Patterns of variation and allometry in sub-cortical structures of the human brain: an evaluation of sex differences and age

This research tests a series of research questions concerning relationships between size, shape (static adult scaling relations) and multivariate patterns of variation in brains of adult modern humans using in vivo measurements from magnetic resonance imaging (MRI) scans. The main research questions consider if patterns of adult human sub-cortical brain dimorphisms are driven by overall brain size differences between the sexes. Sex differences in absolute brain size in humans are well known. There is a general consensus that male brains are larger in absolute size than female brains. However, discrepancies among studies in the presence and extent of dimorphisms indicate uncertainty the degree to which sexual dimorphism (SD) is spread throughout the brain, particularly within sub-cortical structures. Therefore, to address the problem of SD, this project 1) tests brain size variation and scaling relationships in sub-cortical structures between adult human males and females, 2) tests these in younger and older age categories and 3) tests the degree to which sub-cortical brain components covary in size. This study includes two groups of right-handed, native English speakers recruited from the Champaign-Urbana community. These data represent 189 healthy individuals, consisting of four sex and age categories: younger men (n=18), younger women (n=23), older men (n=50), and older women (n=98). Younger individuals ages range from 18-35 years, and older individuals ages range from 50-80 years. The individuals involved in this project were originally recruited for a study on the effects of exercise and aging on cognition (Colcombe, 2004; Erickson et. al., 2004), and were screened for psychiatric illness prior to participation. The results presented here support the hypothesis that sex differences in sub-cortical structures relative to total brain volume are moderate to non-existent between males and females ii" " both in the younger and in the older age groups. Bivariate results indicate two possible patterns of allometry: significant positive allometry with the use of a reduced major axis regression, or allometry supporting a generally isometric to negatively allometric with the use of an ordinary least squares regression. Both results are described. Multivariate results (principal components analysis) of the combined sample indicate size plays a large role in explaining the variation in the data, with other factors offering substantial contributions. On explanation is that patterns of variation in the second and perhaps third principal components might be the result of developmental and functional relationships among sub-cortical structures. The main differences between the older and younger age categories is a higher correlation among regions in the younger category, lending some support to the idea that an extended human lifespan may lead to a breakdown in correlation structure as we age. Reduced major axis regression and ordinary least squares regression offer two alternatives to understanding scaling of sub-cortical structures in the brain. OLS results are in line with expectations of scaling patterns. Issues of sample size are important to the interpretation of results in this study, and are discussed. The effects of developmental processes on adult brain size are described throughout the thesis. In particular, gonadal hormones such as estrogen and testosterone have been hypothesized to result in larger or smaller structures in each of the sexes. The potential impact these hormones have on sex differences in the brain and on behavior support the idea that hormones may play a large role in determining differences in function, and that may or may not result in measurable differences in brain volumes. Finally, implications of this study and avenues for future research are discussed

Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1:a multicentre, single-blind, randomised trial

Background: Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults and leads to severe fatigue, substantial physical functional impairment, and restricted social participation. In this study, we aimed to determine whether cognitive behavioural therapy optionally combined with graded exercise compared with standard care alone improved the health status of patients with myotonic dystrophy type 1. Methods: We did a multicentre, single-blind, randomised trial, at four neuromuscular referral centres with experience in treating patients with myotonic dystrophy type 1 located in Paris (France), Munich (Germany), Nijmegen (Netherlands), and Newcastle (UK). Eligible participants were patients aged 18 years and older with a confirmed genetic diagnosis of myotonic dystrophy type 1, who were severely fatigued (ie, a score of ≥35 on the checklist-individual strength, subscale fatigue). We randomly assigned participants (1:1) to either cognitive behavioural therapy plus standard care and optional graded exercise or standard care alone. Randomisation was done via a central web-based system, stratified by study site. Cognitive behavioural therapy focused on addressing reduced patient initiative, increasing physical activity, optimising social interaction, regulating sleep–wake patterns, coping with pain, and addressing beliefs about fatigue and myotonic dystrophy type 1. Cognitive behavioural therapy was delivered over a 10-month period in 10–14 sessions. A graded exercise module could be added to cognitive behavioural therapy in Nijmegen and Newcastle. The primary outcome was the 10-month change from baseline in scores on the DM1-Activ-c scale, a measure of capacity for activity and social participation (score range 0–100). Statistical analysis of the primary outcome included all participants for whom data were available, using mixed-effects linear regression models with baseline scores as a covariate. Safety data were presented as descriptives. This trial is registered with ClinicalTrials.gov, number NCT02118779. Findings: Between April 2, 2014, and May 29, 2015, we randomly assigned 255 patients to treatment: 128 to cognitive behavioural therapy plus standard care and 127 to standard care alone. 33 (26%) of 128 assigned to cognitive behavioural therapy also received the graded exercise module. Follow-up continued until Oct 17, 2016. The DM1-Activ-c score increased from a mean (SD) of 61·22 (17·35) points at baseline to 63·92 (17·41) at month 10 in the cognitive behavioural therapy group (adjusted mean difference 1·53, 95% CI −0·14 to 3·20), and decreased from 63·00 (17·35) to 60·79 (18·49) in the standard care group (−2·02, −4·02 to −0·01), with a mean difference between groups of 3·27 points (95% CI 0·93 to 5·62, p=0·007). 244 adverse events occurred in 65 (51%) patients in the cognitive behavioural therapy group and 155 in 63 (50%) patients in the standard care alone group, the most common of which were falls (155 events in 40 [31%] patients in the cognitive behavioural therapy group and 71 in 33 [26%] patients in the standard care alone group). 24 serious adverse events were recorded in 19 (15%) patients in the cognitive behavioural therapy group and 23 in 15 (12%) patients in the standard care alone group, the most common of which were gastrointestinal and cardiac. Interpretation: Cognitive behavioural therapy increased the capacity for activity and social participation in patients with myotonic dystrophy type 1 at 10 months. With no curative treatment and few symptomatic treatments, cognitive behavioural therapy could be considered for use in severely fatigued patients with myotonic dystrophy type 1. Funding: The European Union Seventh Framework Programme

Financijsko planiranje primjenom metode linearnog cjelobrojnog programiranja

Financiranje je važna funkcija u poduzeću pomoću koje se odlučuje koliko financijskih sredstava je neophodno, na koje razdoblje, te kako upravljati tim procesom uz ograničene uvjete. Temeljno pitanje s kojim se susreću mnoga poduzeća koja imaju svoju proizvodnju je poboljšanje efikasnosti poslovanja, odnosno minimizacija vlastitih troškova i maksimizacija vlastitog profita. Upravo je problem maksimuma ili minimuma standardni problem u linearnom programiranju. Linearno programiranje je optimizacijski problem, a kada postoje problemi u kojima varijable mogu imati samo cjelobrojne vrijednosti, to se naziva linearno cjelobrojno programiranje. U radu su riješena četiri primjera u kojima je prikazano kako se pomoću linearnog cjelobrojnog programiranja mogu donijeti odluke o novim investicijama, širenju poslovanja i maksimizaciji profita. Koristi se program Solver koji je dio Microsoft Excel-a te omogućava pronalaženje rješenja kompleksnih problema

Financijsko planiranje primjenom metode linearnog cjelobrojnog programiranja

Financiranje je važna funkcija u poduzeću pomoću koje se odlučuje koliko financijskih sredstava je neophodno, na koje razdoblje, te kako upravljati tim procesom uz ograničene uvjete. Temeljno pitanje s kojim se susreću mnoga poduzeća koja imaju svoju proizvodnju je poboljšanje efikasnosti poslovanja, odnosno minimizacija vlastitih troškova i maksimizacija vlastitog profita. Upravo je problem maksimuma ili minimuma standardni problem u linearnom programiranju. Linearno programiranje je optimizacijski problem, a kada postoje problemi u kojima varijable mogu imati samo cjelobrojne vrijednosti, to se naziva linearno cjelobrojno programiranje. U radu su riješena četiri primjera u kojima je prikazano kako se pomoću linearnog cjelobrojnog programiranja mogu donijeti odluke o novim investicijama, širenju poslovanja i maksimizaciji profita. Koristi se program Solver koji je dio Microsoft Excel-a te omogućava pronalaženje rješenja kompleksnih problema

GC/MS and FAB/MS analysis of lipid molecules for taxonomic classification of microorganisms

The goal of this project was to identify the presence of microorganisms in the environment by using their gas chromatography/mass spectral (GC/MS) characteristics as biomarkers. A combination of GC/MS results and pattern recognition statistical evaluation were used to provide a mathematical model with defined parameters for different microorganisms, which allows the organisms to be classified as bacterial, fungal or viral nature. Results from fast atom bombardment mass spectral (FAB/MS) analysis showed differences in the complex lipid profiles for most of the analyzed microorganisms. A general screening method that can provide early detection of microorganisms would permit initiation of most therapeutics. Various drugs are used to treat bacterial, fungal or viral diseases and, when treatment is started early, there is a dramatic reduction in mortality. A methodology for detection and classification of microorganisms is described in this paper

Ixazomib, Lenalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma in Routine Clinical Practice: Extended Follow-Up Analysis and the Results of Subsequent Therapy

Background: We confirmed the benefit of addition of ixazomib to lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM) in unselected real-world population. We report the final analysis for overall survival (OS), second progression free survival (PFS-2), and the subanalysis of the outcomes in lenalidomide (LEN) pretreated and LEN refractory patients. Methods: We assessed 344 patients with RRMM, treated with IRD (N  =  127) or RD (N  = 217). The data were acquired from the Czech Registry of Monoclonal Gammopathies (RMG). With prolonged follow-up (median 28.5 months), we determined the new primary endpoints OS, PFS and PFS-2. Secondary endpoints included the next therapeutic approach and the survival measures in LEN pretreated and LEN refractory patients. Results: The final overall response rate (ORR) was 73.0% in the IRD cohort and 66.8% in the RD cohort. The difference in patients reaching ≥VGPR remained significant (38.1% vs. 26.3%, p = 0.028). Median PFS maintained significant improvement in the IRD cohort (17.5 vs. 12.5 months, p = 0.013) with better outcomes in patients with 1–3 prior relapses (22.3 vs. 12.7 months p = 0.003). In the whole cohort, median OS was for IRD vs. RD patients 40.9 vs. 27.1 months (p = 0.001), with further improvement within relapse 1-3 (51.7 vs. 27.8 months, p ˂ 0.001). The median PFS of LEN pretreated (N = 22) vs. LEN naive (N = 105) patients treated by IRD was 8.7 vs. 23.1 months (p = 0.001), and median OS was 13.2 vs. 51.7 months (p = 0.030). Most patients in both arms progressed and received further myeloma-specific therapy (63.0% in the IRD group and 53.9% in the RD group). Majority of patients received pomalidomide-based therapy or bortezomib based therapy. Significantly more patients with previous IRD vs. RD received subsequent monoclonal antibodies (daratumumab—16.3% vs. 4.3%, p = 0.0054; isatuximab 5.0% vs. 0.0%, p = 0.026) and carfilzomib (12.5 vs. 1.7%, p = 0.004). The median PFS-2 (progression free survival from the start of IRD/RD therapy until the second disease progression or death) was significantly longer in the IRD cohort (29.8 vs. 21.6 months, p = 0.016). There were no additional safety concerns in the extended follow-up. Conclusions: The IRD regimen is well tolerated, easy to administer, and with very good therapeutic outcomes. The survival measures in unsorted real-world population are comparable to the outcomes of the clinical trial. As expected, patients with LEN reatment have poorer outcomes than those who are LEN-naive. The PFS benefit of IRD vs. RD translated into significantly better PFS-2 and OS, but the outcomes must be accounted for imbalances in pretreatment group characteristics (especially younger age and stem cell transplant pretreatment), and in subsequent therapies

More than 2% of circulating tumor plasma cells defines plasma cell leukemia-like multiple myeloma

[Purpose]: Primary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by $20$ 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels. [Methods]: We assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis. [Results]: Newly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P , .001) and overall survival (14.6 v 33.6 months; P 5 .023) than patients with , 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs. [Conclusions]: Our study uncovers that $ 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.Supported by the European Regional Development Fund—New Directions of Biomedical Research in the Ostrava Region (No. CZ.02.1.01/0.0/0.0/18_069/0010060), by the National Institute for Cancer Research (Program EXCELES, ID Project No. LX22NPO5102)—Funded by the European Union—Next Generation EU and by the Ministry of Health of the Czech Republic (AZV—NU21-03-00076), Institutional Support by MH CZ—DRO—FNOs/2019, MH CZ—DRO—FNOs/2020, Student's grant system SGS12/PrF/2022, SGS10/LF/2022 University of Ostrava and by the Ministry of Education, Youth and Sports of the Czech Republic through the e-INFRA CZ (ID:90140). The work was also supported by Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369); Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS No. PI20/00048, PI21/01816); the Cancer Research UK (C355/A26819), FCAECC and AIRC under the Accelerator Award Program (EDITOR); the European Research Council (ERC) 2015 Starting Grant (MYELOMANEXT/680200)

Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial

Background Lyme borreliosis develops in 1-5% of individuals bitten by ticks, but with a diagnostic gap affecting up to 30% of patients, a broadly applicable pharmacological prevention strategy is needed. Topical azithromycin effectively eradicated Borrelia burgdorferi sensu lato from the skin in preclinical studies. We assessed its efficacy in human beings. Methods In this randomised, double-blind, placebo-controlled, multicentre trial done in 28 study sites in Germany and Austria, adults were equally assigned to receive topical 10% azithromycin or placebo twice daily for 3 consecutive days, within 72 h of a tick bite being confirmed. Randomisation numbers, which were stratified by study site, were accessed in study centres via an interactive voice-response system, by pharmacists not involved in the study. The primary outcome was the number of treatment failures, defined as erythema migrans, seroconversion, or both, in participants who were seronegative at baseline, had no further tick bites during the study, and had serology results available at 8 weeks (intention-to-treat [ITT] population). This study is registered with EudraCT, number 2011-000117-39. Findings Between July 7, 2011, and Dec 3, 2012, 1371 participants were randomly assigned to treatment, of whom 995 were included in the ITT population. The trial was stopped early because an improvement in the primary endpoint in the group receiving azithromycin was not reached. At 8 weeks, 11 (2%) of 505 in the azithromycin group and 11 (2%) of 490 in the placebo group had treatment failure (odds ratio 0.97, 95% CI 0 42-2 26, p=0.47). Topical azithromycin was well tolerated. Similar numbers of patients had adverse events in the two groups (175 [26%] of 505 vs 177 [26%] of 490, p=0.87), and most adverse events were mild. Interpretation Topical azithromycin was well tolerated and had a good safety profile. Inclusion of asymptomatic seroconversion into the primary efficacy analysis led to no prevention effect with topical azithromycin. Adequately powered studies assessing only erythema migrans should be considered. A subgroup analysis in this study suggested that topical azithromycin reduces erythema migrans after bites of infected ticks