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Abstract Pathological data showed focal inflammation and regions of diffuse neuronal loss in the cortex of people with multiple sclerosis (MS). In this work, we applied a novel model (“soma and neurite density imaging (SANDI)”) to multishell diffusion-weighted MRI data acquired in healthy subjects and people with multiple sclerosis (pwMS), in order to investigate inflammation and degeneration-related changes in the cortical tissue of pwMS. We aimed to (i) establish whether SANDI is applicable in vivo clinical data; (ii) investigate inflammatory and degenerative changes using SANDI soma fraction (f soma )—a marker of cellularity—in both cortical lesions and in the normal-appearing-cortex and (iii) correlate SANDI f soma with clinical and biological measures in pwMS. We applied a simplified version of SANDI to a clinical scanners. We then provided evidence that pwMS exhibited an overall decrease in cortical SANDI f soma compared to healthy subjects, suggesting global degenerative processes compatible with neuronal loss. On the other hand, we have found that progressive pwMS showed a higher SANDI f soma in the outer part of the cortex compared to relapsing–remitting pwMS, possibly supporting current pathological knowledge of increased innate inflammatory cells in these regions. A similar finding was obtained in subpial lesions in relapsing–remitting patients, reflecting existing pathological data in these lesion types. A significant correlation was found between SANDI f soma and serum neurofilament light chain—a biomarker of inflammatory axonal damage—suggesting a relationship between SANDI soma fraction and inflammatory processes in pwMS again. Overall, our data show that SANDI f soma is a promising biomarker to monitor changes in cellularity compatible with neurodegeneration and neuroinflammation in the cortex of MS patients.

ObjectiveTo identify the optimal dose of selinexor in combination with pomalidomide and dexamethasone (SPd).MethodsAn analysis of efficacy and safety of 2 once-weekly selinexor regimens (60 mg and 40 mg) with pomalidomide and dexamethasone (SPd-60 and SPd-40, respectively) given to patients with relapsed/refractory multiple myeloma (RRMM) in the STOMP (NCT02343042) and XPORT-MM-028 (NCT04414475) trials.ResultsTwenty-eight patients (60.7% males, median age 67.5 years) and 20 patients (35.0% males, median age 65.5 years) were analyzed in the SPd-40 and SPd-60 cohorts, respectively. Overall response rate was 50% (95% confidence interval [CI] 30.6-69.4%) and 65% (95% CI 40.8-84.6%), respectively. Very good partial response or better was reported in 28.6% (95% CI 13.2-48.7%) and 30.0% (95% CI 11.9-54.3%) of patients, respectively. Among 27 responders in both cohorts, the 12-month sustained response rate was 83.3% (95% CI 64.7-100.0%) for SPd-40 and 28.1% (95% CI 8.9-88.8%) for SPd-60. Median progression-free survival was 18.4 months (95% CI 6.5 months, not evaluable [NE]) and 9.5 months (95% CI 7.6 months-NE) for SPd-40 and SPd-60, respectively. Twenty-four-month survival rates were 64.2% (95% CI 47.7-86.3%) for SPd-40 and 51.1% (95% CI 29.9-87.5%) for SPd-60. Treatment-emergent adverse events (TEAEs) included neutropenia (all grades: SPd-40 64.3% versus SPd-60 75.0%), anemia (46.4% versus 65.0%), thrombocytopenia (42.9% versus 45.0%), fatigue (46.4% versus 75.0%), nausea (32.1% versus 70.0%) and diarrhea (28.6% versus 35.0%).ConclusionThe all-oral combination of SPd exhibited preliminary signs of efficacy and was generally tolerable in patients with RRMM. The overall risk-benefit profile favored the SPd-40 regimen.

IntroductionMulti-shell diffusion Magnetic Resonance Imaging (dMRI) data has been widely used to characterise white matter microstructure in several neurodegenerative diseases. The lack of standardised dMRI protocols often implies the acquisition of redundant measurements, resulting in prolonged acquisition times. In this study, we investigate the impact of the number of gradient directions on Diffusion Tensor Imaging (DTI) and on Neurite Orientation Dispersion and Density Imaging (NODDI) metrics.MethodsData from 124 healthy controls collected in three different longitudinal studies were included. Using an in-house algorithm, we reduced the number of gradient directions in each data shell. We estimated DTI and NODDI measures on six white matter bundles clinically relevant for neurodegenerative diseases.ResultsFractional Anisotropy (FA) measures on bundles where data were sampled at the 30% rate, showed a median L1 distance of up to 3.92% and a 95% CI of (1.74, 8.97)% when compared to those obtained at reference sampling. Mean Diffusivity (MD) reached up to 4.31% and a 95% CI of (1.60, 16.98)% on the same premises. At a sampling rate of 50%, we obtained a median of 3.90% and a 95% CI of (1.99, 16.65)% in FA, and 5.49% with a 95% CI of (2.14, 21.68)% in MD. The Intra-Cellular volume fraction (ICvf) median L1 distance was up to 2.83% with a 95% CI of (1.98, 4.82)% at a 30% sampling rate and 3.95% with a 95% CI of (2.39, 7.81)% at a 50% sampling rate. The volume difference of the reconstructed white matter at reference and 50% sampling reached a maximum of (2.09 ± 0.81)%.DiscussionIn conclusion, DTI and NODDI measures reported at reference sampling were comparable to those obtained when the number of dMRI volumes was reduced by up to 30%. Close to reference DTI and NODDI metrics were estimated with a significant reduction in acquisition time using three shells, respectively with: 4 directions at a b value of 700 s/mm2, 14 at 1000 s/mm2, and 32 at 2000 s/mm2. The study revealed aspects that can be important for large-scale clinical studies on bundle-specific diffusion MRI.

IntroductionRecent studies showed that the myelin of the brain changes in the life span, and demyelination contributes to the loss of brain plasticity during normal aging. Diffusion-weighted magnetic resonance imaging (dMRI) allows studying brain connectivity in vivo by mapping axons in white matter with tractography algorithms. However, dMRI does not provide insight into myelin; thus, combining tractography with myelin-sensitive maps is necessary to investigate myelin-weighted brain connectivity. Tractometry is designated for this purpose, but it suffers from some serious limitations. Our study assessed the effectiveness of the recently proposed Myelin Streamlines Decomposition (MySD) method in estimating myelin-weighted connectomes and its capacity to detect changes in myelin network architecture during the process of normal aging. This approach opens up new possibilities compared to traditional Tractometry.MethodsIn a group of 85 healthy controls aged between 18 and 68 years, we estimated myelin-weighted connectomes using Tractometry and MySD, and compared their modulation with age by means of three well-known global network metrics.ResultsFollowing the literature, our results show that myelin development continues until brain maturation (40 years old), after which degeneration begins. In particular, mean connectivity strength and efficiency show an increasing trend up to 40 years, after which the process reverses. Both Tractometry and MySD are sensitive to these changes, but MySD turned out to be more accurate.ConclusionAfter regressing the known predictors, MySD results in lower residual error, indicating that MySD provides more accurate estimates of myelin-weighted connectivity than Tractometry.

Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes. Certain targeted agents used to treat MM, such as selective inhibitors of nuclear export (SINE) compounds, have the potential to mitigate T-cell exhaustion. Herein referred to as XPO1 inhibitors, SINE compounds inhibit the nuclear export protein exportin 1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins and downregulation of oncoprotein expression. The XPO1 inhibitors selinexor and eltanexor reduced T-cell exhaustion in cell lines and animal models, suggesting their potential role in revitalizating these key effector cells. Additional clinical studies are needed to understand how T-cell fitness is impacted by diseases and therapeutic factors in MM, to potentially facilitate the optimal use of available treatments that depend on, and impact, T-cell function. This review summarizes the importance of T-cell fitness and the potential to optimize treatment using T-cell engaging therapies with a focus on XPO1 inhibitors.

White matter bundle segmentation is a cornerstone of modern tractography to study the brain’s structural connectivity in domains such as neurological disorders, neurosurgery, and aging. In this study, we present FIESTA (FIbEr Segmentation in Tractography using Autoencoders), a reliable and robust, fully automated, and easily semi-automatically calibrated pipeline based on deep autoencoders that can dissect and fully populate white matter bundles. This pipeline is built upon previous works that demonstrated how autoencoders can be used successfully for streamline filtering, bundle segmentation, and streamline generation in tractography. Our proposed method improves bundle segmentation coverage by recovering hard-to-track bundles with generative sampling through the latent space seeding of the subject bundle and the atlas bundle. A latent space of streamlines is learned using autoencoder-based modeling combined with contrastive learning. Using an atlas of bundles in standard space (MNI), our proposed method segments new tractograms using the autoencoder latent distance between each tractogram streamline and its closest neighbor bundle in the atlas of bundles. Intra-subject bundle reliability is improved by recovering hard-to-track streamlines, using the autoencoder to generate new streamlines that increase the spatial coverage of each bundle while remaining anatomically correct. Results show that our method is more reliable than state-of-the-art automated virtual dissection methods such as RecoBundles, RecoBundlesX, TractSeg, White Matter Analysis and XTRACT. Our framework allows for the transition from one anatomical bundle definition to another with marginal calibration efforts. Overall, these results show that our framework improves the practicality and usability of current state-of-the-art bundle segmentation framework

Axon radius is a potential biomarker for brain diseases and a crucial tissue microstructure parameter that determines the speed of action potentials. Diffusion MRI (dMRI) allows non-invasive estimation of axon radius, but accurately estimating the radius of axons in the human brain is challenging. Most axons in the brain have a radius below one micrometer, which falls below the sensitivity limit of dMRI signals even when using the most advanced human MRI scanners. Therefore, new MRI methods that are sensitive to small axon radii are needed. In this proof-of-concept investigation, we examine whether a surface-based axonal relaxation process could mediate a relationship between intra-axonal T2 and T1 times and inner axon radius, as measured using postmortem histology. A unique in vivo human diffusion-T1-T2 relaxation dataset was acquired on a 3T MRI scanner with ultra-strong diffusion gradients, using a strong diffusion-weighting (i.e., b = 6,000 s/mm2) and multiple inversion and echo times. A second reduced diffusion-T2 dataset was collected at various echo times to evaluate the model further. The intra-axonal relaxation times were estimated by fitting a diffusion-relaxation model to the orientation-averaged spherical mean signals. Our analysis revealed that the proposed surface-based relaxation model effectively explains the relationship between the estimated relaxation times and the histological axon radius measured in various corpus callosum regions. Using these histological values, we developed a novel calibration approach to predict axon radius in other areas of the corpus callosum. Notably, the predicted radii and those determined from histological measurements were in close agreement.

Abstract There is a lack of consensus on therapy sequencing in previously treated multiple myeloma, particularly after anti‐B‐cell maturation antigen (BCMA) therapy. Earlier reports on selinexor (X) regimens demonstrated considerable efficacy in early treatment, and after anti‐BCMA‐targeted chimeric antigen receptor‐T cell therapy. Here, we present data from 11 heavily pretreated patients who predominantly received BCMA‐antibody‐drug conjugate therapy. We observe that X‐containing regimens are potent and achieve durable responses with numerically higher overall response and clinical benefit rates, as well as median progression free survival compared to patients’ prior anti‐BCMA therapies, despite being used later in the treatment course. In an area of evolving unmet need, these data reaffirm the efficacy of X‐based regimens following broader anti‐BCMA therapy.

IntroductionThe presence of focal cortical and white matter damage in patients with multiple sclerosis (pwMS) might lead to specific alterations in brain networks that are associated with cognitive impairment. We applied microstructure-weighted connectomes to investigate (i) the relationship between global network metrics and information processing speed in pwMS, and (ii) whether the disruption provoked by focal lesions on global network metrics is associated to patients’ information processing speed.Materials and methodsSixty-eight pwMS and 92 healthy controls (HC) underwent neuropsychological examination and 3T brain MRI including multishell diffusion (dMRI), 3D FLAIR, and MP2RAGE. Whole-brain deterministic tractography and connectometry were performed on dMRI. Connectomes were obtained using the Spherical Mean Technique and were weighted for the intracellular fraction. We identified white matter lesions and cortical lesions on 3D FLAIR and MP2RAGE images, respectively. PwMS were subdivided into cognitively preserved (CPMS) and cognitively impaired (CIMS) using the Symbol Digit Modalities Test (SDMT) z-score at cut-off value of −1.5 standard deviations. Statistical analyses were performed using robust linear models with age, gender, and years of education as covariates, followed by correction for multiple testing.ResultsOut of 68 pwMS, 18 were CIMS and 50 were CPMS. We found significant changes in all global network metrics in pwMS vs HC (p < 0.05), except for modularity. All global network metrics were positively correlated with SDMT, except for modularity which showed an inverse correlation. Cortical, leukocortical, and periventricular lesion volumes significantly influenced the relationship between (i) network density and information processing speed and (ii) modularity and information processing speed in pwMS. Interestingly, this was not the case, when an exploratory analysis was performed in the subgroup of CIMS patients.DiscussionOur study showed that cortical (especially leukocortical) and periventricular lesions affect the relationship between global network metrics and information processing speed in pwMS. Our data also suggest that in CIMS patients increased focal cortical and periventricular damage does not linearly affect the relationship between network properties and SDMT, suggesting that other mechanisms (e.g. disruption of local networks, loss of compensatory processes) might be responsible for the development of processing speed deficits.

Abstract The contribution of domestic cattle in human societies is enormous, making cattle, along with other essential benefits, the economically most important domestic animal in the world today. To expand existing knowledge on cattle domestication and mitogenome diversity, we performed a comprehensive complete mitogenome analysis of the species (802 sequences, 114 breeds). A large sample was collected in South‐east Europe, an important agricultural gateway to Europe during Neolithization and a region rich in cattle biodiversity. We found 1725 polymorphic sites (810 singletons, 853 parsimony‐informative sites and 57 indels), 701 unique haplotypes, a haplotype diversity of 0.9995 and a nucleotide diversity of 0.0015. In addition to the dominant T3 and several rare haplogroups (Q, T5, T4, T2 and T1), we have identified maternal line in Austrian Murbodner cattle that possess surviving aurochs’ mitochondria haplotype P1 that diverged prior to the Neolithization process. This is convincing evidence for rare female‐mediated adaptive introgression of wild aurochs into domesticated cattle in Europe. We revalidated the existing haplogroup classification and provided Bayesian phylogenetic inference with a more precise estimated divergence time than previously available. Occasionally, classification based on partial mitogenomes was not reliable; for example, some individuals with haplogroups P and T5 were not recognized based on D‐loop information. Bayesian skyline plot estimates (median) show that the earliest population growth began before domestication in cattle with haplogroup T2, followed by Q (~10.0–9.5 kyBP), whereas cattle with T3 (~7.5 kyBP) and T1 (~3.0–2.5 kyBP) expanded later. Overall, our results support the existence of interactions between aurochs and cattle during domestication and dispersal of cattle in the past, contribute to the conservation of maternal cattle diversity and enable functional analyses of the surviving aurochs P1 mitogenome.

It is currently unknown how quantitative diffusion and myelin MRI designs affect the results of a longitudinal study. We used two independent datasets containing 6 monthly MRI measurements from 20 healthy controls and 20 relapsing-remitting multiple sclerosis (RR-MS) patients. Six designs were tested, including 3 MRI acquisitions, either over 6 months or over a shorter study duration, with balanced (same interval) or unbalanced (different interval) time intervals between MRI acquisitions. First, we show that in RR-MS patients, the brain changes over time obtained with 3 MRI acquisitions were similar to those observed with 5 MRI acquisitions and that designs with an unbalanced time interval showed the highest similarity, regardless of study duration. No significant brain changes were found in the healthy controls over the same periods. Second, the study duration affects the sample size in the RR-MS dataset; a longer study requires more subjects and vice versa. Third, the number of follow-up acquisitions and study duration affect the sensitivity and specificity of the associations with clinical parameters, and these depend on the white matter bundle and MRI measure considered. Together, this suggests that the optimal design depends on the assumption of the dynamics of change in the target population and the accuracy required to capture these dynamics. Thus, this work provides a better understanding of key factors to consider in a longitudinal study and provides clues for better strategies in clinical trial design.

Introduction: Over the past few years, the deep learning community has developed and validated a plethora of tools for lesion detection and segmentation in Multiple Sclerosis (MS). However, there is an important gap between validating models technically and clinically. To this end, a six-step framework necessary for the development, validation, and integration of quantitative tools in the clinic was recently proposed under the name of the Quantitative Neuroradiology Initiative (QNI).Aims: Investigate to what extent automatic tools in MS fulfill the QNI framework necessary to integrate automated detection and segmentation into the clinical neuroradiology workflow.Methods: Adopting the systematic Cochrane literature review methodology, we screened and summarised published scientific articles that perform automatic MS lesions detection and segmentation. We categorised the retrieved studies based on their degree of fulfillment of QNI’s six-steps, which include a tool’s technical assessment, clinical validation, and integration.Results: We found 156 studies; 146/156 (94%) fullfilled the first QNI step, 155/156 (99%) the second, 8/156 (5%) the third, 3/156 (2%) the fourth, 5/156 (3%) the fifth and only one the sixth.Conclusions: To date, little has been done to evaluate the clinical performance and the integration in the clinical workflow of available methods for MS lesion detection/segmentation. In addition, the socio-economic effects and the impact on patients’ management of such tools remain almost unexplored.

Abstract Objective: To design and implement “handshake rounds” as an antibiotic stewardship intervention to reduce inpatient intravenous (IV) antibiotic use in patients with hematologic malignancies. Design: Quasi-experimental analysis of antibiotic use (AU) and secondary outcomes before and and after handshake rounds were implemented. Setting: Quaternary-care, academic medical center. Patients: Hospitalized adults with hematologic malignancies receiving IV antibiotics. Methods: We performed a retrospective review of a preintervention cohort prior to the intervention. A multidisciplinary team developed criteria for de-escalation of antibiotics, logistics of handshake rounds, and outcome metrics. Eligible patients were discussed during scheduled handshake rounds between a hematology–oncology pharmacist and transplant–infectious diseases (TID) physician. Prospective data were collected over 30 days in the postintervention cohort. Due to small sample size, 2:1 matching was used to compare pre- to and postintervention AU. Total AU in days of therapy per 1,000 patient days (DOT/1,000 PD) was reported. Mean AU per patient was analyzed using Wilcoxon rank-sum test. A descriptive analysis of secondary outcomes of pre- and postintervention cohorts was performed. Results: Total AU was substantially lower after the intervention, with 517 DOT/1,000 PD compared to 865 DOT/1,000 PD before the intervention. There was no statistically significant difference in the mean AU per patient between the 2 cohorts. There was a lower rate of 30-day mortality in the postintervention cohort and rates of ICU admissions were similar. Conclusions: Conducting handshake rounds is a safe and effective way to implement an antibiotic stewardship intervention among high-risk patient population such as those with hematologic malignancies.

Objectives and aims: Quantitative MRI (qMRI) has greatly improved the sensitivity and specificity of microstructural brain pathology in multiple sclerosis (MS) when compared to conventional MRI (cMRI). More than cMRI, qMRI also provides means to assess pathology within the normal-appearing and lesion tissue. In this work, we further developed a method providing personalized quantitative T1 (qT1) abnormality maps in individual MS patients by modeling the age dependence of qT1 alterations. In addition, we assessed the relationship between qT1 abnormality maps and patients’ disability, in order to evaluate the potential value of this measurement in clinical practice. Methods: We included 119 MS patients (64 relapsing-remitting MS (RRMS), 34 secondary progressive MS (SPMS), 21 primary progressive MS (PPMS)), and 98 Healthy Controls (HC). All individuals underwent 3T MRI examinations, including Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) for qT1 maps and High-Resolution 3D Fluid Attenuated Inversion Recovery (FLAIR) imaging. To calculate personalized qT1 abnormality maps, we compared qT1 in each brain voxel in MS patients to the average qT1 obtained in the same tissue (grey/white matter) and region of interest (ROI) in healthy controls, hereby providing individual voxel-based Z-score maps. The age dependence of qT1 in HC was modeled using linear polynomial regression. We computed the average qT1 Z-scores in white matter lesions (WMLs), normal-appearing white matter (NAWM), cortical grey matter lesions (GMcLs) and normal-appearing cortical grey matter (NAcGM). Lastly, a multiple linear regression (MLR) model with the backward selection including age, sex, disease duration, phenotype, lesion number, lesion volume and average Z-score (NAWM/NAcGM/WMLs/GMcLs) was used to assess the relationship between qT1 measures and clinical disability (evaluated with EDSS). Results: The average qT1 Z-score was higher in WMLs than in NAWM. (WMLs: 1.366 ± 0.409, NAWM: −0.133 ± 0.288, [mean ± SD], p

Bortezomib (BTZ) is a proteasome inhibitor used in the treatment of multiple myeloma (MM) and other hematological malignancies. Although carfilzomib, a second-generation proteasome inhibitor, is most strongly associated with cardiotoxicity, BTZ has been associated with several cardiovascular complications including congestive heart failure, arrhythmias, and rarely myocarditis. Here, we report the first case of a BTZ-induced perimyocarditis. The patient was a 40-year-old woman with recently diagnosed MM who was admitted to the hospital with syncope at the start of her second cycle of induction therapy with BTZ, lenalidomide, and dexamethasone. She had a witnessed syncopal event in the emergency room with the telemetry showing sustained ventricular tachycardia. Laboratory workup showed elevated N-terminal pro B-type natriuretic peptide and normal troponin I. Transthoracic echocardiogram (TTE) showed a low ejection fraction of 40% with global hypokinesis of the left ventricle and trace pericardial effusion. Cardiac magnetic resonance imaging with gadolinium was consistent with acute myocarditis. The patient had recurrent pleuritic chest pain, and a repeat TTE showed worsening pericardial effusion consistent with pericarditis. Endomyocardial biopsy was done which showed nonspecific myocyte hypertrophy and foci of fibrosis, but was negative for giant cell myocarditis, hemochromatosis, and amyloidosis. Extensive infectious disease workup ruled out known infectious causes for perimyocarditis. Given the close timing between BTZ treatment (5 subcutaneous doses with a cumulative dose of 6.5 mg/m2), the absence of other iatrogenic or infectious causes, and probable or likely association with BTZ as assessed by the validated causality assessment scoring tools, it was concluded that the acute perimyocarditis was secondary to BTZ exposure. Here, we report the first case of BTZ-induced perimyocarditis and discuss the incidence and pathophysiology of BTZ-cardiovascular toxicity.

Limitations in the accuracy of brain pathways reconstructed by diffusion MRI (dMRI) tractography have received considerable attention. While the technical advances spearheaded by the Human Connectome Project (HCP) led to significant improvements in dMRI data quality, it remains unclear how these data should be analyzed to maximize tractography accuracy. Over a period of two years, we have engaged the dMRI community in the IronTract Challenge, which aims to answer this question by leveraging a unique dataset. Macaque brains that have received both tracer injections and ex vivo dMRI at high spatial and angular resolution allow a comprehensive, quantitative assessment of tractography accuracy on state-of-the-art dMRI acquisition schemes. We find that, when analysis methods are carefully optimized, the HCP scheme can achieve similar accuracy as a more time-consuming, Cartesian-grid scheme. Importantly, we show that simple pre- and post-processing strategies can improve the accuracy and robustness of many tractography methods. Finally, we find that fiber configurations that go beyond crossing (e.g., fanning, branching) are the most challenging for tractography. The IronTract Challenge remains open and we hope that it can serve as a valuable validation tool for both users and developers of dMRI analysis methods.

Software Defined Networks (SDN) offer a new architecture and different approach to the management of traffic and network resources. Unlike traditional networks, SDN separates control and data planes and enables centralized network management. Forwarding devices are programmable, network statistics are monitored and behavior adjusted to current traffic conditions. SDN is an answer for meeting the QoS (Quality of Service) demands of environments such as IoT (Internet of Things). This paper provides an overview of contemporary approaches in optimizing such complex scenery, and present-day mechanisms for balanced and efficient use of network capacities, ensuring QoS through traffic-aware routing and dynamically adaptive rules. Key new ideas were identified in optimizing the management of the SDN-IoT network. Ultimately, room for future research has been identified and the need to create a new comprehensive model tailored to the specificities of the SDN-IoT environment has been addressed.

Abstract We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly [QW] or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty‐four patients (median prior therapies, 3 [range, 2‐10]) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose‐limiting toxicities (DLTs) were reported in the selinexor 60 mg twice‐weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D. Common treatment‐related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). Overall response rate was 73% and median progression‐free survival 12.5 months in daratumumab‐naïve patients. SDd was well tolerated and its promising efficacy suggests that further study of this PI‐ and IMiD‐free regimen in RRMM patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted.

In this study, the authors focused on the evaluation of the genetic parameters of longevity, milk yield traits, and type traits in dairy cattle populations in the Republic of Serbia. The total dataset used consisted of production records and pedigree data for 32,512 Holstein cows that calved from 1981 to 2015. The animal model was applied to determine the variance and covariance components and genetic parameters of the analyzed traits by applying the restricted maximum likelihood (REML) approach and using the programs VCE6 and PEST. The heritability of longevity traits was estimated using the Survival Kit V6.0 software package. Variance and covariance were estimated for five production traits: milk yield (MY), fat yield (FY), protein yield (PY), milk fat content (MC), and protein content (PC), and three longevity traits: length of productive life (LPL), lifetime milk yield (LMY), and the number of lactations achieved (NL) as well as for 18 standard type traits. Heritabilities for the milk, fat, and protein yield traits were 0.20 (MY), 0.15 (FY), and 0.19 (PY), respectively. The estimated coefficients of heritability for the longevity traits were higher when using the Weibull proportional hazards model compared to the traditional linear methods and ranged from 0.08 for NL to 0.10 for LPL. Heritability values for the type traits varied from a low of 0.10 (RLSsv—rear legs set–side view) to medium values of 0.32 (ST-stature). Genetic correlations were found between MY and the following longevity traits: LPL, LMY, and NL with values of −0.18, −0.11, and −0.09, respectively. Genetic correlations were found between MY and a number of linear type traits and varied from 0.02 (between MY and RUH-rear udder height) to 0.28 (between MY and FUA-fore udder attachment). Genetic correlations between the 18 investigated type traits ranged from −0.33 between TL (top line) and RTP (rear teats position) to 0.71 between AN (angularity) and RUH (rear udder height). Genetic correlations between most linear type traits and longevity traits (LPL, LMY, and NL) were generally negative and very low. The highest positive genetic correlation was found between UD and LPL (rxy = 0.38).

In the last few years, we have been active participants in globalization and the rapid growth of online commerce. This trend directly impacts logistics, postal, and courier companies. Challenges are visible in the growth and development of these companies, as well as quality of task execution and the ability to adapt to market conditions. With the impact of the SARS-COV-19 virus on the market, and due to locks during the pandemic, shoppers were forced to buy products online. This effect accelerated the trend of purchases via e-commerce, which increased the number of parcels in the technological phases of pick-up and delivery. These companies are the bearers of the first and last technological phase of shipment transport. Due to the increase in the number of shipments, postal and logistics companies are under great pressure. This is because of certain restrictions introduced during the pandemic, but also because of costs, especially fixed costs in the first and last phase of transport. This paper proposes an outsourcing model for the pick-up and delivery to convert fixed costs into variable ones.

Introduction: Multiple Sclerosis (MS) is a common neurological disease primarily characterized by myelin damage in lesions and in normal - appearing white and gray matter (NAWM, NAGM).Several quantitative MRI (qMRI) methods are sensitive to myelin characteristics by measuring specific tissue biophysical properties. However, there are currently few studies assessing the relative reproducibility and sensitivity of qMRI measures to MS pathology in vivo in patients. Methods: We performed two studies. The first study assessed of the sensitivity of qMRI measures to MS pathology: in this work, we recruited 150 MS and 100 healthy subjects, who underwent brain MRI at 3 T including quantitative T1 mapping (qT1), quantitative susceptibility mapping (QSM), magnetization transfer saturation imaging (MTsat) and myelin water imaging for myelin water fraction (MWF). The sensitivity of qMRIs to MS focal pathology (MS lesions vs peri-plaque white/gray matter (PPWM/PPGM)) was studied lesion-wise; the sensitivity to diffuse normal appearing (NA) pathology was measured using voxel-wise threshold-free cluster enhancement (TFCE) in NAWM and vertex-wise inflated cortex analysis in NAGM. Furthermore, the sensitivity of qMRI to the identification of lesion tissue was investigated using a voxel-wise logistic regression analysis to distinguish MS lesion and PP voxels.The second study assessed the reproducibility of myelin-sensitive qMRI measures in a single scanner. To evaluate the intra-session and inter-session reproducibility of qMRI measures, we have investigated 10 healthy subjects, who underwent two brain 3 T MRIs within the same day (without repositioning), and one after 1-week interval. Five region of interest (ROIs) in white and deep grey matter areas were segmented, and inter- and intra- session reproducibility was studied using the intra-class correlation coefficient (ICC). Further, we also investigated the voxel-wise reproducibility of qMRI measures in NAWM and NAGM. Results: qT1 and QSM showed the highest sensitivity to distinguish MS focal WM and cortical pathology from peri-plaque WM (P

White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.

The anisotropy of brain white matter microstructure manifests itself in orientational-dependence of various MRI contrasts, and can result in significant quantification biases if ignored. Understanding the origins of this orientation-dependence could enhance the interpretation of MRI signal changes in development, ageing and disease and ultimately improve clinical diagnosis. Using a novel experimental setup, this work studies the contributions of the intra- and extra-axonal water to the orientation-dependence of one of the most clinically-studied parameters, apparent transverse relaxation T2. Specifically, a tiltable receive coil is interfaced with an ultra-strong gradient MRI scanner to acquire multidimensional MRI data with an unprecedented range of acquisition parameters. Using this setup, compartmental T2 can be disentangled based on differences in diffusional-anisotropy, and its orientation-dependence further elucidated by re-orienting the head with respect to the main magnetic field B→0. A dependence of (compartmental) T2 on the fibre orientation w.r.t. B→0 was observed, and further quantified using characteristic representations for susceptibility- and magic angle effects. Across white matter, anisotropy effects were dominated by the extra-axonal water signal, while the intra-axonal water signal decay varied less with fibre-orientation. Moreover, the results suggest that the stronger extra-axonal T2 orientation-dependence is dominated by magnetic susceptibility effects (presumably from the myelin sheath) while the weaker intra-axonal T2 orientation-dependence may be driven by a combination of microstructural effects. Even though the current design of the tiltable coil only offers a modest range of angles, the results demonstrate an overall effect of tilt and serve as a proof-of-concept motivating further hardware development to facilitate experiments that explore orientational anisotropy. These observations have the potential to lead to white matter microstructural models with increased compartmental sensitivity to disease, and can have direct consequences for longitudinal and group-wise T2- and diffusion-MRI data analysis, where the effect of head-orientation in the scanner is commonly ignored.

In the central nervous system of primates, several pathways are characterized by different spectra of axon diameters. In vivo methods, based on diffusion-weighted magnetic resonance imaging, can provide axon diameter index estimates non-invasively. However, such methods report voxel-wise estimates, which vary from voxel-to-voxel for the same white matter bundle due to partial volume contributions from other pathways having different microstructure properties. Here, we propose a novel microstructure-informed tractography approach, COMMITAxSize, to resolve axon diameter index estimates at the streamline level, thus making the estimates invariant along trajectories. Compared to previously proposed voxel-wise methods, our formulation allows the estimation of a distinct axon diameter index value for each streamline, directly, furnishing a complementary measure to the existing calculation of the mean value along the bundle. We demonstrate the favourable performance of our approach comparing our estimates with existing histologically-derived measurements performed in the corpus callosum and the posterior limb of the internal capsule. Overall, our method provides a more robust estimation of the axon diameter index of pathways by jointly estimating the microstructure properties of the tissue and the macroscopic organisation of the white matter connectivity.

Background and Purpose: Logging is an example of the strongest human influence on forest environment because it causes damages to the forest soil and residual trees. The damages that occur during logging are more frequent in the skidding phase compared to the felling and processing phase. Material and Methods: The research was conducted in mixed stands of fir and spruce in the area of eastern Bosnia and Herzegovina. Felling was conducted by chainsaw and extraction by animals, i.e. by two oxen. The following data were collected: tree species, diameter at breast height, pre-bunching zone (0-30 m or 30-60 m), presence of damages, presence of old damages, number of damages, type of damage, damage position and the size of damage. Results: Damages were recorded on 3.32% of residual trees. The average number of damages per damaged tree was 1.08. The same percentage share of damages was recorded on butt end and root collar (38.46%), while damages on root have a share of 23.08%. Stem damages were not recorded. The most common type of damage was debarked tree (61.54%), then squashed bark (23.08%) and debarked and damaged tree (15.38%). It was recorded that the size of damages varied between 60 and 570 cm2. The average size of damage was 222.54 cm2. Statistical analysis using χ2 test showed significant difference in the proportion of damaged trees among different pre-bunching methods, and did not show significant difference in the proportion of damaged trees between different pre-bunching zones. Conclusions: It can be assumed that oxen logging causes insignificant damages to residual trees. The results of research will be used as a basis for future studies of residual trees’ damaging during wood skidding.

Conventional magnetic resonance imaging (cMRI) in multiple sclerosis (MS) patients provides measures of focal brain damage and activity, which are fundamental for disease diagnosis, prognosis, and the evaluation of response to therapy. However, cMRI is insensitive to the damage to the microenvironment of the brain tissue and the heterogeneity of MS lesions. In contrast, the damaged tissue can be characterized by mathematical models on multishell diffusion imaging data, which measure different compartmental water diffusion. In this work, we obtained 12 diffusion measures from eight diffusion models, and we applied a deep-learning attention-based convolutional neural network (CNN) (GAMER-MRI) to select the most discriminating measures in the classification of MS lesions and the perilesional tissue by attention weights. Furthermore, we provided clinical and biological validation of the chosen metrics—and of their most discriminative combinations—by correlating their respective mean values in MS patients with the corresponding Expanded Disability Status Scale (EDSS) and the serum level of neurofilament light chain (sNfL), which are measures of disability and neuroaxonal damage. Our results show that the neurite density index from neurite orientation and dispersion density imaging (NODDI), the measures of the intra-axonal and isotropic compartments from microstructural Bayesian approach, and the measure of the intra-axonal compartment from the spherical mean technique NODDI were the most discriminating (respective attention weights were 0.12, 0.12, 0.15, and 0.13). In addition, the combination of the neurite density index from NODDI and the measures for the intra-axonal and isotropic compartments from the microstructural Bayesian approach exhibited a stronger correlation with EDSS and sNfL than the individual measures. This work demonstrates that the proposed method might be useful to select the microstructural measures that are most discriminative of focal tissue damage and that may also be combined to a unique contrast to achieve stronger correlations to clinical disability and neuroaxonal damage.

Background: MR imaging of the spinal cord (SC) gray matter (GM) at the cervical and lumbar enlargements' level may be particularly informative in lower motor neuron disorders, e. g., spinal muscular atrophy, but also in other neurodegenerative or autoimmune diseases affecting the SC. Radially sampled averaged magnetization inversion recovery acquisition (rAMIRA) is a novel approach to perform SC imaging in clinical settings with favorable contrast and is well-suited for SC GM quantitation. However, before applying rAMIRA in clinical studies, it is important to understand (i) the sources of inter-subject variability of total SC cross-sectional areas (TCA) and GM area (GMA) measurements in healthy subjects and (ii) their relation to age and sex to facilitate the detection of pathology-associated changes. In this study, we aimed to develop normalization strategies for rAMIRA-derived SC metrics using skull and spine-based metrics to reduce anatomical variability.Methods: Sixty-one healthy subjects (age range 11–93 years, 37.7% women) were investigated with axial two-dimensional rAMIRA imaging at 3T MRI. Cervical and thoracic levels including the level of the cervical (C4/C5) and lumbar enlargements (Tmax) were examined. SC T2-weighted sagittal images and high-resolution 3D whole-brain T1-weighted images were acquired. TCA and GMAs were quantified. Anatomical variables with associations of |r| > 0.30 in univariate association with SC areas, and age and sex were used to construct normalization models using backward selection with TCAC4/C5 as outcome. The effect of the normalization was assessed by % relative standard deviation (RSD) reductions.Results: Mean inter-individual variability and the SD of the SC area metrics were considerable: TCAC4/5: 8.1%/9.0; TCATmax: 8.9%/6.5; GMAC4/C5: 8.6%/2.2; GMATmax: 12.2%/3.8. Normalization based on sex, brain WM volume, and spinal canal area resulted in RSD reductions of 23.7% for TCAs and 12.0% for GM areas at C4/C5. Normalizations based on the area of spinal canal alone resulted in RSD reductions of 10.2% for TCAs and 9.6% for GM areas at C4/C5, respectively.Discussion: Anatomic inter-individual variability of SC areas is substantial. This study identified effective normalization models for inter-subject variability reduction in TCA and SC GMA in healthy subjects based on rAMIRA imaging.

At the typical spatial resolution of MRI in the human brain, approximately 60–90% of voxels contain multiple fiber populations. Quantifying microstructural properties of distinct fiber populations within a voxel is therefore challenging but necessary. While progress has been made for diffusion and T1-relaxation properties, how to resolve intra-voxel T2 heterogeneity remains an open question. Here a novel framework, named COMMIT-T2, is proposed that uses tractography-based spatial regularization with diffusion-relaxometry data to estimate multiple intra-axonal T2 values within a voxel. Unlike previously-proposed voxel-based T2 estimation methods, which (when applied in white matter) implicitly assume just one fiber bundle in the voxel or the same T2 for all bundles in the voxel, COMMIT-T2 can recover specific T2 values for each unique fiber population passing through the voxel. In this approach, the number of recovered unique T2 values is not determined by a number of model parameters set a priori, but rather by the number of tractography-reconstructed streamlines passing through the voxel. Proof-of-concept is provided in silico and in vivo, including a demonstration that distinct tract-specific T2 profiles can be recovered even in the three-way crossing of the corpus callosum, arcuate fasciculus, and corticospinal tract. We demonstrate the favourable performance of COMMIT-T2 compared to that of voxelwise approaches for mapping intra-axonal T2 exploiting diffusion, including a direction-averaged method and AMICO-T2, a new extension to the previously-proposed Accelerated Microstructure Imaging via Convex Optimization (AMICO) framework.

Intravenous immunoglobulin G (IVIgG) is approved for primary immunodeficiency syndromes but may induce anti-cancer effects, and while this has been attributed to its anti-inflammatory properties, IgG against specific tumor targets may play a role. We evaluated IVIgG alone, and with a Heat shock protein (HSP)-90 or proteasome inhibitor, using multiple myeloma and mantle cell lymphoma (MCL) cells in vitro, and with the proteasome inhibitor bortezomib in vivo. IVIgG inhibited the growth of all cell lines tested, induced G1 cell cycle arrest, and suppressed pro-tumor cytokines including Interleukin (IL)-6, IL-8, and IL-10. Genomic and proteomic studies showed that IVIgG reduced tumor cell HSP70-1 levels by suppressing the ability of extracellular HSP70-1 to stimulate endogenous HSP70-1 promoter activity, and reduced extracellular vesicle uptake. Preparations of IVIgG were found to contain high titers of anti-HSP70-1 IgG, and recombinant HSP70-1 reduced the efficacy of IVIgG to suppress HSP70-1 levels. Combining IVIgG with the HSP90 inhibitor AUY922 produced superior cell growth inhibition and correlated with HSP70-1 suppression. Also, IVIgG with bortezomib or carfilzomib was superior to each single agent, and enhanced bortezomib's activity in bortezomib-resistant myeloma cells. Moreover, IVIgG reduced transfer of extracellular vesicles (EVs) to cells, and blocked transfer of bortezomib resistance through EVs. Finally, IVIgG with bortezomib were superior to the single agents in an in vivo myeloma model. These studies support the possibility that anti-HSP70-1 IgG contained in IVIgG can inhibit myeloma and MCL growth by interfering with a novel mechanism involving uptake of exogenous HSP70-1 which then induces its own promoter.

The presence of cortical lesions in multiple sclerosis patients has emerged as an important biomarker of the disease. They appear in the earliest stages of the illness and have been shown to correlate with the severity of clinical symptoms. However, cortical lesions are hardly visible in conventional magnetic resonance imaging (MRI) at 3T, and thus their automated detection has been so far little explored. In this study, we propose a fully-convolutional deep learning approach, based on the 3D U-Net, for the automated segmentation of cortical and white matter lesions at 3T. For this purpose, we consider a clinically plausible MRI setting consisting of two MRI contrasts only: one conventional T2-weighted sequence (FLAIR), and one specialized T1-weighted sequence (MP2RAGE). We include 90 patients from two different centers with a total of 728 and 3856 gray and white matter lesions, respectively. We show that two reference methods developed for white matter lesion segmentation are inadequate to detect small cortical lesions, whereas our proposed framework is able to achieve a detection rate of 76% for both cortical and white matter lesions with a false positive rate of 29% in comparison to manual segmentation. Further results suggest that our framework generalizes well for both types of lesion in subjects acquired in two hospitals with different scanners.

Though tractography is widely used, it has not been systematically validated. Here, authors report results from 20 groups showing that many tractography algorithms produce both valid and invalid bundles.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The aim of this study was to determine allele frequency at the diacylglycerol-O-transferase 1 gene (DGAT1) K232A polymorphic site and effect of allelic variants K and A on milk production traits of Holstein (dairy), Simmental and Brown Swiss (dual purpose) cattle breeds in Croatia. The DNA was extracted from hair of 371 cows, while coding region of DGAT1p.K232A was amplified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Dominant frequency of K allele was determined in all three analysed breeds: Holstein (0.775), Simmental (0.616) and Brown Swiss (0.651). The most Holstein cows were homozygotus for KK variant (0.637), while dominant genotype in other two breeds was KA (Simmental 0.647; Brown Swiss 0.644). Positive effect of KK genotype on milk yield was detected in Holstein and Brown Swiss breeds, while in Simmental breed was negative (-220.8 kg; -463.6 kg) in regard to KA and AA genotype. Milk of cows with KK genotype in Holstein breed, KA in Simmental and AA in Brown Swiss were found as the most favourable in terms of fat content. Cows of AA genotype in all the three analysed breeds have had higher milk protein content. Statistical analysis was performed using the GLM procedure, including genotype and breed effects as independent variables. The effects of DGAT1genotypes on milk quantity and quality were not significant (P>0.05).

The object of the present study was to analyse effect of polymorphic allelic variants of β-lactoglobulin, κ-casein and αs1-casein on total milk yield, fat and protein content in milk of Holstein, Simmental and Brown cattle breeds in Croatia during the first three standard lactations. Although the certain effects of polymorphic variants of β-lactoglobulin, κ-casein and αs1-casein on the level of milk yield in analyzed breeds of cattle are observed, those effects were not significant. The effect of polymorphic variants of β-lactoglobulin, κ-casein and αs1-casein on average fat content in milk of analyzed breeds has noticed, although differences were not significant. Differences in protein content in milk with different polymorphic variants of β-lactoglobulin, κ-casein and αs1-casein were not significant, except in case of BC genotype of αs1-casein, which was significant (P

Virgin forests are relatively rare in the European temperate zone. This is due to the continuous use of forest historically and to increasinghigh population densities. Virgin forests are forest where the structure and dynamics have developed entirely under natural conditions,without any human interference or influence. This article assesses the Plješevica forest in Bosnia Herzegovina to establish whether it canbe classified as virgin forest. The structure and components of the forest were assessed in a 1 ha sample plot and four 400m2 quadrats. Thevalues of the biodiversity indexes (as defined by Shannon and Weaver, Krebs and Meyer), species richness and evenness, the distributionof the different stand development stages and the proportion of dead wood lead to the conclusion that Plješevica forest presents a set ofstructural and dynamic characteristics close to the ones typical for virgin forests in Europe, so in order to maintain its status as such, in themeantime it should undergo a protection management programme.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and potential life-threatening clinical syndrome that results from uncontrolled activation of the immune system. Secondary HLH, more commonly observed in adult patients, is seen in the context of underlying triggering conditions. Epstein-Barr virus (EBV) has been recognized as the leading infectious cause and is associated with a poor outcome. As clinical and laboratory features of HLH could overlap with septic shock syndrome in most patients, the diagnosis of HLH, especially in adults, is the most challenging aspect of the disease that results in delayed recognition and treatment of rapidly progressive multiorgan system failure. We report a case of Hemophagocytic lymphohistiocytosis in a patient who presented with signs of septic shock syndrome and we review the literature on the topic.

Knowledge of spontaneous aberrations, namely, of their frequency in non-irradiated cells is of paramount importance not only in cytogenetic research, but also in contemporary animal production. The paper deals with research on spontaneously emerged chromosomal aberrations in the peripheral blood lymphocytes in the cattle of ‘Buša’ breed. To obtain metaphase chromosomes the conventional method of lymphocyte cultivation was used, albeit slightly modified and adapted to the examined animals and the laboratory conditions. The research findings indicate that a certain percent of spontaneously emerged chromosomal aberrations of chromatid type (gap and break) have been found in the peripheral blood lymphocytes in the cattle of ‘Buša’ breed.

Secondary prevention of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) involves continuous antimicrobial prophylaxis among affected individuals and is recognised as a cornerstone of public health programmes that address these conditions. However, several important scientific issues around the secondary prevention paradigm remain unresolved. This report details research priorities for secondary prevention that were developed as part of a workshop convened by the US National Heart, Lung, and Blood Institute in November 2021. These span basic, translational, clinical and population science research disciplines and are built on four pillars. First, we need a better understanding of RHD epidemiology to guide programmes, policies, and clinical and public health practice. Second, we need better strategies to find and diagnose people affected by ARF and RHD. Third, we urgently need better tools to manage acute RF and slow the progression of RHD. Fourth, new and existing technologies for these conditions need to be better integrated into healthcare systems. We intend for this document to be a reference point for research organisations and research sponsors interested in contributing to the growing scientific community focused on RHD prevention and control., Competing Interests: Competing interests: AB, DW and NS received funding support from the National Institutes of Health. AB received funding support from American Heart Association, Leducq Foundation, Edwards Lifesciences—Every Heartbeat Matters, The Philips Foundation and Thrasher Pediatric Research Fund. MWC received fees as a consultant for Vaxform Incorporated, Serum India Institute and Pfizer Incorporated. MWC is the chief scientific officer and cofounder, with financial interest, in Moleculera Labs, a commercial laboratory for diagnostic testing of autoantibodies against the heart and brain. AR received funding support from the National Health and Medical Research Council. TM received funding support from the Population Health Research Institute (PHRI) & McMaster University, University of Cape Town and University of Witwatersrand., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There is limited information on the human immune response following infection with group A Streptococcus (Strep A). Animal studies have shown, in addition to the M protein, that shared Strep A antigens elicit protective immunity. This study aimed to investigate the kinetics of antibody responses against a panel of Strep A antigens in a cohort of school-aged children in Cape Town, South Africa. Participants provided serial throat cultures and serum samples at two-monthly follow-up visits. Strep A recovered were emm -typed, and serum samples were analyzed by enzyme-linked immunosorbent assay (ELISA) to assess immune responses to thirty-five Strep A antigens (10-shared and 25-M peptides). Serologic evaluations were performed on serial serum samples from 42 selected participants (from 256 enrolled) based on the number of follow-up visits, the frequency of visits, and throat culture results. Among these, there were 44 Strep A acquisitions, 36 of which were successfully emm -typed. Participants were grouped into three clinical event groups based on culture results and immune responses. A preceding infection was most convincingly represented by a Strep A-positive culture with an immune response to at least one shared antigen and M peptide (11 events) or a Strep A-negative culture with antibody responses to shared antigens and M peptides (9 events). More than a third of participants demonstrated no immune response despite a positive culture. This study provided important information regarding the complexity and variability of human immune responses following pharyngeal acquisition of Strep A, as well as demonstrating the immunogenicity of Strep A antigens currently under consideration as potential vaccine candidates. IMPORTANCE There is currently limited information regarding the human immune response to group A streptococcal throat infection. An understanding of the kinetics and specificity of antibody responses against a panel of Group A Streptococcus (GAS) antigens will serve to refine diagnostic approaches and contribute to vaccine efforts, which together will serve to reduce the burden of rheumatic heart disease, a major source of morbidity and mortality especially in the developing world. This study, utilizing an antibody-specific assay, uncovered three patterns of response profiles following GAS infection, among 256 children presenting with sore throat to local clinics. Overall, the response profiles were complex and variable. Of note, a preceding infection was most convincingly represented by a GAS-positive culture with an immune response to at least one shared antigen and M peptide. Also, more than a third of participants demonstrated no immune response despite a positive culture. All antigens tested were immunogenic, providing guidance for future vaccine development., Competing Interests: The authors declare a conflict of interest. James B. Dale is the inventor of certain technologies related to the development of group A streptococcal vaccines. The intellectual property is held by the University of Tennessee Research Foundation.

Background: The genetics of rheumatic heart disease (RHDGen) Network was developed to assist the discovery and validation of genetic variations and biomarkers of risk for rheumatic heart disease (RHD) in continental Africans, as a part of the global fight to control and eradicate rheumatic fever/RHD. Thus, we describe the rationale and design of the RHDGen study, comprising participants from 8 African countries., Methods: RHDGen screened potential participants using echocardiography, thereafter enrolling RHD cases and ethnically-matched controls for whom case characteristics were documented. Biological samples were collected for conducting genetic analyses, including a discovery case-control genome-wide association study (GWAS) and a replication trio family study. Additional biological samples were also collected, and processed, for the measurement of biomarker analytes and the biomarker analyses are underway., Results: Participants were enrolled into RHDGen between December 2012 and March 2018. For GWAS, 2548 RHD cases and 2261 controls (3301 women [69%]; mean age [SD], 37 [16.3] years) were available. RHD cases were predominantly Black (66%), Admixed (24%), and other ethnicities (10%). Among RHD cases, 34% were asymptomatic, 26% had prior valve surgery, and 23% had atrial fibrillation. The trio family replication arm included 116 RHD trio probands and 232 parents., Conclusions: RHDGen presents a rare opportunity to identify relevant patterns of genetic factors and biomarkers in Africans that may be associated with differential RHD risk. Furthermore, the RHDGen Network provides a platform for further work on fully elucidating the causes and mechanisms associated with RHD susceptibility and development.

Aims: The current study sought to investigate the association between the methylenetetrahydrofolate reductase ( MTHFR ) variant (rs1801133) and the risk of developing hypertension (HTN) in an indigenous South African population. Methods: A total of 442 participants (hypertensive, n = 279 and non-hypertensive, n = 163) from the indigenous tribe residing in Mthatha, Eastern Cape (South Africa) were recruited. HTN was defined as a systolic (SBP) and diastolic blood pressure (DBP) of ≥130/80 mmHg following American Heart Association guidelines. The genotyping of MTHFR (rs1801133) was assessed using MassARRAY ® System. Thereafter, the association between rs1801133 in various genetic models and HTN was determined by logistic regression model analysis. Furthermore, the interaction between rs1801133 and selected risk factors on HTN was performed using the open-source multifactor dimensionality reduction (MDR). Results: The low frequency of the T allele (5%) was also observed when compared with the C allele (95%) in both cases and controls. After adjusting for confounding factors (gender, smoking status, BMI, and blood glucose levels), there were no significant associations were observed between rs1801133 and the risk of HTN in all genetic models: genotypic (OR 0.75, 95% CI 0.29-1.95, p = 0.56), dominant (OR 0.86, 95% CI 0.35-2.16, p = 0.75), co-dominant (OR 1.33, 95% CI 0.51-3.48, p = 0.55) and allelic (OR 0.80, 95% CI 0.49-1.62, p = 0.70) in logistic regression analysis. However, a significant interaction was reported among rs1801133, age, and gender ( p < 0.0001) with the risk of HTN. Conclusion: The present study reports on the lack of association between MTHFR (rs1801133) and the risk of HTN in an indigenous South African tribe. However, an interaction between gender, age, and rs1801133 was observed. Thus, future studies with a large sample size are required to further validate these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mabhida, Sharma, Apalata, Masilela, Nomatshila, Mabasa, Fokkens, Benjeddou, Muhamed, Shabalala and Johnson.)

Background: In Ethiopia, despite various public health intervention approaches have been implemented to eliminate malaria, its public health problem remains considerable. There are such numerous studies; however, investigating the trend of malaria infection in various settings is paramount for area-specific evidence-based interventions, evaluating ongoing malaria control programs. Hence, since the trend of malaria infection in Maksegnit has not yet been documented, this study is aimed at assessing the seven-year trend of malaria in Maksegnit Health Center., Methods: An institutional-based retrospective study was conducted to assess the trend of malaria prevalence over the last seven years (2014-2020) using recorded blood smear reports in the laboratory logbook in Maksegnit Health Center, Northwest Ethiopia., Result: Over the last seven years, a total of 28217 clinically malaria-suspected individuals were requested for blood film examination at Maksegnit Health Center. Of whom, microscopically confirmed malaria case was found in 4641/28217 (16.4%). A significant seasonal and interannual variation of malaria cases was observed ( P < 0.001). The highest prevalence was observed in years 2014 (25.5%) and 2020 (25.1%), while the minimum annual prevalence was seen in 2017/18 (6.4%). The month of October (25.5%) had the highest number of malaria cases documented, while February had the least (4.7%). Males and individuals under the age group of 15-45 were the most affected segments of the population. A significant interannual fluctuating prevalence of malaria cases was recorded ranging from 25.5% to 6.4% ( P < 0.001)., Conclusion: Malaria is still a public health threat in the study area despite significant fluctuating patterns of malaria was observed in the last seven years. In particular, a bounced back trend of malaria from 2018 to 2020 is alarming. Thus, the implementation of ongoing intervention approaches should be reconsidered, and uninterrupted efforts of the concerned bodies are still needed., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Tegegne Eshetu et al.)