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Subtalar joint (STJ) dysfunction can contribute to movement disturbances. Vibration energy with color Doppler imaging (VECDI) may be useful for detecting STJ stiffness changes. (1) Support proof-of-concept that VECDI could detect STJ stiffness differences; (2) Establish STJ stiffness range in asymptomatic volunteers; (3) Examine relationships between STJ stiffness and foot mobility; and (4) Assess VECDI precision and reliability for examining STJ stiffness. After establishing cadaveric testing model proof-of-concept, STJ stiffness (threshold units, ΔTU), ankle complex passive range-of-motion (PROM) and midfoot-width-difference (MFWDiff) data were collected in 28 asymptomatic subjects in vivo. Three reliability measurements were collected per variable; Rater-1 collected on all subjects and rater-2 on the first ten subjects. Subjects were classified into three STJ stiffness groups. Cadaveric VECDI measurement intra-rater reliability was 0.80. A significantly lower STJ ΔTU (p = .002) and ankle complex PROM (p < .001) was observed during the screw fixation versus normal condition. A fair correlation (r = 0.660) was observed between cadaveric ΔTU and ankle complex PROM. In vivo VECDI measurements demonstrated good intra-rater (0.76-0.84) versus poor inter-rater (-3.11) reliability. Significant positive correlations were found between STJ stiffness and both dorsum (r = .440) and posterior (r = .390) PROM. MFWDiff exhibited poor relationships with stiffness (r = .103) and either dorsum (r = .256) or posterior (r = .301) PROM. STJ stiffness ranged from 2.33 to 7.50 ΔTUs, categorizing subjects' STJ stiffness as increased (n = 6), normal (n = 15), or decreased (n = 7). Significant ANOVA main effects for classification were found based on ΔTU (p< .001), dorsum PROM (p = .017), and posterior PROM (p = .036). Post-hoc tests revealed significant: (1) ΔTU differences between all stiffness groups (p < .001); (2) dorsum PROM differences between the increased versus normal (p = .044) and decreased (p = .017) stiffness groups; and (3) posterior PROM differences between the increased versus decreased stiffness groups (p = .044). A good relationship was found between STJ stiffness and dorsum PROM in the increased stiffness group (r = .853) versus poor, nonsignificant relationships in the normal (r = -.042) or decreased stiffness (r = -.014) groups. PROM may not clinically explain all aspects of joint mobility. Joint VECDI stiffness assessment should be considered as a complimentary measurement technique.

We report a severe acute respiratory syndrome coronavirus 2 superspreading event in the Netherlands after distancing rules were lifted in nightclubs, despite requiring a negative test or vaccination. This occurrence illustrates the potential for rapid dissemination of variants in largely unvaccinated populations under such conditions. We detected subsequent community transmission of this strain.

Neurocysticercosis (NCC) is caused by infection of the brain by larvae of the parasitic cestode Taenia solium . It is the most prevalent parasitic infection of the central nervous system and one of the leading causes of adult-acquired epilepsy worldwide. However, little is known about how cestode larvae affect neurons directly. To address this, we used whole-cell patch-clamp electrophysiology and calcium imaging in rodent and human brain slices to identify direct effects of cestode larval products on neuronal activity. We found that both whole cyst homogenate and excretory/secretory products of cestode larvae have an acute excitatory effect on neurons, which can trigger seizure-like events in vitro . This effect was mediated by glutamate receptor activation but not by nicotinic acetylcholine receptors, acid-sensing ion channels, or Substance P. Glutamate-sensing fluorescent reporters (iGluSnFR) and amino acid assays revealed that the larval homogenate of the cestodes Taenia crassiceps and Taenia solium contained high concentrations of the amino acids glutamate and aspartate. Furthermore, we found that larvae of both species consistently produce and release these excitatory amino acids into their immediate environment. Our findings suggest that perturbations in glutamatergic signalling may play a role in seizure generation in NCC. One of the main causes of epilepsy in adults – particularly in developing countries – is a parasitic brain infection called neurocysticercosis. This can happen when people swallow tapeworm eggs, which hatch into larvae and migrate throughout the body. When these larvae infect the brain, they form structures called cysts, which can cause seizures. It is thought that inflammation in the brain contributes to the development of seizures in neurocysticercosis, but how this might work is still poorly understood. The larvae produce chemicals that can interact with nearby cells in the body, including the defensive cells of our immune system. However, it remains unknown whether those chemicals also interact with brain cells. De Lange, Tomes et al. set out to determine if tapeworm larvae produced any specific chemicals that affect the activity of brain cells, and if they might play a role in epileptic seizures. To do this, the researchers collected materials from tapeworm larvae, which included both the substances they naturally released and a mixture made from crushed whole larvae. They then applied these substances to brain tissue grown in cell culture while recording the electrical activity of individual brain cells. Experiments using brain tissue derived from rats, mice and humans revealed that the larval products made brain cells more excited and led to them firing more electrical signals than normal. This excitation was strong enough to trigger larger patterns of activity across the brain tissue that mimicked the effect of an epileptic seizure. Further biochemical analysis of the larval products and the larvae themselves revealed that tapeworm larvae continuously release a chemical called glutamate, which is known to excite brain cells. These results suggested that tapeworm larvae might cause epilepsy by producing excess glutamate and overexciting brain cells – a mechanism similar to the way that other brain conditions, like tumors, also trigger seizures. This work has revealed a new mechanism for how tapeworm larvae might cause seizures in neurocysticercosis. The next step will be understanding how the larvae release glutamate into the brain, for example, if they actively produce it, or if it is passively released when they die. In the future, de Lange et al. hope this knowledge will help develop new treatments that help prevent seizures in people with neurocysticercosis.

Advanced colorectal cancer (CRC) consensus molecular subtype 4 (CMS4) or CRC with a low immunoscore is associated with shorter survival times. Non-metastatic CRC with microsatellite instability (MSI) is associated with a lower risk of recurrence. We evaluated outcome (lymph node metastases [LNM] or cancer recurrence) in these tumor subtypes in patients with surgically-removed non-pedunculated T1 CRC by performing a multicenter case-cohort study. We included all patients in 13 hospitals in the Netherlands from 2000–2014 (n = 651). We randomly selected a subgroup of patients (n = 223) and all patients with LNM or recurrence (n = 63), and median follow-up of 44 months. We centrally reviewed tumor-slides, and constructed and immunostained tissue microarrays determining MSI, CMS (MSI/CMS1, CMS2/3, or CMS4), and immunoscore (I-low/I-high). We used weighted Cox proportional hazard models to evaluate the association of MSI, CMS, and immunoscore with LNM or recurrence, adjusting for conventional histologic risk factors. In the randomly selected subgroup of patients, 7.1% of tumors were MSI/CMS1, 91.0% CMS2/3, 1.8% CMS4, and 25% I-low. In the case-cohort, patients with CMS4 tumors had an increased risk for LNM or recurrence compared with patients with tumors of other CMSs (adjusted hazard ratio [HR], 3.97; 95% CI, 1.12–14.06; P = 0.03). Albeit not significant, tumors with MSI had a lower risk for LNM or recurrence than other tumor subtypes (adjusted HR, 0.52; 95% CI, 0.12–2.30; P = 0.39), whereas tumors with a low immunoscore had an increased risk for LNM or recurrence (adjusted HR, 1.30; 95% CI, 0.68–2.48; P = 0.43). In conclusion, in a case-cohort study of patients with non-pedunculated T1 CRC, MSI, and immunoscore were not significantly associated with adverse outcome after surgery. CMS4 substantially increased the risk of adverse outcome. However, CMS4 is rare in T1 CRCs, limiting its value for determining the risk in patients.

Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and 18F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF < 65, n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (pfwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (pfwe = 0.035); the association was negative in CHR with poor outcomes (pfwe = 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.

Knowledge about the efficacy of behavioural intervention technologies that can be used by cancer survivors independently from a health-care provider is scarce. We aimed to assess the efficacy, reach, and usage of Oncokompas, a web-based eHealth application that supports survivors in self-management by monitoring health-related quality of life (HRQOL) and cancer-generic and tumour-specific symptoms and obtaining tailored feedback with a personalised overview of supportive care options. In this non-blinded, randomised, controlled trial, we recruited patients treated at 14 hospitals in the Netherlands for head and neck cancer, colorectal cancer, breast cancer, Hodgkin lymphoma, or non-Hodgkin lymphoma. Adult survivors (aged ≥18 years) were recruited through the Netherlands Cancer Registry (NCR) and invited by their treating physician through the Patient Reported Outcomes Following Initial Treatment and Long term Evaluation of Survivorship (PROFILES) registry. Participants were randomly assigned (1:1) by an independent researcher to the intervention group (access to Oncokompas) or control group (access to Oncokompas after 6 months), by use of block randomisation (block length of 68), stratified by tumour type. The primary outcome was patient activation (knowledge, skills, and confidence for self-management), assessed at baseline, post-intervention, and 3-month and 6-month follow-up. Linear mixed models (intention-to-treat) were used to assess group differences over time from baseline to 6-month follow-up. The trial is registered in the Netherlands Trial Register, NTR5774 and is completed. Between Oct 12, 2016, and May 24, 2018, 625 (21%) of 2953 survivors assessed for eligibility were recruited and randomly assigned to the intervention (320) or control group (305). Median follow-up was 6 months (IQR 6−6). Patient activation was not significantly different between intervention and control group over time (difference at 6-month follow-up 1·7 [95% CI −0·8–4·1], p=0·41). Oncokompas did not improve the amount of knowledge, skills, and confidence for self-management in cancer survivors. This study contributes to the evidence for the development of tailored strategies for development and implementation of behavioural intervention technologies among cancer survivors. Dutch Cancer Society (KWF Kankerbestrijding).

Many studies already reported on the association between patient characteristics on the severity of COVID-19 disease outcome, but the relation with SARS-CoV-2 antibody levels is less clear. To investigate this in more detail, we performed a retrospective observational study in which we used the IgG antibody response from 11,118 longitudinal antibody measurements of 2,082 unique COVID convalescent plasma donors. COVID-19 symptoms and donor characteristics were obtained by a questionnaire. Antibody responses were modelled using a linear mixed-effects model. Our study confirms that the SARS-CoV-2 antibody response is associated with patient characteristics like body mass index and age. Antibody decay was faster in male than in female donors (average half-life of 62 versus 72 days). Most interestingly, we also found that three symptoms (headache, anosmia, nasal cold) were associated with lower peak IgG, while six other symptoms (dry cough, fatigue, diarrhoea, fever, dyspnoea, muscle weakness) were associated with higher IgG concentrations.

Platelet and leukocyte count reference intervals (RIs) for cattle differ by age and while adult RIs are known, RIs for calves are studied less. The aims of this observational study are to evaluate variation of platelet counts of Holstein Friesian calves over the first 14 days of life and to propose RIs for platelet and leukocyte counts of Holstein Friesian calves aged 0–60 days. In a longitudinal study, 19 calves were blood sampled 17 times, in the first 14 days of their lives. Blood was collected in a citrate blood tube and platelet counts were determined. We assessed the course of platelet counts. In a field study, 457 healthy calves were blood sampled once. Blood was collected in an EDTA blood tube and platelet and leukocyte counts were determined. The RIs were calculated by the 2.5 and 97.5 percentiles. Platelet counts started to increase 24 h after birth (mean platelet count 381 × 109/L ± 138 × 109/L) and stabilized after five days (mean platelet count 642 × 109/L ± 265 × 109/L). In calves up to six days of age, platelet counts were lower than in calves older than five days. In conclusion, the RIs of platelet and leukocyte counts in calves were wider in range than the RIs for adult cattle, therefore, calf specific RIs for platelet and leukocyte counts should be used. From 6 until 60 days of age, we propose an RI for platelet counts of 287–1372 × 109/L and for the first 60 days of life an RI for leukocyte counts of 4.0–18.9 × 109/L.

Background Current risk stratification models for early invasive (T1) colorectal cancer are not able to discriminate accurately between prognostic favourable and unfavourable tumours, resulting in over‐treatment of a large (>80%) proportion of T1 colorectal cancer patients. The tumour‐stroma ratio (TSR), which is a measure for the relative amount of desmoplastic tumour stroma, is reported to be a strong independent prognostic factor in advanced‐stage colorectal cancer, with a high stromal content being associated with worse prognosis and survival. We aimed to investigate whether the TSR predicts clinical outcome in patients with non‐pedunculated T1 colorectal cancer. Methods Haematoxylin and eosin (H&E)‐stained tumour tissue slides from a retrospective multicentre case cohort of patients with nonpedunculated surgically treated T1 colorectal cancer were assessed for TSR by two independent observers who were blinded for clinical outcomes. The primary end point was adverse outcome, which was defined as the presence of lymph node metastasis in the resection specimen or colorectal cancer recurrence during follow‐up. Results All 261 patients in the case cohort had H&E slides available for TSR scoring. Of these, 183 were scored as stroma‐low, and 78 were scored as stroma‐high. There was moderate inter‐observer agreement κ = 0.42). In total, 41 patients had lymph node metastasis, 17 patients had recurrent cancer and five had both. Stroma‐high tumours were not associated with an increased risk for an adverse outcome (adjusted hazard ratio = 0.66, 95% confidence interval 0.37–1.18; p = 0.163). Conclusions Our study emphasises that existing prognosticators may not be simply extrapolated to T1 colorectal cancers, even though their prognostic value has been widely validated in more advanced‐stage tumours.

Neurocysticercosis (NCC) is caused by infection of the brain by larvae of the parasitic cestode Taenia solium . It is the most prevalent parasitic infection of the central nervous system and one of the leading causes of adult-acquired epilepsy worldwide. However, little is known about how cestode larvae affect neurons directly. To address this, we used whole-cell patch-clamp electrophysiology and calcium imaging in rodent and human brain slices to identify direct effects of cestode larval products on neuronal activity. We found that both whole cyst homogenate and excretory/secretory products of cestode larvae have an acute excitatory effect on neurons, which can trigger seizure-like events in vitro . This effect was mediated by glutamate receptor activation but not by nicotinic acetylcholine receptors, acid-sensing ion channels, or Substance P. Glutamate-sensing fluorescent reporters (iGluSnFR) and amino acid assays revealed that the larval homogenate of the cestodes Taenia crassiceps and Taenia solium contained high concentrations of the amino acids glutamate and aspartate. Furthermore, we found that larvae of both species consistently produce and release these excitatory amino acids into their immediate environment. Our findings suggest that perturbations in glutamatergic signalling may play a role in seizure generation in NCC. One of the main causes of epilepsy in adults – particularly in developing countries – is a parasitic brain infection called neurocysticercosis. This can happen when people swallow tapeworm eggs, which hatch into larvae and migrate throughout the body. When these larvae infect the brain, they form structures called cysts, which can cause seizures. It is thought that inflammation in the brain contributes to the development of seizures in neurocysticercosis, but how this might work is still poorly understood. The larvae produce chemicals that can interact with nearby cells in the body, including the defensive cells of our immune system. However, it remains unknown whether those chemicals also interact with brain cells. De Lange, Tomes et al. set out to determine if tapeworm larvae produced any specific chemicals that affect the activity of brain cells, and if they might play a role in epileptic seizures. To do this, the researchers collected materials from tapeworm larvae, which included both the substances they naturally released and a mixture made from crushed whole larvae. They then applied these substances to brain tissue grown in cell culture while recording the electrical activity of individual brain cells. Experiments using brain tissue derived from rats, mice and humans revealed that the larval products made brain cells more excited and led to them firing more electrical signals than normal. This excitation was strong enough to trigger larger patterns of activity across the brain tissue that mimicked the effect of an epileptic seizure. Further biochemical analysis of the larval products and the larvae themselves revealed that tapeworm larvae continuously release a chemical called glutamate, which is known to excite brain cells. These results suggested that tapeworm larvae might cause epilepsy by producing excess glutamate and overexciting brain cells – a mechanism similar to the way that other brain conditions, like tumors, also trigger seizures. This work has revealed a new mechanism for how tapeworm larvae might cause seizures in neurocysticercosis. The next step will be understanding how the larvae release glutamate into the brain, for example, if they actively produce it, or if it is passively released when they die. In the future, de Lange et al. hope this knowledge will help develop new treatments that help prevent seizures in people with neurocysticercosis.