Universal fluctuations of global geometrical measurements in planar clusters.

We characterize universal features of the sample-to-sample fluctuations of global geometrical observables, such as the area, width, length, and center-of-mass position, in random growing planar clusters. Our examples are taken from simulations of both continuous and discrete models of kinetically rough interfaces, including several universality classes, such as Kardar-Parisi-Zhang. We mostly focus on the scaling behavior with time of the sample-to-sample deviation for those global magnitudes, but we have also characterized their histograms and correlations.

Shape effects in the fluctuations of random isochrones on a square lattice.

We consider the isochrone curves in first-passage percolation on a 2D square lattice, i.e., the boundary of the set of points which can be reached in less than a given time from a certain origin. The occurrence of an instantaneous average shape is described in terms of its Fourier components, highlighting a crossover between a diamond and a circular geometry as the noise level is increased. Generally, these isochrones can be understood as fluctuating interfaces with an inhomogeneous local width which reveals the underlying lattice structure. We show that once these inhomogeneities have been taken into account, the fluctuations fall into the Kardar-Parisi-Zhang universality class with very good accuracy, where they reproduce the Family-Vicsek Ansatz with the expected exponents and the Tracy-Widom histogram for the local radial fluctuations.

A guide for a student-led doctoral-level qualitative methods short course in epidemiology: faculty and student perspectives.

Qualitative research and mixed methods are core competencies for epidemiologists. In response to the shortage of guidance on graduate course development, we wrote a course development guide aimed at faculty and students designing similar courses in epidemiology curricula. The guide combines established educational theory with faculty and student experiences from a recent introductory course for epidemiology and biostatistics doctoral students at the University of Zurich and Swiss Federal Institute of Technology, Zurich. We propose a student-centred course with inverse classroom teaching and practice exercises with faculty input. Integration of student input during the course development process helps align the course syllabus with student needs. The proposed course comprises six sessions that cover learning outcomes in comprehension, knowledge, application, analysis, synthesis and evaluation. Following an introductory session, the students engage in face-to-face interviews, focus group interviews, observational methods, analysis and how qualitative and quantitative methods are integrated in mixed methods. Furthermore, the course covers interviewer safety, research ethics, quality in qualitative research and a practice session focused on the use of interview hardware, including video and audio recorders. The student-led teaching characteristic of the course allows for an immersive and reflective teaching-learning environment. After implementation of the course and learning from faculty and student perspectives, we propose these additional foci: a student project to apply learned knowledge to a case study; integration in mixed-methods; and providing faculty a larger space to cover theory and field anecdotes.

Is blinding in studies of manual soft tissue mobilisation of the back possible? A feasibility randomised controlled trial with Swiss graduate students.

STUDY DESIGN: Single-centre, two-parallel group, methodological randomised controlled trial to assess blinding feasibility. BACKGROUND: Trials of manual therapy interventions of the back face methodological challenges regarding blinding feasibility and success. We assessed the feasibility of blinding an active manual soft tissue mobilisation and control intervention of the back. We also assessed whether blinding is feasible among outcome assessors and explored factors influencing perceptions about intervention assignment. METHODS: On 7-8 November 2022, 24 participants were randomly allocated (1:1 ratio) to active or control manual interventions of the back. The active group (n = 11) received soft tissue mobilisation of the lumbar spine. The control group (n = 13) received light touch over the thoracic region with deep breathing exercises. The primary outcome was blinding of participants immediately after a one-time intervention session, as measured by the Bang blinding index (Bang BI). Bang BI ranges from -1 (complete opposite perceptions of intervention received) to 1 (complete correct perceptions), with 0 indicating 'random guessing'-balanced 'active' and 'control' perceptions within an intervention arm. Secondary outcomes included blinding of outcome assessors and factors influencing perceptions about intervention assignment among both participants and outcome assessors, explored via thematic analysis. RESULTS: 24 participants were analysed following an intention-to-treat approach. 55% of participants in the active manual soft tissue mobilisation group correctly perceived their group assignment beyond chance immediately after intervention (Bang BI: 0.55 [95% confidence interval (CI), 0.25 to 0.84]), and 8% did so in the control group (0.08 [95% CI, -0.37 to 0.53]). Bang BIs in outcome assessors were 0.09 (-0.12 to 0.30) and -0.10 (-0.29 to 0.08) for active and control participants, respectively. Participants and outcome assessors reported varying factors related to their perceptions about intervention assignment. CONCLUSIONS: Blinding of participants allocated to an active soft tissue mobilisation of the back was not feasible in this methodological trial, whereas blinding of participants allocated to the control intervention and outcome assessors was adequate. Findings are limited due to imprecision and suboptimal generalisability to clinical settings. Careful thinking and consideration of blinding in manual therapy trials is warranted and needed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05822947 (retrospectively registered).

Next-generation sequencing-based gene panel tests for the detection of rare variants and hypomorphic alleles associated with primary open-angle glaucoma.

Primary open-angle glaucoma (POAG) is a complex disease with a strong hereditably component. Several genetic variants have recently been associated with POAG, partially due to technological improvements such as next-generation sequencing (NGS). The aim of this study was to genetically analyze patients with POAG to determine the contribution of rare variants and hypomorphic alleles associated with glaucoma as a future method of diagnosis and early treatment. Seventy-two genes potentially associated with adult glaucoma were studied in 61 patients with POAG. Additionally, we sequenced the coding sequence of CYP1B1 gene in 13 independent patients to deep analyze the potential association of hypomorphic CYP1B1 alleles in the pathogenesis of POAG. We detected nine rare variants in 16% of POAG patients studied by NGS. Those rare variants are located in CYP1B1, SIX6, CARD10, MFN1, OPTC, OPTN, and WDR36 glaucoma-related genes. Hypomorphic variants in CYP1B1 and SIX6 genes have been identified in 8% of the total POAG patient assessed. Our findings suggest that NGS could be a valuable tool to clarify the impact of genetic component on adult glaucoma. However, in order to demonstrate the contribution of these rare variants and hypomorphic alleles to glaucoma, segregation and functional studies would be necessary. The identification of new variants and hypomorphic alleles in glaucoma patients will help to configure the genetic identity of these patients, in order to make an early and precise molecular diagnosis.

Performance of the new MC-80 automated digital cell morphology analyser in detection of normal and abnormal blood cells: Comparison with the CellaVision DM9600.

INTRODUCTION: Mindray MC-80 is an automated system for digital imaging of white blood cells (WBCs) and their pre-classification. The objective of this work is to analyse its performance comparing it with the CellaVision® DM9600. METHODS: A total of 445 samples were used, 194 normal and 251 abnormal: acute leukaemia (100), myelodysplastic syndromes/myeloproliferative neoplasms (33), lymphoid neoplasms (50), plasma cell neoplasms (14), infections (49) and thrombocytopenia (5). WBC pre-classification values with the MC-80 and DM9600 were compared with (1) the microscope, (2) Mindray BC-6800Plus differentials in only normal samples, and (3) confirmed or reclassified images (post-classification). Pearson's correlation, Lin's concordance, Passing-Bablok regression, and Bland-Altman plots were used. Sensitivity, specificity, positive (PPV) and negative (NPV) predictive values for abnormal cells using the MC-80 were calculated. RESULTS: The PPV and NPV were above 98% and 99%, for normal samples. For immature granulocytes (IG), NPV and PPV were 100% and 74.2%. When comparing the WBC differentials using the MC-80, the microscope and the BC-6800Plus, no differences were found except for basophils and IG. Our results showed good agreement between the pre- and post-classification of normal WBC, including IG, quantified by high correlation and concordance values (0.91-1). Sensitivity and specificity for blasts were 0.984 and 0.640. The MC-80 detected abnormal lymphocytes in 30% of the smears from patients with lymphoid neoplasm. Plasma cell identification was better using the DM9600. The sensitivity and specificity for erythroblast detection were 1 and 0.890. CONCLUSION: We found that the MC-80 shows high performance for WBC differentials for both normal samples and patients with haematological diseases.

Association between serum 25-hydroxyvitamin D and prostate-specific antigen: a retrospective study in men without prostate pathology.

Objectives: Recently, vitamin D status has been associated with prostate cancer risk. However, some studies argue that there is no association of vitamin D with prostate cancer risk and serum prostate-specific antigen (PSA) concentrations. No clear conclusions can be drawn from the studies found in the literature. Our aim was to assess the relationship between PSA and 25-hydroxyvitamin D [25(OH)D]. Methods: We selected 415 individuals without prostate pathologies and subgroups were generated according to age and 25(OH)D. Statistical analyses were performed using Shapiro-Wilk test, Student's t and ANOVA tests, and Pearson's correlation. Besides, the minimum sample size needed to obtain statistically significant results between groups according to 25(OH)D concentration was calculated and a Student's t-test for paired samples was performed to study individuals with two PSA measurements over time, where 25(OH)D concentration increased or decreased more than 25 %. Results: We observed a slight correlation between age and PSA concentration (r=0.379, p<0.001). However, we found no significant differences when we compared PSA concentrations between groups according to 25(OH)D concentrations (p=0.891): 1.25 ± 1.32 µg/L (group with 25(OH)D<50 nmol/L) and 1.17 ± 0.90 (group with 25(OH)D≥50 nmol/L). Pearson's correlation coefficient was close to 0. The minimum samples size to obtain statistically significant results was 815,346 men, and we observed no differences in PSA concentrations in individuals with two measurements. Conclusions: Our findings show no association in men without prostate pathologies, based on 25(OH)D levels.

Systematic Review to Inform a World Health Organization (WHO) Clinical Practice Guideline: Benefits and Harms of Transcutaneous Electrical Nerve Stimulation (TENS) for Chronic Primary Low Back Pain in Adults.

PURPOSE: To evaluate benefits and harms of transcutaneous electrical nerve stimulation (TENS) for chronic primary low back pain (CPLBP) in adults to inform a World Health Organization (WHO) standard clinical guideline. METHODS: We searched for randomized controlled trials (RCTs) from various electronic databases from July 1, 2007 to March 9, 2022. Eligible RCTs targeted TENS compared to placebo/sham, usual care, no intervention, or interventions with isolated TENS effects (i.e., combined TENS with treatment B versus treatment B alone) in adults with CPLBP. We extracted outcomes requested by the WHO Guideline Development Group, appraised the risk of bias, conducted meta-analyses where appropriate, and graded the certainty of evidence using GRADE. RESULTS: Seventeen RCTs (adults, n = 1027; adults ≥ 60 years, n = 28) out of 2010 records and 89 full text RCTs screened were included. The evidence suggested that TENS resulted in a marginal reduction in pain compared to sham (9 RCTs) in the immediate term (2 weeks) (mean difference (MD) = -0.90, 95% confidence interval -1.54 to -0.26), and a reduction in pain catastrophizing in the short term (3 months) with TENS versus no intervention or interventions with TENS specific effects (1 RCT) (MD = -11.20, 95% CI -17.88 to -3.52). For other outcomes, little or no difference was found between TENS and the comparison interventions. The certainty of the evidence for all outcomes was very low. CONCLUSIONS: Based on very low certainty evidence, TENS resulted in brief and marginal reductions in pain (not deemed clinically important) and a short-term reduction in pain catastrophizing in adults with CPLBP, while little to no differences were found for other outcomes.

Systematic Review to Inform a World Health Organization (WHO) Clinical Practice Guideline: Benefits and Harms of Needling Therapies for Chronic Primary Low Back Pain in Adults.

PURPOSE: Evaluate benefits and harms of needling therapies (NT) for chronic primary low back pain (CPLBP) in adults to inform a World Health Organization (WHO) standard clinical guideline. METHODS: Electronic databases were searched for randomized controlled trials (RCTs) assessing NT compared with placebo/sham, usual care, or no intervention (comparing interventions where the attributable effect could be isolated). We conducted meta-analyses where indicated and graded the certainty of evidence. RESULTS: We screened 1831 citations and 109 full text RCTs, yeilding 37 RCTs. The certainty of evidence was low or very low across all included outcomes. There was little or no difference between NT and comparisons across most outcomes; there may be some benefits for certain outcomes. Compared with sham, NT improved health-related quality of life (HRQoL) (physical) (2 RCTs; SMD = 0.20, 95%CI 0.07; 0.32) at 6 months. Compared with no intervention, NT reduced pain at 2 weeks (21 RCTs; MD = - 1.21, 95%CI - 1.50; - 0.92) and 3 months (9 RCTs; MD = - 1.56, 95%CI - 2.80; - 0.95); and reduced functional limitations at 2 weeks (19 RCTs; SMD = - 1.39, 95%CI - 2.00; - 0.77) and 3 months (8 RCTs; SMD = - 0.57, 95%CI - 0.92; - 0.22). In older adults, NT reduced functional limitations at 2 weeks (SMD = - 1.10, 95%CI - 1.71; - 0.48) and 3 months (SMD = - 1.04, 95%CI - 1.66; - 0.43). Compared with usual care, NT reduced pain (MD = - 1.35, 95%CI - 1.86; - 0.84) and functional limitations (MD = - 2.55, 95%CI - 3.70; - 1.40) at 3 months. CONCLUSION: Based on low to very low certainty evidence, adults with CPLBP experienced some benefits in pain, functioning, or HRQoL with NT; however, evidence showed little to no differences for other outcomes.

Systematic Review to Inform a World Health Organization (WHO) Clinical Practice Guideline: Benefits and Harms of Structured and Standardized Education or Advice for Chronic Primary low back pain in Adults.

PURPOSE: Evaluate benefits and harms of education/advice for chronic primary low back pain (CPLBP) in adults to inform a World Health Organization (WHO) standard clinical guideline. METHODS: Electronic databases were searched for randomized controlled trials (RCTs) assessing education/advice compared with placebo/sham, usual care, or no intervention (including comparison interventions where the attributable effect of education/advice could be isolated). We conducted meta-analyses and graded the certainty of evidence. RESULTS: We screened 2514 citations and 86 full text RCTs and included 15 RCTs. Most outcomes were assessed 3 to 6 months post-intervention. Compared with no intervention, education/advice improved pain (10 RCTs, MD = -1.1, 95% CI -1.63 to -0.56), function (10 RCTs, SMD = -0.51, 95% CI -0.89 to -0.12), physical health-related quality of life (HRQoL) (2 RCTs, MD = 24.27, 95% CI 12.93 to 35.61), fear avoidance (5 RCTs, SMD = -1.4, 95% CI -2.51 to -0.29), depression (1 RCT; MD = 2.10, 95% CI 1.05 to 3.15), and self-efficacy (1 RCT; MD = 4.4, 95% CI 2.77 to 6.03). Education/advice conferred less benefit than sham Kinesio taping for improving fear avoidance regarding physical activity (1 RCT, MD = 5.41, 95% CI 0.28 to 10.54). Compared with usual care, education/advice improved pain (1 RCT, MD = -2.10, 95% CI -3.13 to -1.07) and function (1 RCT, MD = -7.80, 95% CI -14.28 to -1.32). There was little or no difference between education/advice and comparisons for other outcomes. For all outcomes, the certainty of evidence was very low. CONCLUSION: Education/advice in adults with CPLBP was associated with improvements in pain, function, HRQoL, and psychological outcomes, but with very low certainty.

Comparative Efficacy of Conservative Surgery vs Minor Amputation for Diabetic Foot Osteomyelitis.

BACKGROUND: There is uncertainty regarding the optimal surgical intervention for diabetic foot osteomyelitis (DFO). Conservative surgery-amputation-free resection of infected bone and soft tissues-is gaining traction as an alternative to minor amputation. Our primary objective was to explore the comparative effectiveness of conservative surgery and minor amputations in clinical failure risk 1 year after index intervention. We also aimed to explore microbiological recurrence at 1 year, and revision surgery risk over a 10-year study period. METHODS: Retrospective, single-center chart review of DFO patients undergoing either conservative surgery or minor amputation. We used multivariable Cox regression and Kaplan-Meier estimates to explore the effect of surgical intervention on clinical failure (recurrent diabetic foot infection at surgical site within 1 year after index operation), microbiological recurrence at 1 year, and revision surgery risk over a 10-year follow-up period. RESULTS: 651 patients were included (conservative surgery, n = 121; minor amputation, n = 530). Clinical failure occurred in 34 (28%) patients in the conservative surgery group, and in 111 (21%) of the minor amputation group at 1 year (P = .09). After controlling for potential confounders, we found no association between conservative surgery and clinical failure at 1 year (adjusted hazard ratio [HR] 1.3, 95% CI 0.8-2.1). We found no between-group differences in microbiological recurrence at 1 year (conservative surgery: 8 [6.6%]; minor amputation: 33 [6.2%]; P = .25; adjusted HR 1.1, 95% CI 0.5-2.6). Over the 10-year period, the conservative group underwent significantly more revision surgeries (conservative surgery: 85 [70.2%]; minor amputation: 252 [47.5%]; P < .01; adjusted HR 1.3, 95% CI 0.9-1.8). CONCLUSION: We found that with comorbidity-based patient selection, conservative surgery in the treatment of DFO was associated with the same rates of clinical failure and microbiological recurrence at 1 year, but with significantly more revision surgeries during follow-up, compared with minor amputations. LEVEL OF EVIDENCE: Level III, retrospective comparative effectiveness study.

Certainty of the Global Burden of Disease 2019 Modelled Prevalence Estimates for Musculoskeletal Conditions: A Meta-Epidemiological Study.

Objectives: To describe and assess the risk of bias of the primary input studies that underpinned the Global Burden of Disease Study (GBD) 2019 modelled prevalence estimates of low back pain (LBP), neck pain (NP), and knee osteoarthritis (OA), from Australia, Brazil, Canada, Spain, and Switzerland. To evaluate the certainty of the GBD modelled prevalence evidence. Methods: Primary studies were identified using the GBD Data Input Sources Tool and their risk of bias was assessed using a validated tool. We rated the certainty of modelled prevalence estimates based on the GRADE Guidelines 30-the GRADE approach for modelled evidence. Results: Seventy-two primary studies (LBP: 67, NP: 2, knee OA: 3) underpinned the GBD estimates. Most studies had limited representativeness of their study populations, used suboptimal case definitions and applied assessment instruments with unknown psychometric properties. The certainty of modelled prevalence estimates was low, mainly due to risk of bias and indirectness. Conclusion: Beyond the risk of bias of primary input studies for LBP, NP, and knee OA in GBD 2019, the certainty of country-specific modelled prevalence estimates still have room for improvement.

Kimura disease as an uncommon cause of persistent hypereosinophilia: a diagnostic challenge.

Kimura disease (KD) is an unusual inflammatory disease of unknown etiology. Despite being described many years ago, KD might cause diagnostic difficulty or be confused with other conditions. Here, we present a 33-year-old Filipino woman who was referred to our hospital for evaluation of persistent eosinophilia and intense pruritus. Blood analysis and peripheral blood smear review showed high eosinophil counts (3.8 x109/L, 40%) that did not show morphological abnormalities. Besides, high serum IgE concentration was detected (33,528 kU/L). Serological tests were positive for Toxocara canis and treatment with albendazol was initiated. Nevertheless, increased eosinophil counts were still present after several months, alongside with high serum IgE concentrations and intense pruritus. During her follow-up, an inguinal adenopathy was detected. The biopsy revealed lymphoid hyperplasia with reactive germinal centers and massive eosinophil infiltration. Proteinaceous deposits of eosinophilic material were also observed. All these findings, together with peripheral blood eosinophilia and high IgE concentrations, confirmed the diagnosis of KD. The diagnosis of KD should be considered in the differential diagnosis of long-standing unexplained eosinophilia in association with high IgE concentrations, pruritus and lymphadenopathies.

Local Antibiotics in the Treatment of Diabetic Foot Infections: A Narrative Review.

Along with the increasing global burden of diabetes, diabetic foot infections (DFI) and diabetic foot osteomyelitis (DFO) remain major challenges for patients and society. Despite progress in the development of prominent international guidelines, the optimal medical treatment for DFI and DFO remains unclear as to whether local antibiotics, that is, topical agents and local delivery systems, should be used alone or concomitant to conventional systemic antibiotics. To better inform clinicians in this evolving field, we performed a narrative review and summarized key relevant observational studies and clinical trials of non-prophylactic local antibiotics for the treatment of DFI and DFO, both alone and in combination with systemic antibiotics. We searched PubMed for studies published between January 2000 and October 2022, identified 388 potentially eligible records, and included 19 studies. Our findings highlight that evidence for adding local antibiotic delivery systems to standard DFO treatment remains limited. Furthermore, we found that so far, local antibiotic interventions have mainly targeted forefoot DFO, although there is marked variation in the design of the included studies. Suggestive evidence emerging from observational studies underscores that the addition of local agents to conventional systemic antibiotics might help to shorten the clinical healing time and overall recovery rates in infected diabetic foot ulcers, although the effectiveness of local antibiotics as a standalone approach remains overlooked. In conclusion, despite the heterogeneous body of evidence, the possibility that the addition of local antibiotics to conventional systemic treatment may improve outcomes in DFI and DFO cannot be ruled out. Antibiotic stewardship principles call for further research to elucidate the potential benefits of local antibiotics alone and in combination with conventional systemic antibiotics for the treatment of DFI and DFO.

Do religious beliefs influence the acceptance of xenotransplantation? Veterinary students.

BACKGROUND: Xenotransplantation could be a source of organs for transplantation given the global organ shortage. It is important to know the opinion and variables that influence the acceptance of xenotransplantation of the professionals who will work in the genetic manipulation, production, and care of animals to be used for this purpose. OBJECTIVE: Analyze the influence of religious beliefs on the attitude toward xenotransplantation in veterinary students. METHODS: The study population included 2683 veterinary students from different courses and Spanish Universities. Instrument evaluation included a validated self-administered and anonymously completed questionnaire (PCID-XENOTx-Ríos). The survey was self-administered and completed anonymously. Consent to collaborate in the study was requested. Variables for the study included attitude toward xenotransplantation and toward religion, considering the following options: practicing Catholic, nonpracticing Catholic, non-Catholic, and atheist/agnostic. Statistics were performed using descriptive analysis, Student t test, -X2, and Fisher's exact test. RESULTS: Of the total number of participants, 7 did not answer this question. Those in favor of xenotransplantation were 92.9% (n = 247) of practicing Catholics, 92.8% (n = 812) of nonpracticing Catholics, and 87.3% (n = 69) of those professing another non-Catholic religion compared with 93.5% (n = 1361) of those considering themselves agnostic/atheist (P = .037). CONCLUSIONS: Religion is an influential factor in attitudes toward organ xenotransplantation. Those who practice Catholicism and those who consider themselves agnostic/atheist are more accepting of organ procurement for transplantation than those who practice other religious doctrines.

Serous body fluid evaluation using the new automated haematology analyser Mindray BC-6800Plus.

OBJECTIVES: Cellular analysis of body fluids (BF) has clinical relevance in several medical conditions. The objective of this study is twofold: (1) evaluate the analytical performance of the BF mode of Mindray BC-6800 Plus compared to manual counts under microscopy and (2) analyse if the high-fluorescent cell counts provided by the analyser (HF-BF) are useful to detect malignancy. METHODS: A total of 285 BF was analysed: 250 corresponding to patients without neoplasia and 35 to patients with malignant diseases. Manual differential counts were performed in BF with ≥250 cells/µL. Percentages and absolute counts were obtained on the BC-6800Plus for total nucleated cells (TC-BF), mononuclear, polymorphonuclear and HF-BF. Statistical analysis was performed using Mann-Whitney U-test, Spearman's correlation, Passing-Bablok regression, Bland-Altman graph and ROC curve. RESULTS: To compare manual and automatic total cell counts, samples were divided in three groups: <250, 250-1,000 and >1,000 cells/µL. Correlation was good in all cases (r=0.72, 0.73 and 0.92, respectively) without significant differences between both methods (p=0.65, 0.39 and 0.30, respectively). The concordance between methods showed values of 90%. Considering malignant samples, median HF-BF values showed significant higher values (102 cells/µL) with respect to non-malignant (4 cells/µL) (p<0.001). The cut-off value of 8.5 HF-BF/µL was able to discriminate samples containing malignant cells showing sensitivity and specificity values of 89 and 71%, respectively. Considering both, HF-BF and TC-BF values, sensitivity and specificity values were 100 and 53%, respectively. CONCLUSIONS: This study reveals that the Mindray BC-6800Plus offers an accurate and acceptable performance, showing results consistent with the manual method. It is recommended to consider both HF-BF and TC-BF values for the screening of the microscopic evaluation to ensure the detection of all malignant samples.