Individual Patient Research Articles

Multiple sclerosis: new insights into molecular pathogenesis and novel platforms for disease treatment.

Multiple sclerosis (MS), a chronic inflammatory disorder, affects the central nervous system via myelin degradation. The cause of MS is not fully known, but during recent years, our knowledge has deepened significantly regarding the different aspects of MS, including etiology, molecular pathophysiology, diagnosis and therapeutic options. Myelin basic protein (MBP) is the main myelin protein that accounts for maintaining the stability of the myelin sheath. Recent evidence has revealed that MBP citrullination or deamination, which is catalyzed by Ca2+ dependent peptidyl arginine deiminase (PAD) enzyme leads to the reduction of positive charge, and subsequently proteolytic cleavage of MBP. The overexpression of PAD2 in the brains of MS patients plays an essential role in new epitope formation and progression of the autoimmune disorder. Some drugs have recently entered phase III clinical trials with promising efficacy and will probably obtain approval in the near future. As different therapeutic platforms develop, finding an optimal treatment for each individual patient will be more challenging. This review provides a comprehensive insight into MS with a focus on its pathogenesis and recent advances in diagnostic methods and its present and upcoming treatment modalities. MS therapy alters quickly as research findings and therapeutic options surrounding MS expand. McDonald's guidelines have created different criteria for MS diagnosis. In recent years, ever-growing interest in the development of PAD inhibitors has led to the generation of many reversible and irreversible PAD inhibitors against the disease with satisfactory therapeutic outcomes.

Ultrasound-Derived Fat Fraction for Hepatic Steatosis Assessment: Prospective Study of Agreement With MRI PDFF and Sources of Variability in a Heterogeneous Population.

BACKGROUND. Metabolic dysfunction-associated steatotic liver disease is a growing global public health concern. Quantitative ultrasound measurements, such as ultrasound-derived fat fraction (UDFF), could provide noninvasive, cost-effective, and portable steatosis evaluation. OBJECTIVE. The purpose of this article was to evaluate utility of UDFF for steatosis assessment using proton density fat fraction (PDFF) as reference in patients undergoing liver MRI for heterogeneous indications and to assess UDFF variability. METHODS. This prospective study included a primary analysis of 187 patients (mean age, 53.8 years; 112 men, 75 women) who underwent 3-T liver MRI for any clinical indication from December 2020 to July 2021. Patients underwent investigational PDFF measurement, including determination of PDFFwhole-liver (mean PDFF of entire liver), and PDFFvoxel (PDFF in single voxel within right lobe, measured by MR spectroscopy), as well as investigational ultrasound with UDFF calculation (mean of five inter-costal measurements) within 1 hour after MRI. In a subanalysis, 21 of these patients underwent additional UDFF measurements 1, 3, and 5 hours after meal consumption. The study also included repeatability and reproducibility analysis of 30 patients (mean age, 26.3 years; 10 men, 20 women) who underwent clinical abdominal ultrasound between November 2022 and January 2023; in these patients, three operators sequentially performed UDFF measurements. RESULTS. In primary analysis, UDFF and PDFFwhole-liver measurements showed intra-class correlation coefficient (ICC) of 0.79. In Bland-Altman analysis, UDFF and PDFFvoxel measurements showed mean difference of 1.5% (95% CI, 0.6-2.4%), with 95% limits of agreement from -11.0% to 14.0%. UDFF measurements exhibited AUC for detecting PDFFvoxel at historic thresholds of 6.5% and greater, 17.4% and greater, and 22.1% and greater of 0.90, 0.95, and 0.95, respectively. In subanalysis, mean UDFF was not significantly different across time points with respect to meal consumption (p = .21). In repeatability and reproducibility analysis, ICC for intraoperator repeatability ranged from 0.98 to 0.99 and for interoperator reproducibility from 0.90 to 0.96. Visual assessment of patient-level data plots indicated increasing variability of mean UDFF measurements across operators and of intercostal measurements within individual patients with increasing steatosis. CONCLUSION. UDFF showed robust agreement with PDFF, diagnostic performance for steatosis grades, and intraoperator repeatability and interoperator reproducibility. Nonetheless, UDFF exhibited bias toward slightly larger values versus PDFF; intraoperator and interoperator variation increased with increasing steatosis. CLINICAL IMPACT. UDFF shows promise for steatosis assessment across diverse populations, although continued optimization remains warranted.

Cavernous Malformation From Cranial Nerves: A Systematic Review With a Novel Classification and Patient-Level Analysis.

Cavernous malformations (CMs) occurring in the cranial nerve (CN) are extremely rare, and there is currently no comprehensive review on CN CMs, leading to a lack of sufficient understanding of CN CMs. We aimed to systematically review all published CN CM cases; summarize the epidemiology, clinical manifestations, treatment, and prognosis of CN CMs; and identify factors influencing the prognosis of CN CMs. This systematic review identified all cases potentially diagnosed with CN CM through a systematic search of PubMed, SCOPUS, Web of Science, and Cochrane databases. This represents the most comprehensive systematic review to date. We classified CN CMs based on their anatomic origins. Patient characteristics, disease manifestations, treatment approaches, and prognosis were summarized descriptively. Further analysis was conducted to identify factors influencing the prognosis of CN CMs. The final analysis included 108 articles (127 individual patient cases). The optic nerve (49/128, 38.3%) is the most commonly affected nerve. Notably, CN CMs can be categorized into 3 types: Intraneural, Perineural, and Extraneural. Preoperative nerve function status and novel classification were associated with the prognosis of CN CMs (P = .001; P < .001). The postoperative neurological deterioration rate for the Intraneural type was 19/37 (51.4%); for the Extraneural type, it was 13/69 (18.8%); and for the Perineural type, it was 1/22 (4.5%) (P < .001). We reviewed all the published CN CMs to date, offering a comprehensive description of CN CMs for the first time and identifying prognostic factors. The classification of CN CMs proposed in this study could serve as guidance for the selection of intraoperative treatment regimens. The findings of this systematic review are expected to provide a foundation for clinical decision-making in this crucial rare disease and lay the groundwork for developing relevant clinical guidelines.

Volumetric evaluation of osteotomy gap following mandibular bilateral sagittal split osteotomy using a novel semi-automated approach: a pilot study

ObjectivesTo establish an analysis pipeline for the volumetric evaluation of the osteotomy site after bilateral sagittal split osteotomy (BSSO).Patients and methodsCone-beam computed tomography (CBCT) was performed before, directly after BSSO, and 6–12 months after surgery. Image segmentations of each osteotomy gap data set were performed manually by four physicians and were compared to a semi-automatic segmentation approach.ResultsFive patients with a total of ten osteotomy gaps were included. The mean interclass correlation coefficient (ICC) of individual patients was 0.782 and the standard deviation 0.080 when using the manual segmentation approach. However, the mean ICC of the evaluation of anatomical sites and time points separately was 0.214, suggesting a large range of deviation within the manual segmentation of each rater. The standard deviation was 0.355, further highlighting the extent of the variation. In contrast, the semi-automatic approach had a mean ICC of 0.491 and a standard deviation of 0.365, which suggests a relatively higher agreement among the operators compared to the manual segmentation approach. Furthermore, the volume of the osteotomy gap in the semi-automatic approach showed the same tendency in every site as the manual segmentation approach, but with less deviation.ConclusionThe semi-automatic approach developed in the present study proved to be valid as a standardised method with high repeatability. Such image analysis methods could help to quantify the progression of bone healing after BSSO and beyond, eventually facilitating the earlier identification of patients with retarded healing.

Simultaneous versus Sequential Cochlear Implantation in Adults: Quantitative and Qualitative Outcomes.

To compare speech recognition and quality of life outcomes between bilateral sequentially and simultaneously implanted adult cochlear implant (CI) recipients who initially qualify for a CI in both ears. Retrospective chart review. Tertiary referral center. Retrospective chart review identified adults who underwent bilateral CI, either simultaneously or sequentially, at a high-volume center between 2012 and 2022. Sequentially implanted patients were only included if the second ear qualified for CI in quiet (defined as best-aided AzBio quiet testing <60%), at time of initial CI evaluation. Of 112 bilateral CI patients who qualified in both ears at initial evaluation, 95 underwent sequential implantation and 17 simultaneous. Age, duration, and etiology of hearing loss, and CI usage were similar between groups. Preoperatively, the sequential group had lower pure-tone average (PTA) in the 1st ear than the simultaneously implanted group (P = <.001) but, no difference in 2nd ear PTA (P = .657). Preoperative speech recognition scores were significantly higher for the sequential group; however, this was not true for postoperative scores. There was no difference in the proportion of patients showing significant CI-only or bilateral performance improvement between the groups. Both groups demonstrated similar benefit in quality of life measures. Our findings indicate both simultaneous and sequential cochlear implantation are effective in improving hearing performance and quality of life. Thus, bilateral versus simultaneous implantation should be discussed and tailored for each individual patient.

A quality improvement study on how a simulation model can help decision making on organization of ICU wards

BackgroundIntensive Care Unit (ICU) capacity management is essential to provide high-quality healthcare for critically ill patients. Yet, consensus on the most favorable ICU design is lacking, especially whether ICUs should deliver dedicated or non-dedicated care. The decision for dedicated or non-dedicated ICU design considers a trade-off in the degree of specialization for individual patient care and efficient use of resources for society. We aim to share insights of a model simulating capacity effects for different ICU designs. Upon request, this simulation model is available for other ICUs.MethodsA discrete event simulation model was developed and used, to study the hypothetical performance of a large University Hospital ICU on occupancy, rejection, and rescheduling rates for a dedicated and non-dedicated ICU design in four different scenarios. These scenarios either simulate the base-case situation of the local ICU, varying bed capacity levels, potential effects of reduced length of stay for a dedicated design and unexpected increased inflow of unplanned patients.ResultsThe simulation model provided insights to foresee effects of capacity choices that should be made. The non-dedicated ICU design outperformed the dedicated ICU design in terms of efficient use of scarce resources.ConclusionsThe choice to use dedicated ICUs does not only affect the clinical outcome, but also rejection- rescheduling and occupancy rates. Our analysis of a large university hospital demonstrates how such a model can support decision making on ICU design, in conjunction with other operation characteristics such as staffing and quality management.

Inpatient versus Outpatient Alveolar Bone Grafting: A Nationwide Cost Analysis.

To compare postoperative outcomes and costs between inpatient and outpatient ABG in the United States. Retrospective cohort. Multi-institutional/national. Patients who underwent ABG (n = 6649) were identified in the National Surgical Quality Improvement Program Pediatric database from 2012-2021. Inpatient and outpatient cohorts were matched using coarsened exact matching. Thirty-day readmission, reoperation, and complications. A modified Markov model was developed to estimate the cost difference between cohorts. One-way and probabilistic sensitivity analyses were performed. After matching, 3718 patients were included, of which 1859 patients were in each hospital-setting cohort. The inpatient cohort had significantly higher rates of reoperations (0.6% vs. 0.2%; p = 0.032) and surgical site infections (0.8% vs. 0.2%; p = 0.018). The total cost of outpatient ABG was estimated to be $10,824 vs. $20,955 for inpatient ABG, resulting in $10,131 cost savings per patient. Probabilistic sensitivity analysis revealed that all 10,000 simulations resulted in consistent cost savings for the outpatient cohort that ranged from $8000 to $24,000. Outpatient ABG has become increasingly more popular over the past ten years, with a majority of cases being performed in the ambulatory setting. If deemed safe for the individual patient, outpatient ABG may confer a lower risk of nosocomial complications and offer significant cost savings to the healthcare economy.

Rates and Predictors of Pain Reduction With Intracranial Stimulation for Intractable Pain Disorders.

Intracranial modulation paradigms, namely deep brain stimulation (DBS) and motor cortex stimulation (MCS), have been used to treat intractable pain disorders. However, treatment efficacy remains heterogeneous, and factors associated with pain reduction are not completely understood. We performed an individual patient review of pain outcomes (visual analog scale, quality-of-life measures, complications, pulse generator implant rate, cessation of stimulation) after implantation of DBS or MCS devices. We evaluated 663 patients from 36 study groups and stratified outcomes by pain etiology and implantation targets. Included studies comprised primarily retrospective cohort studies. MCS patients had a similar externalized trial success rate compared with DBS patients (86% vs 81%; P = .16), whereas patients with peripheral pain had a higher trial success rate compared with patients with central pain (88% vs 79%; P = .004). Complication rates were similar for MCS and DBS patients (12% vs 15%; P = .79). Patients with peripheral pain had lower likelihood of device cessation compared with those with central pain (5.7% vs 10%; P = .03). Of all implanted patients, mean pain reduction at last follow-up was 45.8% (95% CI: 40.3-51.2) with a 31.2% (95% CI: 12.4-50.1) improvement in quality of life. No difference was seen between MCS patients (43.8%; 95% CI: 36.7-58.2) and DBS patients (48.6%; 95% CI: 39.2-58) or central (41.5%; 95% CI: 34.8-48.2) and peripheral (46.7%; 95% CI: 38.9-54.5) etiologies. Multivariate analysis identified the anterior cingulate cortex target to be associated with worse pain reduction, while postherpetic neuralgia was a positive prognostic factor. Both DBS and MCS have similar efficacy and complication rates in the treatment of intractable pain. Patients with central pain disorders tended to have lower trial success and higher rates of device cessation. Additional prognostic factors include anterior cingulate cortex targeting and postherpetic neuralgia diagnosis. These findings underscore intracranial neurostimulation as an important modality for treatment of intractable pain disorders.

Precise Classification, and Accurate Diagnosis: Key Elements for Effective Treatment and Management of Headache Disorders

Introduction Tension-type headaches (TTH) are a significant health concern that demands precise diagnostic approaches and effective management strategies. A nuanced understanding of their pathophysiology and diagnostic challenges is not just pivotal, but a responsibility we share, for enhancing patient care. Aim This article aims to explore the complex realm of TTH diagnosis and management, underlining the need for precision in diagnostics and the intricate balance of cost-effectiveness. It also delves into the diverse therapeutic options available for treating TTH, presenting a stimulating challenge for healthcare professionals, researchers, and medical students. State of Knowledge Initial diagnosis involves excluding secondary headaches by identifying red flags indicative of serious underlying conditions. A detailed medical history, complemented by patient-recorded pain diaries, enhances diagnostic accuracy. Ancillary procedures like neuroimaging, despite cost-effectiveness debates, are often preferred by clinicians to mitigate diagnostic risks. Validated tools such as the MIDAS and HIT-6 questionnaires provide valuable insights into headache-related disability. Differential diagnosis among headache types relies on recognizing distinctive clinical features. Summary (Conclusions) Effectively managing TTH necessitates a multifaceted approach, incorporating pharmacological, non-pharmacological, and lifestyle interventions tailored to individual patient needs. Collaborative efforts spanning legal, technological, and research domains are crucial for advancing headache diagnostics and therapeutics. While technological advancements offer promise, interdisciplinary collaboration remains fundamental in optimizing patient care outcomes.

Management of blood thinning medications in elderly populations presenting with rectal bleeding: Are we doing right?

Introduction Rectal bleeding commonly occurs in elderly patients using blood thinners, posing management challenges due to limited guidance on reversal agents and medication restart criteria. This study aims to review the demographics and management of elderly patients with rectal bleeding while on blood thinners. Methods A retrospective analysis of patients aged 60 or older presenting with rectal bleeding at West Suffolk Hospital’s emergency department was conducted from January 2018 to December 2020. Data were extracted from electronic records, focusing on patients using blood thinners and adhering to British Society of Gastroenterology guidelines. All patients ceased blood-thinning medications upon admission. The hospital’s ethics committee approved the study, which focused on demographics, diagnosis, and management, particularly regarding re-initiation of blood-thinning medicines. Results During the study period, 170 patients were admitted to the emergency department of West Suffolk Hospital. 93 (54.71%) patients were included in the study. The average age of the participants was 82 years, and 62.3% were male. All patients were followed up for three months. Atrial fibrillation accounted for 52% of patients, while previous strokes accounted for 20%. The most typical pathology was diverticulosis. Regarding restarting of anticoagulants, Among patients on DOAC (Direct oral anticoagulant), 39% were restarted on discharge, 23% were switched to warfarin, and another 23% were not restarted; 15% planned to restart after seven days. For those on Warfarin, 62% were restarted on discharge, 22% stopped the medication, and the rest were switched to Dual Oral Anticoagulant. Among aspirin patients, 60% were restarted at discharge, while the remaining discontinued. All patients receiving clopidogrel and dual antiplatelet therapy were started at discharge. None of the patients were readmitted during the follow-up period of 3 months. Conclusion Restarting of blood-thinning drugs in patients with rectal bleeding is subject to individual patient variation. Necessitates more extensive trials to achieve greater standardization.

Automated detection of cognitive impairment in clinical practice.

Cognitive impairment is now recognized as an impending public health crisis. About one-third of adults are concerned about their cognition, and the prevalence of objective cognitive impairment is much higher among those with neurological disorders. Existing screening tools are narrowly focused on detecting dementia in older adults and must be clinician-administeredand scored, making them impractical for many neurology practices. This study examined the utility of a brief, self-administered, computerized cognitive screening tool, the Brief Assessment of Cognitive Health (BACH), in identifying cognitive impairment in adults. 912 adults (ages 18-84) completed BACH and a neuropsychological battery. Multivariable models were developed to provide a BACH index score reflecting the probability of cognitive impairment for individual patients. Predictive accuracy was compared to that of the Montreal Cognitive Assessment (MoCA) in a subset of 160 older adults from a Memory Disorders clinic. The final multivariable model showed good accuracy in identifying cognitively impaired individuals (c = 0·77). Compared to MoCA, BACH had superior predictive accuracy in identifying older patients with cognitive impairment (c = 0·79 vs. 0·67) as well as differentiating those with MCI or dementia from those without cognitive impairment (c = 0·86 vs. c = 0·67). Results suggest that cognitive impairment can be identified in adults using a brief, self-administered, automated cognitive screening tool, and BACH provides several advantages over existing screeners: self-administered; automatic scoring; immediate results in health record; easily interpretable score; utility in wide range of patients; and flags for treatable factors that may contribute to cognitive complaints (i.e., depression, sleep problems, and stress).

Robust Radiotherapy Planning with Spatially Based Uncertainty Sets

Radiotherapy treatment planning is a challenging large-scale optimization problem plagued by uncertainty. Following the robust optimization methodology, we propose a novel, spatially based uncertainty set for robust modeling of radiotherapy planning, producing solutions that are immune to unexpected changes in biological conditions. Our proposed uncertainty set realistically captures biological radiosensitivity patterns that are observed using recent advances in imaging, while its parameters can be personalized for individual patients. We exploit the structure of this set to devise a compact reformulation of the robust model. We develop a row-generation scheme to solve real, large-scale instances of the robust model. This method is then extended to a relaxation-based scheme for enforcing challenging, yet clinically important, dose-volume cardinality constraints. The computational performance of our algorithms, as well as the quality and robustness of the computed treatment plans, are demonstrated on simulated and real imaging data. Based on accepted performance measures, such as minimal target dose and homogeneity, these examples demonstrate that the spatially robust model achieves almost the same performance as the nominal model in the nominal scenario, and otherwise, the spatial model outperforms both the nominal and the box-uncertainty models.

Fit2Drive: Screening Older Drivers with Cognitive Concerns

ObjectivesThe purpose of this study was to identify the most parsimonious combination of cognitive tests that accurately predicts the likelihood of passing an on-road driving evaluation in order to develop a screening measure that can be administered as an in-office test. DesignThis was a psychometric study of the new test's diagnostic accuracy. Settings and ParticipantsThe study was conducted at the Florida Atlantic University's Memory Center and Clinical Research Unit, both easily accessible to older drivers. Participants were older drivers who received a driving evaluation at the Memory Center and agreed to have their results included in the Driving Repository and community-based older drivers who volunteered to participate. MethodsMini-Mental State Exam (MMSE), Trail Making Tests A and B, Clock Test, Hopkins Verbal Learning Test, and Driving Health Inventory results were compared with an on-road driving evaluation to identify those tests that best predict the ability to pass the on-road evaluation. ResultsAltogether, 412 older drivers, 179 men and 233 women, were included in the analysis. Fifty-four percent of Driving Repository participants failed the on-road evaluation compared with 8% of the community sample. The highest correlation to the on-road evaluation was Trails B time in seconds r = −0.713 (P < .001). Variables with high multicollinearity and/or low correlation with the on-road evaluation were eliminated and sets of receiver operating characteristics curves were generated to assess the predictive accuracy of the remaining tests. A linear combination of Trails B in seconds and MMSE using the highest of the Serial 7s or WORLD spelled backward scores accounted for the highest area under the curve of 0.915. Finally, an algorithm was created to rapidly generate the prediction for an individual patient. Conclusions and ImplicationsThe Fit2Drive algorithm demonstrated a strong 91.5% predictive accuracy. Usefulness in office-based patient consultations is promising but remains to be rigorously tested.

Association between overweight and obesity with coronary artery bypass graft failure: an individual patient data analysis of clinical trials.

The association between obesity and graft failure after coronary artery bypass grafting has not been previously investigated. We pooled individual patient data from randomized clinical trials with systematic postoperative coronary imaging to evaluate the association between obesity and graft failure at the individual graft and patient levels. Penalized cubic regression splines and mixed-effects multivariable logistic regression models were performed. Six trials comprising 3928 patients and 12048 grafts were included. The median time to imaging was 1.03 (interquartile range 1.00-1.09) years. By body mass index (BMI) category, 800 (20.4%) patients were normal weight (BMI 18.5-24.9), 1668 (42.5%) were overweight (BMI 25-29.9), 983 (25.0%) were obesity class 1 (BMI 30-34.9), 344 (8.8%) were obesity class 2 (BMI 35-39.9) and 116 (2.9%) were obesity class 3 (BMI 40+). As a continuous variable, BMI was associated with reduced graft failure [adjusted odds ratio (aOR) 0.98 (95% confidence interval (CI) 0.97-0.99)] at the individual graft level. Compared to normal weight patients, graft failure at the individual graft level was reduced in overweight [aOR 0.79 (95% CI 0.64-0.96)], obesity class 1 [aOR 0.81 (95% CI 0.64-1.01)] and obesity class 2 [aOR 0.61 (95% CI 0.45-0.83)] patients, but not different compared to obesity class 3 [aOR 0.94 (95% CI 0.62-1.42)] patients. Findings were similar, but did not reach significance, at the patient level. In a pooled individual patient data analysis of randomized clinical trials, BMI and obesity appear to be associated with reduced graft failure at 1 year after coronary artery bypass grafting.

Association of immune checkpoint inhibitors with SARS-CoV-2 infection rate and prognosis in patients with solid tumors: a systematic review and meta-analysis.

https://www.crd.york.ac.uk/prospero/#recordDetails PROSPERO, identifier CRD42023393511.

Gut-directed hypnosis and hypnotherapy for irritable bowel syndrome: a mini-review.

Irritable bowel syndrome (IBS) is a frequent health condition which can be associated with functional disability and reduced health-related quality of life. IBS is classified as a disorder of the brain-gut axis. IBS is a very heterogenous condition with regards to the underlying pathophysiological mechanisms, the clinical picture and the amount of functional impairment. Within a biopsychosocial model of IBS psychosocial factors can play a role in the in the predisposition, triggering and development of chronicity. Somatic or psychosocial or a mixture of both factors might predominate in an individual patient. Gut-directed hypnosis is a special type of medical hypnosis combining standardised gut-directed suggestions (hypnosis) with suggestions tailored to the psychological characteristics of the patient (hypnotherapy). Of brain-gut behavioral therapies, cognitive bahvioral-based interventions and gut-directed hypnosis have the largest evidence for both short-term and long-term efficacy in controlled trials for IBS and are recommended by current European and North American gastroenterology guidelines as second line treatment options. Standardised gut-directed hypnosis is available by audiotapes and can be part of a multicomponent self-management approach by digital health applications. It can be used - based on the patient's preferences-as first line therapy for mild forms of IBS. Severe forms of IBS require face-to-face interdisciplinary management. Standardised gut-directed hypnosis and hypnotherapy tailored to the individual patient can be part of this approach.

Tumour Microenvironment Contribution to Checkpoint Inhibitor Therapy in Classic Hodgkin Lymphoma

Classic Hodgkin lymphoma (cHL) is a B-cell lymphoma in which tumour cells, the so-called Hodgkin Reed–Sternberg (HRS) cells, are admixed with non-malignant cell types that are a functional part of the disease. Immune cells, fibroblasts, specialised mesenchymal cells, and microvasculature together make up the tumour microenvironment and have functional interactions with tumour cells. HRS cells are surrounded by T and B cells admixed with plasma cells, macrophages, eosinophils, and mast cells. A cross-talk occurs between HRS cells and immune cells of the TME. This cross-talk is mediated either by a large network of cytokines and chemokines expressed by HRS cells or molecules produced by different cell types of the TME, i.e., CD30/CD30L, CD40/CD40L, OX40L/OX40, Il- 3/Il-3R, CCR5/CCL5, CD74 macrophage migration inhibitory factor/macrophages, and PD-L1/PD-1. The over-expression of CD30 and CD40, members of the TNF receptor family, is a hallmark of HRS cells. This review highlights the current development of newer therapeutic strategies as a means of immune checkpoint blockade and suggests that further research should explore innovative molecules aimed at targeting components of HL that are involved in cancer cell growth and/or immune escape. Hopefully, this will influence sensitivity or resistance to checkpoint inhibitor therapy in an individual patient.

Removing the physician from the equation: Patient-controlled, home-based therapeutic drug self-monitoring of tacrolimus.

The dosing of tacrolimus, which forms the backbone of immunosuppressive therapy after kidney transplantation, is complex. This is due to its variable pharmacokinetics (both between and within individual patients), narrow therapeutic index, and the severe consequences of over- and underexposure, which may cause toxicity and rejection, respectively. Tacrolimus is, therefore, routinely dosed by means of therapeutic drug monitoring (TDM). TDM is performed for as long as the transplant functions and frequent and often lifelong sampling is therefore the rule. This puts a significant burden on patients and transplant professionals and is associated with high healthcare-associated costs. Furthermore, by its very nature, TDM is reactive and has no predictive power. Finally, the current practice of TDM does not foresee in an active role for patients themselves. Rather, the physician or pharmacist prescribes the next tacrolimus dose after obtaining the concentration measurement test results. In this article, we propose a strategy of patient-controlled, home-based, self-TDM of the immunosuppressant tacrolimus after transplantation. We argue that with the combined use of population tacrolimus pharmacokinetic models, home-based sampling by means of dried blood spotting and implementation of telemedicine, this may become a feasible approach in the near future.

WONOEP 2022: Neurotechnology for the diagnosis of epilepsy.

Epilepsy's myriad causes and clinical presentations ensure that accurate diagnoses and targeted treatments remain a challenge. Advanced neurotechnologies are needed to better characterize individual patients across multiple modalities and analytical techniques. At the XVIth Workshop on Neurobiology of Epilepsy: Early Onset Epilepsies: Neurobiology and Novel Therapeutic Strategies (WONOEP 2022), the session on "advanced tools" highlighted a range of approaches, from molecular phenotyping of genetic epilepsy models and resected tissue samples to imaging-guided localization of epileptogenic tissue for surgical resection of focal malformations. These tools integrate cutting edge research, clinical data acquisition, and advanced computational methods to leverage the rich information contained within increasingly large datasets. A number of common challenges and opportunities emerged, including the need for multidisciplinary collaboration, multimodal integration, potential ethical challenges, and the multistage path to clinical translation. Despite these challenges, advanced epilepsy neurotechnologies offer the potential to improve our understanding of the underlying causes of epilepsy and our capacity to provide patient-specific treatment.

Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.

In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant. In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48weeks (median period of 84weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients. Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy. Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.