Safe Stop IPI-NIVO trial: early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab - study protocol.

BACKGROUND: Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. METHODS: The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. DISCUSSION: From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05652673, registration date: 08-12-2022.

Evaluation of a new two-step frailty assessment of head and neck patients in a prospective cohort.

PURPOSE: Assessing frailty, in head and neck cancer (HNC) patients is key when choosing appropriate treatment. Optimal screening is challenging, as it should be feasible and should avoid over-referral for comprehensive geriatric assessment (CGA) This study aims to evaluate the association between geriatric assessment using a new two-step care pathway, referral to geriatrician and adverse outcomes. METHODS: This institutional retrospective analysis on a prospective cohort analysed the multimodal geriatric assessment (GA) of newly diagnosed HNC patients. Uni- and multivariable logistic regression was performed to study the association between the screening tests, and referral to the geriatrician for complete geriatric screening, and adverse outcomes. RESULTS: This study included 539 patients, of whom 276 were screened. Patients who underwent the GA, were significantly older and more often had advanced tumour stages compared to non-screened patients. Referral to the geriatrician was done for 30.8% of patients. Of the 130 patients who underwent surgery, 26/130 (20%) experienced clinically relevant postoperative complications. Of the 184 patients who underwent (radio)chemotherapy, 50/184 (27.2%) had clinically relevant treatment-related toxicity. Age, treatment intensity, polypharmacy and cognitive deficits, were independently associated with referral to geriatrician. A medium to high risk of malnutrition was independently associated with acute radiation induced toxicity and adverse outcomes in general. CONCLUSION: The current study showed a 30.8% referral rate for CGA by a geriatrician. Age, treatment intensity, cognitive deficits and polypharmacy were associated with higher rates of referral. Furthermore, nutritional status was found to be an important negative factor for adverse treatment outcomes, that requires attention.

The effect of smell training on COVID-19 induced smell loss.

OBJECTIVE: while smell training appears to be effective for post viral smell loss, its effectiveness in COVID-19 induced smell loss is currently not well known. Therefore, we aim to investigate the potential effect of smell training on patients with COVID-19 induced smell loss. METHODS: we conducted a case-control study with two comparable cohorts. One of which (n=111) was instructed to perform smell training twice daily for 12 weeks, therapeutical adherence was monitored on a daily schedule, while the other cohort (n=50) did not perform smell training. The Sniffin' Sticks Test (SST) was used to objectify participants' sense of smell at baseline and after 12 weeks, reported as a Threshold, Discrimination, and Identification (TDI) score. We also determined the association between therapeutical adherence and the TDI scores. RESULTS: we found a significant difference in psychophysical smell function between patients with COVID-19 induced smell disorders who performed 12 weeks of smell training and those who did not. Median TDI difference between groups was 2.00 However, there was no association between the therapeutical adherence and olfactory function. CONCLUSION: we discovered a significant moderate difference in psychophysical smell function between patients with COVID-19-induced smell disorders who performed smell training and those who did not, implying a possible advantage of training. However, no relationship was found between therapeutical adherence of smell training and olfactory function.

Age-specific incidence and treatment patterns of head and neck cancer in the Netherlands-A cohort study.

OBJECTIVES: To explore the incidence and treatment pattern of head and neck cancer in different age groups. DESIGN: Cohort study. SETTING: Netherlands Cancer Registry. PARTICIPANTS: All new primary head and neck cancer cases diagnosed between 2010 and 2014 were included and categorised into different age groups. MAIN OUTCOME MEASURES: Tumour site, stage, treatment modality, location of diagnosis and treatment. RESULTS: The study population was composed of 11 558 tumours. Oral cancer was the most common primary site (31%), followed by laryngeal (25%) and oropharyngeal cancer (22%). Ninety-six per cent of the entire study population was diagnosed and/or treated in a certified head and neck oncology centre which was lower in the 80+ population (92%). Multimodality treatment was less frequently applied with increasing age (eg oral cavity: 17% in 80+ vs 34% in 60-; P < .001). The percentage of patients not receiving tumour-directed treatment increased with age (eg oropharyngeal cancer: 25% in 80+ vs 6% in 80-; P < .001). CONCLUSIONS: This study confirms that less multimodal and tumour-directed treatment is applied with the increasing age of head and neck cancer patients.

High sensitivity and negative predictive value of sentinel lymph node biopsy in a retrospective early stage oral cavity cancer cohort in the Northern Netherlands.

OBJECTIVES: In cT1-2N0, oral squamous cell carcinoma (OSCC) occult metastases are detected in 23%-37% of cases. Sentinel lymph node biopsy (SLNB) was introduced in head and neck cancer as a minimally invasive alternative for an elective neck dissection in neck staging. Meta-analyses of SLNB accuracy show heterogeneity in the existing studies for reference standards, imaging techniques and pathological examination. The aim of this study was to assess the sensitivity and negative predictive value (NPV) of the SLNB in detecting occult metastases in cT1-2N0 OSCC in a well-defined cohort. DESIGN: Retrospective study. The SLNB procedure consisted of lymphoscintigraphy, SPECT/CT-scanning and gamma probe detection. Routine follow-up was the reference standard for the SLNB negative neck. Histopathological examination of sentinel lymph nodes (SLN) consisted of step serial sectioning, haematoxylin-eosin and cytokeratin AE1/3 staining. SETTING: Two comprehensive oncology centres. PARTICIPANTS: A total of 91 consecutive patients with primary cT1-2N0 OSCC treated by primary resection and neck staging by SLNB procedure between 2008 and 2016. MAIN OUTCOME MEASURES: Sensitivity and negative predictive value. RESULTS: In all cases, SLNs were harvested. A total of 25 (27%) patients had tumour-positive SLNs. The median follow-up was 32 months (range 2-104). Four patients were diagnosed with an isolated regional recurrence in the SLNB negative neck side resulting in an 85% sensitivity and a 94% NPV. CONCLUSION: In our cohort, the SLNB detected occult metastases in early OSCC with 85% sensitivity and 94% NPV. This supports that SLNB is a reliable procedure for surgical staging of the neck in case of oral cT1-2N0 SCC.

Detection of HPV-associated oropharyngeal tumours in a 16-year cohort: more than meets the eye.

BACKGROUND: Accurate assessment of the prevalence of the human papilloma virus (HPV) in oropharyngeal tumours (OpSCC) is important because HPV-positive OpSCC are consistently associated with an improved overall survival. Recently, an algorithm has become available that reliably detects clinically relevant HPV in tumour tissue, however, no complete cohorts have been tested. The aim was to determine the prevalence of active high-risk HPV infection in a complete cohort of OpSCC collected over a 16-year period. METHODS: Using a triple algorithm of p16 immunohistochemistry, HPV-BRISH and HPV-PCR, we assessed the prevalence of active HPV infection in all OpSCC diagnosed in our hospital from 1997 to 2012 (n=193) and a random selection of 200 oral tumours (OSCC). RESULTS: Forty-seven OpSCC (24%) were HPVGP PCR-positive; 42 cases were HPV16+, 1 HPV18+, 3 HPV33+ and 1 HPV35+. Brightfield in situ hybridisation did not identify additional HPV-positive cases. Human papilloma virus-associated tumour proportion increased from 13% (1997-2004) to 30% (2005-2012). Human papilloma virus-positivity was an independent predictor for longer disease-specific survival (HR=0.22; 95%CI:0.10-0.47). Only one OSCC was HPV+. CONCLUSIONS: In our cohort, the incidence of HPV-associated OpSCC is low but increasing rapidly. The strict detection algorithm, analysis of disease-specific survival and the complete cohort, including palliatively treated patients, may influence the reported prevalence and prognostic value of HPV in OpSCC.

Functional brain network analysis using minimum spanning trees in Multiple Sclerosis: an MEG source-space study.

Cognitive dysfunction in Multiple Sclerosis (MS) is closely related to altered functional brain network topology. Conventional network analyses to compare groups are hampered by differences in network size, density and suffer from normalization problems. We therefore computed the Minimum Spanning Tree (MST), a sub-graph of the original network, to counter these problems. We hypothesize that functional network changes analysed with MSTs are important for understanding cognitive changes in MS and that changes in MST topology also represent changes in the critical backbone of the original brain networks. Here, resting-state magnetoencephalography (MEG) recordings from 21 early MS patients and 17 age-, gender-, and education-matched controls were projected onto atlas-based regions-of-interest (ROIs) using beamforming. The phase lag index was applied to compute functional connectivity between regions, from which a graph and subsequently the MST was constructed. Results showed lower global integration in the alpha2 (10-13Hz) and beta (13-30Hz) bands in MS patients, whereas higher global integration was found in the theta band. Changes were most pronounced in the alpha2 band where a loss of hierarchical structure was observed, which was associated with poorer cognitive performance. Finally, the MST in MS patients as well as in healthy controls may represent the critical backbone of the original network. Together, these findings indicate that MST network analyses are able to detect network changes in MS patients, which may correspond to changes in the core of functional brain networks. Moreover, these changes, such as a loss of hierarchical structure, are related to cognitive performance in MS.

Structural degree predicts functional network connectivity: a multimodal resting-state fMRI and MEG study.

Communication between neuronal populations in the human brain is characterized by complex functional interactions across time and space. Recent studies have demonstrated that these functional interactions depend on the underlying structural connections at an aggregate level. Multiple imaging modalities can be used to investigate the relation between the structural connections between brain regions and their functional interactions at multiple timescales. We investigated if consistent modality-independent functional interactions take place between brain regions, and whether these can be accounted for by underlying structural properties. We used functional MRI (fMRI) and magnetoencephalography (MEG) recordings from a population of healthy adults together with a previously described structural network. A high overlap in resting-state functional networks was found in fMRI and especially alpha band MEG recordings. This overlap was characterized by a strongly interconnected functional core network in temporo-posterior brain regions. Anatomically realistically coupled neural mass models revealed that this strongly interconnected functional network emerges near the threshold for global synchronization. Most importantly, this functional core network could be explained by a trade-off between the product of the degrees of structurally-connected regions and the Euclidean distance between them. For both fMRI and MEG, the product of the degrees of connected regions was the most important predictor for functional network connectivity. Therefore, irrespective of the modality, these results indicate that a functional core network in the human brain is especially shaped by communication between high degree nodes of the structural network.

The impact of organisational external peer review on colorectal cancer treatment and survival in the Netherlands.

BACKGROUND: Organisational external peer review was introduced in 1994 in the Netherlands to improve multidisciplinary cancer care. We examined the clinical impact of this programme on colorectal cancer care. METHODS: Patients with primary colorectal cancer were included from 23 participating hospitals and 7 controls. Hospitals from the intervention group were dichotomised by their implementation proportion (IP) of the recommendations from each peer review (high IP vs low IP). Outcome measures were the introduction of new multidisciplinary therapies and survival. RESULTS: In total, 45 705 patients were included (1990-2010). Patients from intervention hospitals more frequently received adjuvant chemotherapy for stage III colon cancer. T2-3/M0 rectal cancer patients from hospitals with a high IP had a higher chance of receiving preoperative radiotherapy (OR 1.31, 95% CI 1.11-1.55) compared with the controls and low IP group (OR 0.75, 95% CI 0.63-0.88). There were no differences in the use of preoperative chemoradiation for T4/M0 rectal cancer. Survival was slightly higher in colon cancer patients from intervention hospitals but unrelated to the phase of the programme in which the hospital was at the time of diagnosis. CONCLUSIONS: Some positive effects of external peer review on cancer care were found, but the results need to be interpreted cautiously due to the ambiguity of the outcomes and possible confounding factors.

Is locally advanced head and neck cancer 'increasing' in the Netherlands? The paradox of absolute numbers, standardized incidence rates and proportional share.

BACKGROUND: Several reports have indicated that locally advanced head and neck cancer (LAHNC) has increased in the past decade. However, incidence trends cannot be easily compared because slightly different definitions of LAHNC were used. AIM: To investigate if the incidence of locally advanced disease (LAD) in the oral cavity, oropharynx, hypopharynx and larynx is indeed increasing over time, considering the growing and ageing population in the Netherlands. PATIENTS AND METHODS: Data were obtained from the Netherlands Cancer Registry (NCR). Primary head and neck squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx and larynx diagnosed between 1989 and 2017 were included. Yearly numbers and European standardized incidence rates (ESRs) were reported by extent of disease. The annual percentage change (APC) over time in ESRs was calculated to assess trends. RESULTS: Absolute numbers and ESRs of LAD increased over time for oral cavity and most prominently for oropharynx carcinomas (before 1996, APC: 0.4, 95%CI: 0.1; 0.8 and APC: 5.7 (95%CI: 3.1; 8.4) after 1996: 1.5 (1.0; 2.0) respectively. For hypopharynx cancer the absolute number and ESR of LAD increased until 1997 and declined with 0.8% per year since 1997. Absolute numbers of patients with larynx cancer stayed stable over time, while ESR decreased (APC: -0.8 (95%CI: -1.1; -0.6)). CONCLUSION: The perception of an increasing trend in LAD in the Netherlands can be attributed to the increasing incidence of oral cavity and oropharynx carcinomas. For LAD of the hypopharynx a decreasing trend was observed. In larynx cancer, the proportional share of LAD of the larynx increased, even though incidence rates declined.

Disentangling heterogeneity in contemporary undifferentiated arthritis - A large cohort study using latent class analysis.

OBJECTIVES: Undifferentiated arthritis(UA) is clinically heterogeneous and differs in outcomes ranging from spontaneous resolution to RA-development. Therefore, we hypothesized that subgroups exist within UA and we aimed to identify homogeneous groups based on clinical features, and thereafter to relate these groups to the outcomes spontaneous resolution and RA-development. These outcomes can only be studied in UA-patients in which DMARD-treatment does not influence the natural disease course; these cohorts are scarce. METHODS: We studied autoantibody-negative UA-patients (not fulfilling 1987/2010 RA-criteria, no alternate diagnosis), included in the Leiden Early Arthritis Clinic between 1993 and 2006, when early DMARD-treatment in UA was infrequent. Latent class analysis was used to identify subgroups based on combinations of clinical features. Within these subgroups, test-characteristics were assessed for spontaneous resolution of arthritis and RA-development within 1 year. RESULTS: 310 consecutive UA-patients were studied. Five classes were identified: location and number of swollen joints were most distinguishing. Classes were characterized by: 1) polyarthritis, often symmetric; 2) oligoarthritis, frequently with subacute onset; 3) wrist-monoarthritis, often with subacute onset, increased BMI and without morning stiffness; 4) small-joint monoarthritis, often without increased acute phase reactants, and 5) large-joint monoarthritis, often with subacute onset. Studying the classes in relation to the outcomes revealed that patients without spontaneous resolution (thus having persistent disease) were nearly absent in the classes characterized by monoarthritis (specificity >90%). Additionally, patients who developed RA were infrequent in monoarthritis classes (sensitivity <7%). CONCLUSION: Using a data-driven unsupervised approach, five subgroups within contemporary UA were identified. These have differences in the natural course of disease.

Optimizing parameter choice for FSL-Brain Extraction Tool (BET) on 3D T1 images in multiple sclerosis.

BACKGROUND: Brain atrophy studies often use FSL-BET (Brain Extraction Tool) as the first step of image processing. Default BET does not always give satisfactory results on 3DT1 MR images, which negatively impacts atrophy measurements. Finding the right alternative BET settings can be a difficult and time-consuming task, which can introduce unwanted variability. AIM: To systematically analyze the performance of BET in images of MS patients by varying its parameters and options combinations, and quantitatively comparing its results to a manual gold standard. METHODS: Images from 159 MS patients were selected from different MAGNIMS consortium centers, and 16 different 3DT1 acquisition protocols at 1.5 T or 3T. Before running BET, one of three pre-processing pipelines was applied: (1) no pre-processing, (2) removal of neck slices, or (3) additional N3 inhomogeneity correction. Then BET was applied, systematically varying the fractional intensity threshold (the "f" parameter) and with either one of the main BET options ("B" - bias field correction and neck cleanup, "R" - robust brain center estimation, or "S" - eye and optic nerve cleanup) or none. For comparison, intracranial cavity masks were manually created for all image volumes. FSL-FAST (FMRIB's Automated Segmentation Tool) tissue-type segmentation was run on all BET output images and on the image volumes masked with the manual intracranial cavity masks (thus creating the gold-standard tissue masks). The resulting brain tissue masks were quantitatively compared to the gold standard using Dice overlap coefficient (DOC). Normalized brain volumes (NBV) were calculated with SIENAX. NBV values obtained using for SIENAX other BET settings than default were compared to gold standard NBV with the paired t-test. RESULTS: The parameter/preprocessing/options combinations resulted in 20,988 BET runs. The median DOC for default BET (f=0.5, g=0) was 0.913 (range 0.321-0.977) across all 159 native scans. For all acquisition protocols, brain extraction was substantially improved for lower values of "f" than the default value. Using native images, optimum BET performance was observed for f=0.2 with option "B", giving median DOC=0.979 (range 0.867-0.994). Using neck removal before BET, optimum BET performance was observed for f=0.1 with option "B", giving median DOC 0.983 (range 0.844-0.996). Using the above BET-options for SIENAX instead of default, the NBV values obtained from images after neck removal with f=0.1 and option "B" did not differ statistically from NBV values obtained with gold-standard. CONCLUSION: Although default BET performs reasonably well on most 3DT1 images of MS patients, the performance can be improved substantially. The removal of the neck slices, either externally or within BET, has a marked positive effect on the brain extraction quality. BET option "B" with f=0.1 after removal of the neck slices seems to work best for all acquisition protocols.

A population-based study of the epidemiology of oral squamous cell carcinoma in the Netherlands 1989-2018, with emphasis on young adults.

There has been an increasing trend in oral squamous cell carcinoma (OSCC) in patients under 45 years of age. The aim of this study was to evaluate the burden of OSCC in the Netherlands between 1989 and 2018 among young adults (age 20-34 years) when compared to adults (age 35-44 years), and to describe the burden in older groups as well, utilizing cancer registry data to characterize incidence patterns by age, sex, and risk factors. A total of 18,963 cases of OSCC were reported. The overall incidence rate, as measured by annual percentage change (APC), increased significantly from 1989 to 2010 by 1.3% per year (95% confidence interval (CI) 0.9-1.7%) but decreased thereafter by -0.9% (95% CI -2.5% to 0.7%). Annual incidence increased significantly by 2.4% (95% CI 1.1-3.8%) for patients aged 20-34 years, while it decreased for those aged 35-44 years by -0.9% (95% CI -1.7% to 0.0%). In patients older than 60 years, incidence rates increased overall (60-74 years: APC 1.8%, 95% CI 1.5-2.1%; ≥75 years: APC 1.5%, 95% CI 1.2-1.9%). Overall, 66.5% of patients were smokers and 65.3% were alcohol consumers. The marked differences in incidence within the young age subgroups warrants further investigation to elucidate any likely disparity in biological process and clinical outcomes in these populations.

Dynamics underlying spontaneous human alpha oscillations: a data-driven approach.

Although the cognitive and clinical correlates of spontaneous human alpha oscillations as recorded with electroencephalography (EEG) or magnetoencephalography (MEG) are well documented, the dynamics underlying these oscillations is still a matter of debate. This study proposes a data-driven method to reveal the dynamics of these oscillations. It demonstrates that spontaneous human alpha oscillations as recorded with MEG can be viewed as noise-perturbed damped harmonic oscillations. This provides evidence for the hypothesis that these oscillations reflect filtered noise and hence do not possess limit-cycle dynamics. To illustrate the use of the model, we apply it to two data-sets in which a decrease in alpha power can be observed across conditions. The associated differences in the estimated model parameters show that observed decreases in alpha power are associated with different kinds of changes in the dynamics. Thus, the model parameters are useful dynamical biomarkers for spontaneous human alpha oscillations.

Prognoses for head and neck cancers in Europe diagnosed in 1995-1999: a population-based study.

BACKGROUND: head and neck cancers are a heterogeneous group of malignancies, affecting various sites and subsites, with differing prognoses. The aim of this study was to analyse survival for European head and neck cancer patients in populations covered by population-based cancer registries (CRs), in relation to tumour subsite as prognostic factor. PATIENTS AND METHODS: we analysed 51 912 adult head and neck cancer cases (36 322 mouth-pharynx and 15 590 larynx) diagnosed from 1995 to 1999 and archived by 45 CRs in 20 countries participating in EUROCARE-4. Five-year age-standardised relative survival was estimated for mouth-pharynx and larynx sites by sex and country. Relative survival was modelled to provide estimates of relative excess risks (RERs) of death by country, adjusted for confounding factors. RESULTS: a large but site-variable proportion of tumours were incompletely specified. Five-year age-standardised relative survival was low in Slovakia and high in The Netherlands. Adjustment for subsite reduced RERs of death for most countries; 5-year relative survival increased from 1990-1994 to 1995-1999 for all subsites, while between-country differences in survival narrowed. CONCLUSION: differences in subsite distribution explain a considerable part of the survival differences for head and neck cancers, however, incomplete/inaccurate subsite reporting complicate interpretation.

Incidental findings during the diagnostic work-up in the head and neck cancer pathway: Effects on treatment delay and survival.

OBJECTIVES: As a result of the increasing number of diagnostic scans, incidental findings (IFs) are more frequently encountered during oncological work-up in patients with head and neck squamous cell carcinomas (HNSCC). IFs are unintentional discoveries found on diagnostic imaging. Relevant IFs implicate clinical consequences, resulting in delay in oncologic treatment initiation, which is associated with unfavorable outcomes. This study is the first to investigate the incidence and nature of IFs over the years and establish the effect of relevant IFs on delay. MATERIAL AND METHODS: This retrospective study compared two time periods (2010-2011 and 2016-2017), described associations between relevant IFs and delay in carepathway interval (days between first visit and treatment initiation) and assessed the effect of relevant IFs on overall two-year survival. RESULTS: In total, 592 patients were included. At least one IF was found in 61.5% of the patients, most frequently on chest-CT. In 128 patients (21.6%) a relevant IF was identified, resulting for the majority in radiologist recommendations (e.g. additional scanning). Presence of a relevant IF was an independent significant factor associated with delay in treatment initiation. The risk of dying was higher for patients with a relevant IF, although not significant in the multivariable model (HR: 1.46, p = 0.079). CONCLUSION: In diagnostic work-up for HNSCC patients, relevant IFs are frequently encountered. As the frequency of additional imaging rises over the years, the number of IFs increased simultaneously. These relevant IFs yield clinical implications and this study described that relevant IFs result in significant delay in treatment initiation.

Cortico-spinal synchronization reflects changes in performance when learning a complex bimanual task.

Motor performance is accompanied by neural activity in various cortical and sub-cortical areas. This intricate network has to be delicately orchestrated. We analyzed the role of beta synchronization in motor learning using magneto-encephalography combined with electromyography. Cortico-spinal synchronization in the beta band was found to be of particular importance in establishing bimanual movement patterns in the context of a 3:2 polyrhythmic (isometric) force production task. Its dynamics correlated highly with the learning of this complex bimanual motor skill. We submit that the cortical dynamics entrains the spinal motor system by which cortico-spinal beta synchrony serves higher-level motor control functions as primary means of information transfer along the neural axis.

Graph theoretical analysis of magnetoencephalographic functional connectivity in Alzheimer's disease.

In this study we examined changes in the large-scale structure of resting-state brain networks in patients with Alzheimer's disease compared with non-demented controls, using concepts from graph theory. Magneto-encephalograms (MEG) were recorded in 18 Alzheimer's disease patients and 18 non-demented control subjects in a no-task, eyes-closed condition. For the main frequency bands, synchronization between all pairs of MEG channels was assessed using a phase lag index (PLI, a synchronization measure insensitive to volume conduction). PLI-weighted connectivity networks were calculated, and characterized by a mean clustering coefficient and path length. Alzheimer's disease patients showed a decrease of mean PLI in the lower alpha and beta band. In the lower alpha band, the clustering coefficient and path length were both decreased in Alzheimer's disease patients. Network changes in the lower alpha band were better explained by a 'Targeted Attack' model than by a 'Random Failure' model. Thus, Alzheimer's disease patients display a loss of resting-state functional connectivity in lower alpha and beta bands even when a measure insensitive to volume conduction effects is used. Moreover, the large-scale structure of lower alpha band functional networks in Alzheimer's disease is more random. The modelling results suggest that highly connected neural network 'hubs' may be especially at risk in Alzheimer's disease.

Treating infections with ionizing radiation: a historical perspective and emerging techniques.

BACKGROUND: Widespread use and misuse of antibiotics have led to a dramatic increase in the emergence of antibiotic resistant bacteria, while the discovery and development of new antibiotics is declining. This has made certain implant-associated infections such as periprosthetic joint infections, where a biofilm is formed, very difficult to treat. Alternative treatment modalities are needed to treat these types of infections in the future. One candidate that has been used extensively in the past, is the use of ionizing radiation. This review aims to provide a historical overview and future perspective of radiation therapy in infectious diseases with a focus on orthopedic infections. METHODS: A systematic search strategy was designed to select studies that used radiation as treatment for bacterial or fungal infections. A total of 216 potentially relevant full-text publications were independently reviewed, of which 182 focused on external radiation and 34 on internal radiation. Due to the large number of studies, several topics were chosen. The main advantages, disadvantages, limitations, and implications of radiation treatment for infections were discussed. RESULTS: In the pre-antibiotic era, high mortality rates were seen in different infections such as pneumonia, gas gangrene and otitis media. In some cases, external radiation therapy decreased the mortality significantly but long-term follow-up of the patients was often not performed so long term radiation effects, as well as potential increased risk of malignancies could not be investigated. Internal radiation using alpha and beta emitting radionuclides show great promise in treating fungal and bacterial infections when combined with selective targeting through antibodies, thus minimizing possible collateral damage to healthy tissue. CONCLUSION: The novel prospects of radiation treatment strategies against planktonic and biofilm-related microbial infections seem feasible and are worth investigating further. However, potential risks involving radiation treatment must be considered in each individual patient.