Transitivity, coherence, and reliability of network meta-analyses comparing proximal humerus fracture treatments: a meta-epidemiological study.

BACKGROUND: Network meta-analyses can be valuable for decision-makers in guiding clinical practice. However, for network meta-analysis results to be reliable, the assumptions of both transitivity and coherence must be met, and the methodology should adhere to current best practices. We aimed to assess whether network meta-analyses of randomized controlled trials (RCTs) comparing interventions for proximal humerus fractures provide reliable estimates of intervention effects. METHODS: We searched PubMed, EMBASE, The Cochrane Library, and Web of Science for network meta-analyses comparing interventions for proximal humerus fractures. We critically assessed the methodology regarding the development of a protocol, search strategy, trial inclusion, outcome extraction, and the methods used to conduct the network meta-analyses. We assessed the transitivity and coherence of the network graphs for the Constant score (CS), Disabilities of the Arm, Shoulder, and Hand score (DASH), and additional surgery. Transitivity was assessed by comparing probable effect modifiers (age, gender, fracture morphology, and comorbidities) across intervention comparisons. Coherence was assessed using Separating Indirect from Direct Evidence (SIDE) (Separating Indirect from Direct Evidence) and the design-by-treatment interaction test. We used CINeMA (Confidence in Network Meta-analyses) to assess the confidence in the results. RESULTS: None of the three included network meta-analyses had a publicly available protocol or data-analysis plan, and they all had methodological flaws that could threaten the validity of their results. Although we did not detect incoherence for most comparisons, the transitivity assumption was violated for CS, DASH, and additional surgery in all three network meta-analyses. Additionally, the confidence in the results was 'very low' primarily due to within-study bias, reporting bias, intransitivity, imprecision, and heterogeneity. CONCLUSIONS: Current network meta-analyses of RCTs comparing interventions for proximal humerus fractures do not provide reliable estimates of intervention effects. We advise caution in using these network meta-analyses to guide clinical practice. To improve the utility of network meta-analyses to guide clinical practice, journal editors should require that network meta-analyses are done according to a predefined analysis plan in a publicly available protocol and that both coherence and transitivity have been adequately assessed and reported.

Patients' behaviour after referral to a wound care clinic for diabetic foot ulcer care: a grounded theory study.

OBJECTIVE: The aim of this study was to construct a grounded theory regarding patients' activity behaviour over time after referral to an outpatient clinic for diabetic foot ulcer (DFU) care. METHOD: A constructivist grounded theory approach was used. Data from observations of and interviews with participants were collected and analysed using the constant comparative method. Based on this, the grounded theory 'Just a bump in the road' was constructed. RESULTS: The cohort included five participants who considered their ulcers as 'Just a bump in the road' in their lives, and four subcategories were embedded in this core category: 'Restricting my freedom'; 'Trusting or doubting the system'; 'Feeling no pain or illness'; and 'Receiving insufficient information'. Together, these categories describe the participants' behaviour and underlying concerns related to daily activities after referral to an outpatient clinic for the care of their DFU. CONCLUSION: The grounded theory 'Just a bump in the road' describes how participants with a DFU viewed their condition as merely a passing phase that would end with them regaining what they considered a normal life. Integrating these results into clinical practice could lead to improved care and a focus shift among health professionals from viewing patients as being defined by their wounds to seeing them as people who live with a wound.

Considerable gaps and differences in rehabilitation after major lower extremity amputations across regions and municipalities in Denmark - A national survey.

INTRODUCTION: Equal access to healthcare is a fundamental principle in the fully tax-financed Danish healthcare system. This study reveals whether this system lives up to the principle of equal access when it comes to the rehabilitation of patients who have major lower extremity amputations. METHODS: With the aim of exploring possible inequality in rehabilitation for patients having major lower extremity amputation in Denmark, a nationwide electronic survey was conducted in the autumn of 2020, which included all hospitals and municipalities in Denmark. RESULTS: Eighty six percent of hospitals (n = 19) and 97% (n = 95) of municipalities responded. Of the 32% (n = 6) of hospitals and 78% (n = 74) of municipalities that provided prosthesis rehabilitation, the majority (hospitals 50% /municipalities 91%) provided prostheses for <10 patients in 2019, and 36% reported having competencies at only a general level among physiotherapists performing prosthetic training. Psychosocial rehabilitation modalities were lacking overall. CONCLUSIONS: This national study documents pronounced geographic inequality in access to qualified rehabilitation services for the relatively few patients undergoing lower extremity amputations in Denmark. The decentralised organisation of amputation rehabilitation makes it difficult to build and maintain specialist competencies among healthcare professionals. Inconsistent availability of psychosocial rehabilitation modalities of all kinds found in this study points to a need for action particularly among patients not in prosthetic rehabilitation where palliative needs should also be considered.

Optimizing literature search in systematic reviews - are MEDLINE, EMBASE and CENTRAL enough for identifying effect studies within the area of musculoskeletal disorders?

BACKGROUND: When conducting systematic reviews, it is essential to perform a comprehensive literature search to identify all published studies relevant to the specific research question. The Cochrane Collaborations Methodological Expectations of Cochrane Intervention Reviews (MECIR) guidelines state that searching MEDLINE, EMBASE and CENTRAL should be considered mandatory. The aim of this study was to evaluate the MECIR recommendations to use MEDLINE, EMBASE and CENTRAL combined, and examine the yield of using these to find randomized controlled trials (RCTs) within the area of musculoskeletal disorders. METHODS: Data sources were systematic reviews published by the Cochrane Musculoskeletal Review Group, including at least five RCTs, reporting a search history, searching MEDLINE, EMBASE, CENTRAL, and adding reference- and hand-searching. Additional databases were deemed eligible if they indexed RCTs, were in English and used in more than three of the systematic reviews. Relative recall was calculated as the number of studies identified by the literature search divided by the number of eligible studies i.e. included studies in the individual systematic reviews. Finally, cumulative median recall was calculated for MEDLINE, EMBASE and CENTRAL combined followed by the databases yielding additional studies. RESULTS: Deemed eligible was twenty-three systematic reviews and the databases included other than MEDLINE, EMBASE and CENTRAL was AMED, CINAHL, HealthSTAR, MANTIS, OT-Seeker, PEDro, PsychINFO, SCOPUS, SportDISCUS and Web of Science. Cumulative median recall for combined searching in MEDLINE, EMBASE and CENTRAL was 88.9% and increased to 90.9% when adding 10 additional databases. CONCLUSION: Searching MEDLINE, EMBASE and CENTRAL was not sufficient for identifying all effect studies on musculoskeletal disorders, but additional ten databases did only increase the median recall by 2%. It is possible that searching databases is not sufficient to identify all relevant references, and that reviewers must rely upon additional sources in their literature search. However further research is needed.

Small-angle neutron scattering study of the ultrastructure of chloroplast thylakoid membranes - periodicity and structural flexibility of the stroma lamellae.

The multilamellar organization of freshly isolated spinach and pea chloroplast thylakoid membranes was studied using small-angle neutron scattering. A broad peak at ~0.02Å(-1) is ascribed to diffraction from domains of ordered, unappressed stroma lamellae, revealing a repeat distance of 294ű7Å in spinach and 345ű11Å in pea. The peak position and hence the repeat distance of stroma lamellae is strongly dependent on the osmolarity and the ionic strength of the suspension medium, as demonstrated by varying the sorbitol and the Mg(++)-concentration in the sample. For pea thylakoid membranes, we show that the repeat distance decreases when illuminating the sample with white light, in accordance with our earlier results on spinach, also regarding the observation that addition of an uncoupler prohibits the light-induced structural changes, a strong indication that these changes are driven by the transmembrane proton gradient. We show that the magnitude of the shrinkage is strongly dependent on light intensity and that the repeat distance characteristic of the dark state after illumination is different from the initial dark state. Prolonged strong illumination leads to irreversible changes and swelling as reflected in increased repeat distances. The observed reorganizations are discussed within the frames of the current structural models of the granum-stroma thylakoid membrane assembly and the regulatory mechanisms in response to variations in the environmental conditions in vivo. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial.

A meta-epidemiological study found that meta-analyses of the same trials may obtain drastically conflicting results.

OBJECTIVES: To assess how much protocols reduce methodological flexibility and variation of results in meta-analyses comparing operative with nonoperative treatments for proximal humerus fractures. STUDY DESIGN AND SETTING: A meta-epidemiological study. We searched four bibliographic databases for eligible meta-analyses. We contacted the authors of the meta-analyses, requesting a copy of their protocol. We identified the included studies and extracted intervention effect data for functional outcome, quality of life, and adverse events. Using the same intervention effect data for each outcome domain, we conducted multiple meta-analyses using differing combinations of methodological choices (analytical scenarios) without restricting the available methodological choices (as if no protocol was used). For each protocol, we repeated this process but restricted the available choices to those listed in the protocol. We then compared the distributions of effect estimates with and without protocols. Methodological flexibility was estimated as the difference in number of possible meta-analyses and the variation of results as the difference between the most conflicting effect estimates. RESULTS: We identified 23 meta-analyses, included 24 primary studies, and obtained three protocols. The protocols markedly reduced methodological flexibility (range for functional outcomes 94%-99%; quality of life 58%-76%; adverse events 87%-91%). The corresponding reduction in the variation of the results varied (range for functional outcomes; 33%-78%, quality of life; 10%-24%; adverse events 10%-13%). CONCLUSION: Although the protocols consistently reduced methodological flexibility, the reduction in the variation (bias) of results varied. Consequently, review authors may obtain conflicting results based on the same data. We advise caution when interpreting the conclusions of meta-analyses with absent or imprecise protocols.

A 12-Week Supervised Exercise Therapy Program for Patients with Diabetic Foot Ulcers: Program Development and Preliminary Feasibility.

Exercise therapy helps improve glycaemic control and insulin sensitivity and may be relevant in treating patients with diabetic foot ulcers (DFUs). This study describes the development of a 12-week exercise therapy program for patients with DFUs and the preliminary feasibility of the program focusing on the program's inclusion, adherence, and safety. The development process is built on knowledge from a published systematic review on exercise for people with DFUs and a grounded theory study on the main concerns of people with DFUs regarding physical activity. The development involved doctors, wound care nurses, podiatrists, and feedback from patients and physical therapists using semi-structured interviews. The program was designed as a combination of aerobic and resistance training exercises. The aerobic exercise phase on the stationary bike of 30-minute duration was aimed at a moderate intensity. Resistance exercises were conducted with a 15-repetition maximum approach (four to five sets per trial) throughout the 12-week period. Three patients were included and received the exercise intervention. Except for recruitment and retention rates, acceptance levels were met for all other research progression criteria. Patients found the intervention relevant, wanted further guidance on continuing exercising, and would have liked the intervention closer to their home for example, a municipality setting. Although the exercise therapy program for patients with DFUs was developed in a thorough process with the inclusion of available evidence and the involvement of patients and other stakeholders conclusions on feasibility are limited due to the low recruitment rate. A reconsideration of the setting is needed in future exercise intervention studies.

Benefits and Harms of Exercise Therapy for Patients With Diabetic Foot Ulcers: A Systematic Review.

AIM: Exercise therapy is a core element in the treatment of diabetes, but the benefits and harms for patients with a diabetic foot ulcer (DFU) are unknown. We therefore aimed to systematically review the benefits on health-related quality of life (HRQoL) and harms of exercise therapy for patients with DFU. METHODS: We searched 6 major databases. We performed citation and reference searches of included studies and contacted authors of ongoing trials. We included randomized controlled trials (RCTs) to assess potential benefits on HRQoL and harms of exercise therapy. Observational studies were included to identify potential harms of exercise therapy. RESULTS: We included 10 published publications of 9 trials and results from 2 unpublished trials including a total of 281 individuals with DFUs receiving various forms of exercise therapy. Due to lack of HRQoL measurements and high heterogeneity, it was not possible to perform meta-analyses. Results on HRQoL was present in one unpublished study. Harms reported ranged from musculoskeletal problems, increased wound size, to amputation; however, no safe conclusions could be drawn from the available data due to high heterogeneity and risk of bias in the trials. CONCLUSIONS/INTERPRETATION: Protective strategies are often preferred over therapeutic exercise that might have unforeseen consequences for patients over time. Based on the current literature, no evidence-based recommendations can be provided on the benefits and harms of exercise therapy for patients with DFUs. Well-conducted RCTs are needed to guide rehabilitation including detailed description of adverse events and an exercise program in a semisupervised or fully supervised setting.

Inforatio technique to promote wound healing of diabetic foot ulcers: study protocol for a parallel-group, evaluator-blinded, randomised clinical trial.

INTRODUCTION: Diabetic foot ulcers (DFUs) are associated with extensive consequences for the affected patients and treatment of these hard-to-heal ulcers is known for being challenging. New treatment methods to supplement the current standard care may improve the prognosis for these patients.A preceding feasibility trial with promising results, facilitated this trial that aims to study the effect of a novel simple treatment, called inforatio technique, which may promote healing of DFUs. The inforatio technique is a minimally invasive procedure where small cuts are made on wound beds with punch biopsy tools. METHODS AND ANALYSIS: This multicentre randomised clinical trial will be conducted at outpatient clinics at Zealand University Hospital, Herlev University Hospital, Slagelse Hospital and Nykoebing Falster Hospital. 100 participants will be included and randomised in a 1:1 ratio to either a control group that receives usual care or an intervention group that receives both usual care and the inforatio technique.The primary outcome is complete healing evaluated on digital images by blinded observers. It is not possible to blind participants or the outpatient clinic staff because the inforatio technique is visible in wound beds after application. Change in EQ-5D-5L (EuroQoL-5 Dimension- 5 Level) Visual Analogue Scale Score and Wound-QoL Global Score from baseline to end of follow-up are secondary outcomes. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Danish National Committee on Health Research Ethics on 15 December 2021 (approval ID: SJ-904). Trial results are planned to be published in a high-impact peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05189470.

[Monoclonal gammopathy of undetermined significance].

This review summarises the work-up of patients with monoclonal gammopathy of undetermined significance (MGUS). In persons above 70 years of age, around 5% have MGUS, a premalignant state with a monoclonal plasma immunoglobulin or light chain (M protein) in blood and/or urine. Continuous follow-up is recommended due to a risk of malignant progression of around 1% per year. Immunoglobulin M MGUS primarily progresses to Waldenström's macroglobulinaemia, whereas non-immunoglobulin M MGUS typically progresses to multiple myeloma or amyloid light-chain amyloidosis. Treatment is unnecessary unless in rare cases of severe non-malignant complications. Screening is not advised.

Interrater Reliability of Dynamic Muscle Testing After Breast Cancer Surgery in Women at High Risk of Lymphedema: To Improve Quality in Clinical Practice.

Background: The purpose of this study is to determine the interrater reliability of dynamic muscle tests in the early rehabilitation phase in women after breast cancer surgery with axillary lymph node dissection (ALND) based on the "preventive intervention against lymphedema after breast cancer" (LYCA) randomised controlled trial. Methods: Fifteen women treated with breast cancer surgery including ALND were recruited from participants in the LYCA trial. In this interrater reliability study, women were tested in 4 dynamic muscle tests by 2 physiotherapists at a Capital Hospital in Denmark. Intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs) was used to assess the relative reliability between raters. A Bland-Altman plot and limits of agreement were calculated to describe the absolute reliability. Results: All 6 subtests displayed high interrater reliability. ICC values were: leg press 0.96 (95% CI = 0.87-0.99), elbow flexion (contralateral) 0.94 (0.83-0.98), elbow flexion (affected arm) 0.93 (0.80-0.98), elbow extension 0.80 (0.41-0.93), shoulder abduction (contralateral) 0.89 (0.68-0.96), and shoulder abduction (affected arm) 0.91 (0.74-0.97). Cumulated interrater reliability for the test battery was very high (ICC = 0.99, 95% CI = 0.990-1.0). The absolute reliability of this study was considered high, and the absence of large shifts between mean and the line of 0 difference suggest no systematic bias that could influence clinical interpretation. Conclusions: The dynamic muscle tests evaluated in this study had high interrater reliability and can be used reliably in women in the postoperative phase after breast cancer surgery with ALND.

Peptide Vaccination Against PD-L1 With IO103 a Novel Immune Modulatory Vaccine in Multiple Myeloma: A Phase I First-in-Human Trial.

Background: Immune checkpoint blockade with monoclonal antibodies targeting programmed death 1 (PD-1) and its ligand PD-L1 has played a major role in the rise of cancer immune therapy. We have identified naturally occurring self-reactive T cells specific to PD-L1 in both healthy donors and cancer patients. Stimulation with a PD-L1 peptide (IO103), activates these cells to exhibit inflammatory and anti-regulatory functions that include cytotoxicity against PD-L1-expressing target cells. This prompted the initiation of the present first-in-human study of vaccination with IO103, registered at clinicaltrials.org (NCT03042793). Methods: Ten patients with multiple myeloma who were up to 6 months after high dose chemotherapy with autologous stem cell support, were enrolled. Subcutaneous vaccinations with IO103 with the adjuvant Montanide ISA 51 was given up to fifteen times during 1 year. Safety was assessed by the common toxicity criteria for adverse events (CTCAE). Immunogenicity of the vaccine was evaluated using IFNγ enzyme linked immunospot and intracellular cytokine staining on blood and skin infiltrating lymphocytes from sites of delayed-type hypersensitivity. The clinical course was described. Results: All adverse reactions to the PD-L1 vaccine were below CTCAE grade 3, and most were grade 1-2 injection site reactions. The total rate of adverse events was as expected for the population. All patients exhibited peptide specific immune responses in peripheral blood mononuclear cells and in skin-infiltrating lymphocytes after a delayed-type hypersensitivity test. The clinical course was as expected for the population. Three of 10 patients had improvements of responses which coincided with the vaccinations. Conclusion: Vaccination against PD-L1 was associated with low toxicity and high immunogenicity. This study has prompted the initiation of later phase trials to assess the vaccines efficacy. Clinical Trial Registration: clinicaltrials.org, identifier NCT03042793.

Packing properties of 1-alkanols and alkanes in a phospholipid membrane.

We have used vibrating tube densitometry to investigate the packing properties of four alkanes and a homologous series of ten alcohols in fluid-phase membranes of dimyristoyl phosphatidylcholine (DMPC). It was found that the volume change of transferring these compounds from their pure states into the membrane, DeltaV(m)(pure-->mem), was positive for small (C4-C6) 1-alkanols while it was negative for larger alcohols and all alkanes. The magnitude of DeltaV(m)(pure-->mem) ranged from about +4 cm3/mol for alcohols with an alkyl chain about half the length of the fatty acids of DMPC, to -10 to -15 cm3/mol for the alkanes and long chain alcohols. On the basis of these observations, previously published information on the structure of the membrane-solute complexes and the free volume properties of (pure) phospholipid membranes, we suggest that two effects dominate the packing properties of hydrophobic solutes in DMPC. First, perturbation of the tightly packed interfacial zone around the ester bonds and first few methylene groups of DMPC brings about a positive contribution to DeltaV(m)(pure-->mem). This effect dominates the volume behavior for alcohols like 1-butanol, 1-pentanol and 1-hexanol. More hydrophobic solutes penetrate into the membrane core, which is loosely packed. In this region, they partially occupy interstitial (or free-) volume, which bring about a denser molecular packing and generate a negative contribution to DeltaV(m)(pure-->mem).

[Positive results with haematology webcasting for junior doctors]. / Positive erfaringer med fjernundervisning i hæmatologi for yngre læger

Webcasting is an educational activity where the teacher and the participants are separated in space and time when using modern information technology. It is widely used for all learning levels and in all educational forms of haematology training in Europe. A working group in the Education Council of internal medicine, haematology in the eastern part of Denmark initiated a project with webcasting from local haematological departments. The aim of the education project was to contribute to spreading knowledge and support the training of specialist in haematology. Our experience is hereby reported.

[Severe haemolysis caused by Mycoplasma pneumoniae]. / Mycoplasma pneumoniae-udløst autoimmun hæmolyse

Mycoplasma pneumoniae is naturally resistant to betalactamase antibiotics but is sensitive to macrolides. Occasionally, infections with M. pneumoniae can lead to severe anaemia due to its ability to cause haemolysis when cold agglutination occurs. Increasing bacterial resistance to macrolid antibiotics is a growing concern worldwide. We present two cases where infection with M. pneumoniae caused severe haemolysis, one of which was macrolide-resistant.

Vitellogenin as biomarker for estrogenicity in flounder Platichthys flesus in the field and exposed to 17α-ethinylestradiol via food and water in the laboratory.

The ability of 17α-ethinylestradiol (EE2) to elevate vitellogenin levels were investigated in male flounder Platichthys flesus and vitellogenin concentrations in flounders from the Danish coastal environment were determined. Male flounders were exposed to 17α-ethinylestradiol (EE2) via food or water. Average vitellogenin concentrations in the control fish ranged between 25 and 100 ng mL(-)(1). Exposure to 5.1, 8.1 and 16.8 ng EE2 L(-)(1) in water and 500 and 5000 ng EE2 kg(-)(1) body weight (bw) every second day in the food increased the plasma vitellogenin concentration in a concentration and time dependent manner, whereas exposure to 2.7 ng EE2 L(-)(1) in water for 21 d and 5 and 50 ng EE2 kg(-)(1) bw for 12 days in the food did not. EE2 could be detected in liver and testes (but not in muscle) after exposure to 8.1 and 16.8 ng EE2 L(-)(1) in the water and 5000 ng EE2 kg(-)(1) bw in the food; the highest concentration was 6 ng g(-)(1) wet weight in liver. The majority of the male flounders collected from nine coastal Danish sites from 1999 to 2004 had vitellogenin concentrations below 100 ng mL(-)(1), and only at two sites moderate estrogenic inputs were indicated.

Effect of mechanical brushing on survival and hemodynamic characteristics of tunneled hemodialysis catheters.

PURPOSE: Tunneled catheters used for hemodialysis treatment often become dysfunctional due to deposition of clotting material within the catheter lumen. In a retrospective study design we investigated the effect of mechanical brushing of dysfunctional tunneled catheters using a metal guide wire with simultaneous installation of urokinase. MATERIALS AND METHODS: During a period of 26 months all together 24 different catheters in 21 chronic hemodialysis patients were brushed due to insufficient blood flow or increased arterial or venous line pressures resulting in repeated alarms during dialysis treatments. RESULTS: Median functional survival after brushing was 45 days with 8 catheters being exchanged (n=5) or rebrushed (n=3) within 10 dialysis sessions (4 weeks). After 2 months all together 13 (54%) catheters were exchanged due to repeated dysfunction and by 3 months functional survival was only about 35%. The catheters needing exchange were characterized by low flow and high arterial line resistance already in the dialysis sessions immediately following the brushing procedure. Median survival of the exchanged catheters was considerably longer (>400 days) as compared to the brushed catheters. CONCLUSIONS: In conclusion mechanical brushing of dysfunctional tunneled hemodialysis catheters can prolong short term function but only affects long term catheter survival in a minority of the patients.