Human brain mapping using co-registered fUS, fMRI and ESM during awake brain surgeries: A proof-of-concept study.

Accurate, depth-resolved functional imaging is key in both understanding and treatment of the human brain. A new sonography-based imaging technique named functional Ultrasound (fUS) uniquely combines high sensitivity with submillimeter-subsecond spatiotemporal resolution available in large fields-of-view. In this proof-of-concept study we show that: (A) fUS reveals the same eloquent regions as found by fMRI while concomitantly visualizing in-vivo microvascular morphology underlying these functional hemodynamics and (B) fUS-based functional maps are confirmed by Electrocortical Stimulation Mapping (ESM), the current gold-standard in awake neurosurgical practice. This unique cross-modality experiment was performed using motor, visual and language-related functional tasks in patients undergoing awake brain tumor resection. The current work serves as an important milestone towards further maturity of fUS as well as a novel avenue to increase our understanding of hemodynamics-based functional brain imaging.

Determining the protocol requirements of in-home cat food digestibility testing.

In-home cat food digestibility testing has the potential to yield data that are highly representative of the pet population for which the food is intended. However, no standardized and validated in-home digestibility test protocols are currently available. Such protocols for in-home testing should address key factors that explain variation in cat food digestibility values and here we investigated the required period of adaptation, fecal collection and sample sizes. Thirty privately-owned indoor housed cats of various breeds (20♀ 10♂, 5.9 ± 3.9 yr, 4.5 ± 1.3 kg) received a relatively low and high digestible complete dry extruded food with the marker titanium (Ti) dioxide. Foods were given in a cross-over design of 2 periods of 8 consecutive days each. Owners collected feces daily for the determination of daily fecal Ti concentrations and digestibility of dry matter, crude protein, crude fat, and gross energy. Data originating from 26 cats were analyzed as mixed models and broken line regressions to investigate the required adaptation and fecal collection period. Bootstrap sampling was used to assess the impact of increasing the number of fecal collection days and sample size on the precision of the digestibility estimates. Feces were collected on 347 out of 416 study days (16 days/cat; 26 cats), implying the necessity for multiple collection days to account for cats not defecating every day. Cats showed stable fecal marker concentrations from day 2 onwards when fed the low digestible food and from 3 onwards when fed the high digestible food. Digestibility values were stable from day 1, 2 or 3 onwards, depending on the test food and nutrient. Increasing the number of fecal collection days from 1 to 6 days did not result in more precise digestibility estimates, whereas increasing the number of animals from 5 to 25 cats did. For future in-home digestibility tests of cat food, the findings support a minimum of 2 adaptation days and 3 fecal collection days. Appropriate sample sizes depend on the test food, the nutrient of interest, and the acceptable margin of error. The findings of this study support the protocol development for future in-home digestibility testing of cat foods.

Risk of Four Geriatric Syndromes: A Comparison of Mental Health Care and General Hospital Inpatients.

An observational, cross-sectional study is conducted to compare elevated risk scores of four geriatric syndromes (falls, malnutrition, physical impairment, delirium) in older hospitalized psychiatric patients (n=178) with patients hospitalized in a general hospital (n=687). The median age of all patients was 78 years (IQR 73.3-83.3), 53% were female. After correction for age and gender, we found significantly more often an elevated risk in the mental health care group, compared to the general hospital group of falls (Odds Ratio (OR) = 1.75; 95% Confidence Interval (CI) 1.18-2.57), malnutrition (OR = 4.12; 95% CI 2.67-6.36) and delirium (OR = 6.45; 95% CI 4.23-9.85). The risk on physical impairment was not statistically significantly different in both groups (OR = 1.36; 95% CI .90-2.07). Older mental health care patients have a higher risk to develop geriatric syndromes compared to general hospital patients with the same age and gender, which might be explained by a higher level of frailty.

A dual marker technique to estimate individual feed intake in young pigs.

Accurate estimation of individual feed intake (FI) of pigs could help better understand the variation in performance between individual animals. We studied dual marker methods to estimate individual FI in pigs. This method is based on the measurement of the ratio between two indigestible markers in faeces. Twelve 6.5-week-old individually housed male pigs were assigned to one of three oral dosing treatments supplying 180 mg of ytterbium chloride (YbCl3)/day and 111 mg of dotriacontane (C32)/day as reference markers, either once (R1), three times (R3) or five times (R5) daily. Pigs were offered a diet containing 0.46 g/kg of chromium chloride (CrCl3) and 0.15 g/kg of hexatriacontane (C36) as in-feed markers. The experiment lasted for 10 days: days -5 to 0: adaptation; days 1-3: dosing of reference marker; days 2-4: total faecal collection. Spot faecal samples were taken on day 3 at 1200 h, 1700 h and on day 4 at 0700 h. Pigs were fed restrictedly three times daily, at 133.6 g/kg BW0.60. Individual measured FI was recorded daily and was compared to predicted FI using the ratio of the dual marker pairs (Yb:Cr and C32:C36), both in total faecal collection and spot samples. Due to unequal variance, R1 pigs were omitted from the statistical treatment comparison. When using total faecal collection samples, the absolute prediction error (APE) (predicted FI minus measured FI) in R3 and R5 pigs was numerically lower than in R1 pigs, regardless of the marker pair used. The APE measured by C32:C36 was numerically lower than measured by Yb:Cr at all frequencies, and significantly (P = 0.039) in R3 pigs (C32:C36: 0.15 ± 0.02 kg/day; Yb:Cr: 0.29 ± 0.04 kg/day). This was related to a larger difference in faecal recovery between Yb and Cr compared with C32 and C36. Daily total faecal collection revealed that for R3 pigs, starting faecal collections 2 days after the onset of provision of the reference marker improved the APE when compared with starting after 1 day. When using C32:C36 to predict feed intake, pooled, but not single spot samples gave similar APEs compared with total faecal collections. Therefore, we recommend dosing the reference marker three times per day for 2 days on days 1 and 2, combined with pooled spot faecal sampling collected on days 3 and 4. In this way, absolute prediction errors of 10%-15% of simultaneously measured intakes of multiple nutrient resources in a complex housing system are feasible using the dual marker technique.

Exploring temporal relationships among worrying, anxiety, and somatic symptoms.

OBJECTIVES: The role of anxiety symptoms in the development of functional somatic symptoms (FSS) is unknown. Somatic symptoms may be triggered by or give rise to anxiety symptoms. This study aimed to 1) explore interrelationships among within-day worrying, feeling anxious, and somatic symptoms, and 2) investigate the association between these interrelationships and overall level of FSS. METHODS: This study included 767 participants (83% females, mean age 39 years), who were recruited through an online crowdsourcing study in the Dutch general population. Somatic, and anxiety symptoms were reported thrice daily (6-h intervals) for 30 days using electronic diaries. FSS were assessed at baseline (PHQ-15). Temporal relationships among worrying, feeling anxious, and somatic symptoms were modeled using a multilevel vector autoregressive model. RESULTS: We observed large heterogeneity in the within-person interrelationships among worrying, feeling anxious and somatic symptoms. Averaged over participants, higher-than-usual somatic symptoms were associated with increases in levels of worrying six hours later (B = 0.017, 95% CI [0.006, 0.027]). At the between-person level, FSS levels predicted the persistence of feeling anxious (B = 0.230 95% CI [0.105, 0.350]) and the carry-over of worrying to feeling anxious over six-hours (B = 0.159, 95% CI [0.031, 0.283]). CONCLUSIONS: In contrast to what we expected, higher levels of somatic symptoms over multiple weeks were associated with the persistence and carry-over of within-day anxiety-related symptoms. One within-person association between psychological and somatic symptoms during the day was observed, suggesting that, over a time span of 6-h, anxiety symptoms relate to somatic symptoms only in a minority of people from the general population.

Bayesian cosmic density field inference from redshift space dark matter maps.

We present a self-consistent Bayesian formalism to sample the primordial density fields compatible with a set of dark matter density tracers after a cosmic evolution observed in redshift space. Previous works on density reconstruction did not self-consistently consider redshift space distortions or included an additional iterative distortion correction step. We present here the analytic solution of coherent flows within a Hamiltonian Monte Carlo posterior sampling of the primordial density field. We test our method within the Zel'dovich approximation, presenting also an analytic solution including tidal fields and spherical collapse on small scales. Our resulting reconstructed fields are isotropic and their power spectra are unbiased compared to the true field defined by our mock observations. Novel algorithmic implementations are introduced regarding the mass assignment kernels when defining the dark matter density field and optimization of the time-step in the Hamiltonian equations of motions. Our algorithm, dubbed barcode, promises to be specially suited for analysis of the dark matter cosmic web down to scales of a few megaparsecs. This large-scale structure is implied by the observed spatial distribution of galaxy clusters - such as obtained from X-ray, Sunyaev-Zel'dovich, or weak lensing surveys - as well as that of the intergalactic medium sampled by the Ly α forest or perhaps even by deep hydrogen intensity mapping. In these cases, virialized motions are negligible, and the tracers cannot be modelled as point-like objects. It could be used in all of these contexts as a baryon acoustic oscillation reconstruction algorithm.

pH-responsive poly(lactide-co-glycolide) nanoparticles containing near-infrared dye for visualization and hyaluronic acid for treatment of osteoarthritis.

This study focuses on intra-articular (IA) drug delivery system for the treatment of knee osteoarthritis (OA). In osteoarthritic condition the synovial fluid presents pockets with lower pH environment. To take advantage of these pH differences, poly(lactic-co-glycolic acid (PLGA) nanoparticles (NPs) and pH- responsive PLGA NPs encapsulated with ammonium bicarbonate (NH4HCO3) were generated. The nanoparticles were loaded with hyaluronic acid (HA) as a possible model drug for OA and with near-infrared dye (NIR) that was used to visualize the NPs with molecular imaging techniques. These NPs were characterized by dynamic light scattering, transmission electron microscopy and compared in in vitro, in vivo and ex vivo experiments in the treatment of OA. The results indicate that the NPs were sufficiently small, displayed a uniform size distribution and were non-toxic both in vitro and in vivo. Both NPs treatment seem to induced a reduction in OA progression, with pH- responsive NPs showing the more pronounced effect. This is probably because the pockets of low pH environment in the synovial fluid trigger a burst release of the pH-responsive NPs. This result is corroborated by in vitro experiments since the pH- responsive NPs showed an extracellular burst release behavior and higher chondrocyte vitality than non-responsive NPs. This study demonstrates that PLGA NPs containing HA and NH4HCO3 are candidates for the treatment of knee OA.

Subtyping psychological distress in the population: a semi-parametric network approach.

AIMS: The mechanisms underlying both depressive and anxiety disorders remain poorly understood. One of the reasons for this is the lack of a valid, evidence-based system to classify persons into specific subtypes based on their depressive and/or anxiety symptomatology. In order to do this without a priori assumptions, non-parametric statistical methods seem the optimal choice. Moreover, to define subtypes according to their symptom profiles and inter-relations between symptoms, network models may be very useful. This study aimed to evaluate the potential usefulness of this approach. METHODS: A large community sample from the Canadian general population (N = 254 443) was divided into data-driven clusters using non-parametric k-means clustering. Participants were clustered according to their (co)variation around the grand mean on each item of the Kessler Psychological Distress Scale (K10). Next, to evaluate cluster differences, semi-parametric network models were fitted in each cluster and node centrality indices and network density measures were compared. RESULTS: A five-cluster model was obtained from the cluster analyses. Network density varied across clusters, and was highest for the cluster of people with the lowest K10 severity ratings. In three cluster networks, depressive symptoms (e.g. feeling depressed, restless, hopeless) had the highest centrality. In the remaining two clusters, symptom networks were characterised by a higher prominence of somatic symptoms (e.g. restlessness, nervousness). CONCLUSION: Finding data-driven subtypes based on psychological distress using non-parametric methods can be a fruitful approach, yielding clusters of persons that differ in illness severity as well as in the structure and strengths of inter-symptom relationships.

Adjuvant androgen deprivation therapy for poor-risk, androgen receptor-positive salivary duct carcinoma.

AIM: Salivary duct carcinoma (SDC), an aggressive subtype of salivary gland cancer, is androgen receptor (AR)-positive in 67-96% of cases. In patients with locally recurrent and metastatic (R/M) AR-positive SDC, androgen deprivation therapy (ADT) has an overall response rate of 18-64.7%. In this study, we describe the efficacy of adjuvant ADT in patients with poor-risk (stage 4a) AR-positive SDC. METHODS: This is a retrospective cohort study in which patients with stage 4a AR-positive SDC were offered adjuvant ADT, i.e. bicalutamide, luteinizing hormone-releasing hormone (LHRH) analogue or a combination of these after tumour resection. In the control group, data were collected on patients with stage 4a SDC who underwent a tumour resection but did not receive adjuvant ADT. RESULTS: Twenty-two AR-positive SDC patients were treated with adjuvant ADT for a median duration of 12 months. The control group consisted of 111 SDC patients. After a median follow-up of 20 months in the ADT-treated patients and 26 months in the control group, the 3-year disease-free survival (DFS) was estimated as 48.2% (95% confidence interval [CI] 14.0-82.4%) and 27.7% (95% CI 18.5-36.9%) (P = 0.037). Multivariable Cox regression analysis showed a hazard ratio of 0.138 (95% CI 0.025-0.751, P = 0.022) for DFS and 0.064 (95% CI 0.005-0.764, P = 0.030) for overall survival (OS) in favour of the ADT-treated patients. CONCLUSION: Poor-risk, AR-positive SDC patients who received adjuvant ADT have a significantly longer DFS compared with patients in the control group, who did not receive adjuvant ADT. For OS, this was just below and above the significance level, in case there was or was no correction for confounders.

Haematoma and abscess after neuraxial anaesthesia: a review of 647 cases.

Although rare, spinal haematoma and abscess after central neuraxial blocks may cause severe permanent neurological injury. Optimal treatment and outcome remain unclear. In order to identify possible predisposing patient characteristics and describe the ensuing clinical course, we searched Medline, Embase, and the Cochrane Library for reports of spinal haematomas and abscesses associated with central neuraxial blocks. Extracted data included patient characteristics, symptoms, treatment, and outcome. We analysed 409 reports, including 647 patients (387 patients with spinal haematoma and 260 patients with spinal abscess). Spinal haematoma and abscess occurred predominantly after epidural anaesthesia (58% and 83%, respectively). Neurological recovery was correlated with the severity of initial neurological deficit. When decompression of spinal haematoma was delayed for >12 h after clinical diagnosis, neurological outcome was worse compared with earlier decompression (odds ratio 4.5, 95% confidence interval 2.1-9.9, P<0.001, n=163). After spinal haematoma, 47% of published patients had full recovery, 28% had partial recovery, and in 25% no recovery was observed. Good outcome after conservative management was observed in patients with mild symptoms or with spontaneous recovery during the diagnostic and therapeutic workup. After spinal abscess, 68% of reported patients recovered fully, 21% showed partial recovery, and no recovery was reported in 11%. Persistent neurological symptoms after spinal haematoma and abscess are common and correlate with the severity of initial neurological deficit. Neurological outcome seems worse when decompressive surgery of haematoma is delayed. Notwithstanding the considerable risk of selection bias and publication bias, conservative management may be feasible in patients with mild symptoms or spontaneous recovery.

Oral cholera vaccination promotes homing of IgA+ memory B cells to the large intestine and the respiratory tract.

Oral cholera vaccination is used to induce immune responses in the intestines to protect against cholera infection. However, oral vaccination may also affect immune responses in other mucosal tissues. To study this, tissue-specific homing potential and kinetics of B-cell responses were characterized after oral cholera vaccination. Healthy adult volunteers received two doses of Dukoral® and blood, saliva, nasal wash, and fecal samples were collected over time to detect vaccine-specific antibodies. Additionally, homing potential of lymphocytes to small intestine, colon, airways, skin, and periphery was measured by expression of Integrin ß1 and ß7, CCR9, CCR10, CCR7, and CLA. After vaccination, antibody responses to cholera toxin B (CTB) and Dukoral® were detected in serum and nasal wash. CTB-specific memory B cells in peripheral blood and tissue homing profiles of memory B cells peaked at day 18. IgA+ memory B cells expressed markers that enable homing to the airways and colon, while IgA- memory B cells primarily expressed small-intestine-homing markers. These data show that oral cholera vaccination has a differential effect on immune responses in various mucosal sites, including the respiratory tract.

Functioning before and after a major depressive episode: pre-existing vulnerability or scar? A prospective three-wave population-based study.

BACKGROUND: The vulnerability hypothesis suggests that impairments after remission of depressive episodes reflect a pre-existing vulnerability, while the scar hypothesis proposes that depression leaves residual impairments that confer risk of subsequent episodes. We prospectively examined vulnerability and scar effects in mental and physical functioning in a representative Dutch population sample. METHODS: Three waves were used from the Netherlands Mental Health Survey and Incidence Study-2, a population-based study with a 6-years follow-up. Mental and physical functioning were assessed with the Medical Outcomes Study Short Form (SF-36). Major depressive disorder (MDD) was assessed with the Composite International Diagnostic Interview 3.0. Vulnerability effects were examined by comparing healthy controls (n = 2826) with individuals who developed a first-onset depressive episode during first follow-up but did not have a lifetime diagnosis of MDD at baseline (n = 181). Scarring effects were examined by comparing pre- and post-morbid functioning in individuals who developed a depressive episode after baseline that was remitted at the third wave (n = 108). RESULTS: Both mental (B = -5.4, s.e. = 0.9, p < 0.001) and physical functioning (B = -8.2, s.e. = 1.1, p < 0.001) at baseline were lower in individuals who developed a first depressive episode after baseline compared with healthy controls. This effect was most pronounced in people who developed a severe episode. No firm evidence of scarring in mental or physical functioning was found. In unadjusted analyses, physical functioning was still lowered post-morbidly (B = -5.1, s.e. = 2.1, p = 0.014), but this effect disappeared in adjusted analyses. CONCLUSIONS: Functional impairments after remission of depression seem to reflect a pre-existing vulnerability rather than a scar.

[DoNTRuN a neurosurgical trainee network; network for the advancement of clinical research]. / DoNTRuN, een neurochirurgisch assistentennetwerk.

There is a lot of research into the effectiveness of interventions, but good evidence for many interventions is missing. This is very true of simple and frequently performed treatments. These interventions are often done by trainees in the course of their specialist training, and for this reason they are in a unique position to carry out research into them. There are far fewer high-quality, multicentre clinical trials in the surgical specialisations than in any other specialisation. As trainee neurosurgeons, we are of the opinion that this can be improved upon. With the establishment of the Dutch Neurosurgical Trainee Research Network (DoNTRuN), a national network, we are aiming to initiate and carry out new clinical trials. This initiative, which is currently unique in the Netherlands, will not only enable us to set up multicentre clinical trials relatively simply, but will also educate trainees in the carrying out of thorough clinical research, an area neglected in the current training program.

Correlative light and electron microscopy reveals discrepancy between gold and fluorescence labelling.

Electron microscopy (EM) is traditionally employed as a follow-up to fluorescence microscopy (FM) to resolve the cellular ultrastructures wherein fluorescently labelled biomolecules reside. In order to translate the information derived from FM studies to EM analysis, biomolecules of interest must be identified in a manner compatible with EM. Although fluorescent signals can serve this purpose when FM is combined with EM in correlative light and electron microscopy (CLEM), the traditional immunogold labelling remains commonly used in this context. In order to investigate how much these two strategies relate, we have directly compared the subcellular localization of on-section fluorescence labelling with on-section immunogold labelling. In addition to antibody labelling of LAMP-1, bioorthogonal click labelling was used to localize soluble cysteine cathepsins or membrane-associated sialylated glycans. We reveal and characterize the existence of inherent discrepancies between the fluorescence signal and the distribution of gold particles in particular in the case of membrane-associated antigens.