risk of bias associated with inadequate blinding. The heterogeneity of methodologies, cancer populations and techniques used in the included studies precluded pooling of data and therefore meta-analysis was not carried out. A subgroup analysis on acupuncture for cancer-induced bone pain was not conducted because none of the studies made any reference to bone pain. Studies either reported that there were no adverse events as a result of treatment, or did not report adverse events at all. AUTHORS' CONCLUSIONS: There is insufficient evidence to judge whether acupuncture is effective in treating cancer pain in adults.

Transcutaneous electrical nerve stimulation for acute pain.

BACKGROUND: This is a second update of a Cochrane Review originally published in Issue 2, 2009. Transcutaneous Electrical Nerve Stimulation (TENS) is a non-pharmacological agent, based on delivering low voltage electrical currents to the skin. TENS is used by people to treat a variety of pain conditions. OBJECTIVES: To assess the analgesic effectiveness of TENS, as a sole treatment, for acute pain in adults. SEARCH METHODS: We searched the following databases up to 3 December 2014: the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE; EMBASE; CINAHL; and AMED. We also checked the reference lists of included trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of adults with acute pain (< 12 weeks) if they examined TENS given as a sole treatment and assessed pain with subjective pain scales. Trials were eligible if they compared TENS to placebo TENS, no treatment controls, pharmacological interventions or non-pharmacological interventions. We excluded trials on experimental pain, case reports, clinical observations, letters, abstracts or reviews. Also we excluded trials investigating the effect of TENS on pain during childbirth (labour), primary dysmenorrhoea or dental procedures. Studies where TENS was given with another treatment as part of the formal trial design were excluded. We did not restrict any articles based on language of publication. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and carried out study selection, data extraction, 'Risk of bias' assessment and analyses of data. We extracted data on the following: types of participants and pain condition, trial design and methods, treatment parameters, adverse effects, and outcome measures. We contacted trial authors for additional information if necessary. MAIN RESULTS: We included 12 trials in the original review (2009) and included no further trials in the first update (2011). An additional seven new trials met the inclusion criteria in this second update. In total, we included 19 RCTs involving 1346 participants at entry, with 11 trials awaiting classification either because the full text was unavailable or information in the full text failed to clarify eligibility. We excluded most trials because TENS was given in combination with another treatment as part of the formal study design or TENS was not delivered using appropriate TENS technique. The types of acute pain included in this Cochrane Review were procedural pain, e.g. cervical laser treatment, venepuncture, screening flexible sigmoidoscopy and non-procedural pain, e.g. postpartum uterine contractions and rib fractures. We pooled data for pain intensity for six trials (seven comparisons) comparing TENS with placebo but the I(2) statistic suggested substantial heterogeneity. Mean difference (MD) with 95% confidence intervals (CIs) on a visual analogue scale (VAS, 100 mm) was -24.62 mm (95% CI -31.79 to -17.46) in favour of TENS. Data for the proportion of participants achieving ≥ 50% reduction in pain was pooled for four trials (seven comparisons) and relative risk was 3.91 (95% CI 2.42 to 6.32) in favour of TENS over placebo. We pooled data for pain intensity from five trials (seven comparisons) but the I(2) statistic suggested considerable heterogeneity. MD was -19.05 mm (95% CI -27.30 to -10.79) in favour of TENS using a random-effects model. It was not possible to pool other data. There was a high risk of bias associated with inadequate sample sizes in treatment arms and unsuccessful blinding of treatment interventions. Seven trials reported minor adverse effects, such as mild erythema and itching underneath the electrodes and participants disliking TENS sensation. AUTHORS' CONCLUSIONS: This Cochrane Review update includes seven new trials, in addition to the 12 trials reviewed in the first update in 2011. The analysis provides tentative evidence that TENS reduces pain intensity over and above that seen with placebo (no current) TENS when administered as a stand-alone treatment for acute pain in adults. The high risk of bias associated with inadequate sample sizes in treatment arms and unsuccessful blinding of treatment interventions makes definitive conclusions impossible. There was incomplete reporting of treatment in many reports making replication of trials impossible.

Age-Related Emergency Department Reliance in Patients with Sickle Cell Disease.

BACKGROUND: Emergency Department Reliance (EDR: total emergency department [ED] visits/total ambulatory [outpatient + ED] visits) differentiates acute episodic ED users from those who may not have adequate access to outpatient care. OBJECTIVE: This study's aim was to investigate age-related patterns of EDR and associated health-care costs in pediatric patients with sickle cell disease (SCD) and those transitioning from pediatric to adult care. METHODS: State Medicaid data were used for this study. Patients with two or more SCD diagnoses and one or more blood transfusion were included. Quarterly rates of ED visits, EDR, SCD complications associated with ED visits, and ED visits resulting in hospitalization were evaluated. Risk factors associated with high EDR and the association between high EDR and health-care costs were explored through regression analyses. RESULTS: A total of 3208 patients were included. The most common SCD complications associated with ED visits were pain, infection, and pneumonia. Beginning at the age of 15 years, EDR rose from 0.17 to 0.29 visits per quarter at age 22 years, and remained high throughout adulthood. Regression analyses indicated that patients were most likely to have high EDR during the post-transition period and when experiencing an SCD complication. Patients with high EDR incurred statistically significantly higher inpatient and ED costs, resulting in significantly higher total health-care costs. CONCLUSIONS: Compared to children, patients transitioning to adulthood relied more on the ED for their care. In addition, patients with high EDR incurred more days in the hospital and significantly higher health-care costs, highlighting the need to improve transition-related support, including better access to primary care and increased engagement with patients with SCD.

Narrative review: what constitutes contemporary, high-quality end-of-life care and can lessons be learned from medieval history?

BACKGROUND AND OBJECTIVE: In modern Britain, palliative and end-of-life care is governed by quality standards and guidance, which should consider spiritual and psychological needs. However, there are significant gaps in provision of services which was highlighted during the coronavirus disease 2019 (COVID-19) pandemic where many individuals and families suffered profound spiritual and existential distress. Significant gaps remain in the provision of services to support patients with spiritual and psychological needs which can affect the management of physical symptoms. During the medieval period in Western Europe, it was important to prepare well for death throughout life. It has been suggested that lessons may be learned from medieval preparations for death which might benefit those approaching end-of-life in contemporary society. It is therefore timely to consider medieval attitudes to death and reflect on how these might inform modern end-of-life care. The objective of this review is to synthesise literature addressing modern end-of-life care in the UK and contrast this with literature on preparations for death during the medieval period in Western Europe. Our aim is to determine whether there is wisdom to be gained from history which could inform our approaches to end-of-life care today. METHODS: Using online databases and broad keyword searches along with experts in the field of medieval history, we identified literature and translations of texts with a focus on preparations for death during both periods. These were narratively synthesised and discussed. KEY CONTENT AND FINDINGS: A key finding is that the medieval attitude to death was as an integral part of life, whereas in modern society death is not usually considered until the situation arises. The review highlights a need for a better understanding of the individuality of spiritual and existential needs during end-of-life care in modern society, which will vary according to individual choice, culture, societal group, religion, and belief. CONCLUSIONS: The lessons we can learn from our medieval counterparts include the need for lifelong and individual preparations for the end of life, with emphasis on spiritual needs. Alongside palliative interventions, we need to take time to appreciate what gives individuals spiritual support and provide the resources to facilitate this.

Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis.

Myelofibrosis (MF) is a Philadelphia chromosome-negative stem cell myeloproliferative neoplasm (MPN) associated with cytopenias, splenomegaly, constitutional symptoms, and poor prognosis. MF patients commonly express JAK2 V617F mutation and activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Agents targeting the JAK/STAT pathway have demonstrated efficacy in patients with MF. This study evaluated panobinostat, a pan-deacetylase inhibitor that depletes JAK2 V617F levels and JAK/STAT signalling in MPN cells, in patients with primary MF, post-essential thrombocythaemia MF, and post-polycythaemia vera MF. Patients received panobinostat 40 mg administered three times per week. Dose reductions were permitted for toxicities. The primary endpoint was response rate at 6 months using International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) consensus criteria. Analyses of peripheral blood cells from treated patients revealed that panobinostat inhibited JAK/STAT signalling, decreased inflammatory cytokine levels, and decreased JAK2 V617F allelic burden. However, panobinostat was poorly tolerated at the dose and schedule evaluated, and only 16 of 35 patients completed ≥2 cycles of treatment. One patient (3%) achieved an IWG-MRT response. Common adverse events were thrombocytopenia (71.4%) and diarrhoea (80.0%). Although molecular correlative analyses suggested that panobinostat inhibits key intracellular targets, limited clinical activity was observed because of poor tolerance.

Age-related treatment patterns in sickle cell disease patients and the associated sickle cell complications and healthcare costs.

BACKGROUND: This study explored the blood transfusion patterns, SCD complications, utilization of iron chelation therapies (ICT), healthcare resource use, and costs in pediatric, transitioning (18 years old) and adult patients with SCD. PROCEDURE: Data from Florida (1998-2009), New Jersey (1996-2009), Missouri (1997-2010), Kansas (2001-2009), and Iowa (1998-2010) state Medicaid were used. Patients with ≥2 SCD diagnoses and ≥1 transfusion event were included. Rates of transfusion events, SCD complications, and proportion of eligible patients receiving ICT were calculated. ICT eligibility was defined as receiving ≥10 transfusions over lifetime. SCD complications included pain, pulmonary event, infection event, renal, cardiovascular, stroke, leg ulcers, and avascular necrosis. Regressions were used to assess risk factors for transfusion and identify the main drivers of costs. RESULTS: The sample included 3,208 patients. The transfusion rate increased from 1-year-old to a peak at 16 years old, then dropped until age 26 and remained stable thereafter. In contrast the frequency of diagnoses for SCD complications increased markedly after age 16. Post-transition patients (≥18 years old) were significantly associated with fewer transfusions (odds ratio: 0.80, P = 0.002). Among eligible patients for ICT, there was no statistically significant difference in total cost between the ICT and no ICT groups (adjusted cost difference, $136, P = 0.114). CONCLUSIONS: Patients transitioning to adult care received less transfusions and hydroxyurea, less ICT when eligible for chelation therapy, had higher healthcare costs and suffered from more frequent SCD related complications than pediatric patients. These findings highlight the changes in treatment patterns corresponding to transition to adult care.

The palatability and tolerability of deferasirox taken with different beverages or foods.

BACKGROUND: Deferasirox is a once-daily, oral iron chelator that was developed out of a need for a long-acting, conveniently-administered chelator for patients with transfusional hemosiderosis. The approved mode of administration requires taking deferasirox on an empty stomach with water, apple juice, or orange juice to limit variation in bioavailability. This required administration schedule might not be palatable for patients. Additionally, approximately one-quarter of patients experience mild to moderate gastrointestinal (GI) symptoms, which may pose additional challenges, particularly in the younger and older age ranges. We present a trial to assess the palatability and safety of various administration modes of deferasirox in pediatric and adult patients. PROCEDURES: Participants rated palatability in a 4-week run-in phase, where deferasirox was administered per label. Subsequently, patients rated several administration modes during a 3-month assessment phase. RESULTS: Palatability was more favorable during the assessment phase, with 47% of patient ratings for palatability being favorable while only 38% were favorable during the run-in phase. The most highly rated choice was deferasirox taken with a soft food at breakfast. In addition, there was an indication of improved GI tolerability during the assessment phase (symptoms were reported in 37% of patients during run-in and 32% during the assessment phase; rates of diarrhea decreased significantly). Although trough PK values increased, no major new toxicities were observed. CONCLUSIONS: These data indicate that different administration options may improve palatability and GI tolerability, which could have a positive impact on treatment adherence. (ClinicalTrials.gov number, NCT00845871)

Perspective on salutogenic approaches to persistent pain with a focus on mindfulness interventions.

In this article, we provide a unique perspective on the use of mindfulness interventions in a whole health framework embedded within the theory of salutogenesis and the concept of painogenic environments. We argue that mindfulness is a valuable tool to bridge exploration of inner experiences of bodily pain with socio-ecological influences on thoughts and emotions. We outline research from neuroimaging studies that mindfulness techniques mediate neural processing and neuroplastic changes that alleviate pain and related symptoms. We also review evidence examining behavioural changes associated with mindfulness meditation providing evidence that it promotes self-regulatory activity, including the regulation and control of emotion and catalysation of health behaviour changes; both of which are important in chronic illness. Our viewpoint is that mindfulness could be a core element of salutogenic approaches to promote health and well-being for people living with pain because it rebuilds a fractured sense of cohesion. Mindfulness empowers people in pain to embrace their existence; shifting the focus away from pain and giving their lives meaning. We propose that integrating mindfulness into activities of daily living and individual or community-based activities will promote living well in the modern world, with or without pain; thus, promoting individual potential for fulfilment. Future research should consider the effects of mindfulness on people with pain in real-life settings, considering social, environmental, and economic factors using a broader set of outcomes, including self-efficacy, sense of coherence and quality of life.

Understanding pain in modern society: insights from attitudes to pain in the Medieval Period.

Historical records provide knowledge about the way people lived in the past. Our perspective is that historical analyses of the Medieval Period provide insights to inform a fuller understanding of pain in the present era. In this article, we appraise critiques of the writings of people living with pain during the mid (high) to late Medieval Period (c. 1,000-1,500 AD) to gain insights into the nature, attitudes, lived experience, and sense-making of pain. In the Medieval Period, pain was understood in terms of Galen's four humours and the Church's doctrine of pain as a "divine gift", "punishment for sin" and/or "sacrificial offering". Many treatments for pain were precursors of those used in modern time and society considered pain to be a "shared experience". We argue that sharing personal stories of life is a fundamental human attribute to foster social cohesion, and that nowadays sharing personal stories about pain is difficult during biomedically-focussed time-constrained clinical consultations. Exploring pain through a medieval lens demonstrates the importance of sharing stories of living with pain that are flexible in meaning, so that people can connect with a sense of self and their social world. We advocate a role for community-centred approaches to support people in the creation and sharing of their personal pain stories. Contributions from non-biomedical disciplines, such as history and the arts, can inform a fuller understanding of pain and its prevention and management.

The effect of deferasirox on cardiac iron in thalassemia major: impact of total body iron stores.

We present results from a prospective, multicenter, open-label, single-arm study evaluating response of cardiac and liver iron to deferasirox therapy for 18 months. Twenty-eight patients with abnormal T2* and normal left ventricular ejection fraction were enrolled from 4 US centers. All patients initially received deferasirox doses of 30 to 40 mg/kg per day. Patients were severely iron overloaded: mean liver iron concentration (LIC) 20.3 mg Fe/g dry weight, serum ferritin 4417 ng/mL, and cardiac T2* 8.6 ms. In the intent-to-treat population, 48% reached the primary endpoint (cardiac T2* improvement at 18 months, P = not significant). There were 2 deaths: 1 from congestive heart failure and 1 from sepsis. In the 22 patients completing the trial, LIC and cardiac T2* improvements were 16% (P = .06) and 14% (P = .07), respectively. Cardiac T2* improvement (13 patients) was predicted by initial LIC, final LIC, and percentage LIC change, but not initial cardiac T2*. Cardiac iron improved 24% in patients having LIC in the lower 2 quartiles and worsened 8.7% in patients having LIC in the upper 2 quartiles. Left ventricular ejection fraction was unchanged at all time points. Monotherapy with deferasirox was effective in patients with mild to moderate iron stores but failed to remove cardiac iron in patients with severe hepatic iron burdens. This study was registered at www.clinicaltrials.gov as #NCT00447694.

Economic impact on US Medicare of a new diagnosis of myelodysplastic syndromes and the incremental costs associated with blood transfusion need.

BACKGROUND: Recent retrospective studies suggest myelodysplastic syndromes (MDSs) are more common than previously recognized and patients who develop transfusional dependence may be at risk for increased comorbid complications. STUDY DESIGN AND METHODS: A retrospective review was undertaken of Medicare claims focusing on costs associated with patients with a new claim listing ICD-9-CM Diagnosis Code 238.7 in first quarter of 2003. Patients were followed until 2005 to assess resource use and costs. RESULTS: A total of 512 patients aged 65 years or more with newly diagnosed MDS were identified. Forty percent had received red blood cell transfusions between 2003 and 2005. During the 3-year follow-up, transfused patients experienced increased prevalence of cardiac diseases, dyspnea, and infections. Cumulative 3-year mean Medicare costs for MDS patients were $49,156. Transfused patients had greater use of hospital inpatient and outpatient services and incurred significantly higher mean costs than nontransfused patients ($88,824 vs. $29,519, p < 0.001). After adjustment for baseline characteristics and clinical complications, transfusion was independently associated with a 48% increase in monthly costs in addition to the cost of transfusion administration. CONCLUSION: MDS places a significant economic burden on the US Medicare system. MDS patients requiring transfusions experience higher prevalence of new comorbid conditions and incur significantly higher Medicare costs than nontransfused patients during the initial 3 years after diagnosis.