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Salivation is easily taken for granted, but without normal salivation, simple essential tasks such as chewing and swallowing become difficult, with consequences for quality of life, nutrition and oral health. Many important drug classes cause dry mouth as a side effect, contributing substantially to patient non-compliance. Available treatments are mostly palliative. Cannabis user complaints of dry mouth prompted a study that showed that basal salivation is likely regulated by cannabinoid CB1 receptors on neurons that innervate the submandibular gland. But what about stimulated salivation? The adjoining parotid gland releases saliva in response to olfactory or other cues and contributes a large portion of the net salivation in humans. We investigated cannabinoid regulation of stimulated salivation using functional and protein-expression studies in mice. In developing a model of stimulated salivary responses to food-related odorants in mice, we noted sex-dependent responses to food-related cues. Only male mice learned to salivate in response to the odor of peanut butter while only female mice responded to a chocolate hazelnut spread. Both males and females responded to sugar or marmite. Testing peanut butter, we found that the cannabinoid receptor agonist CP55940 (0.5 mg/kg, IP) lowered baseline salivation, as shown previously, but also prevented the odorant-induced increase in salivation. CB1 receptors are expressed in axons innervating the parotid gland, paralleling our findings in the submandibular gland. Notably, we also found that CB1 deletion impaired some responses (those to peanut butter and chocolate hazelnut spread) but not others (sugar or marmite). In mice, the CB1 antagonist SR141716 (4 mg/kg, IP) prevented a previously learned salivary response to peanut butter. We find that CB1 receptors are expressed in a subset of glomeruli in coronal sections of olfactory bulb that may serve as a site of action for scent-specific effects of CB1 receptors. We additionally observe CB1 expression in accessory olfactory bulb. In summary, we find a novel sex-dependence in responses to a subset of food-related odorant cues and that cannabinoid receptors regulate some of these responses. We propose that CB1 receptors act at the parotid gland to inhibit stimulated salivation but also in the olfactory system, where functional CB1 receptors are required for salivary responses to specific appetitive odors., (© 2024. The Author(s).)

The extent to which mental health services for youths embody system-of-care (SOC) principles is an important quality indicator. This study tested whether youth and family experiences of SOC principles varied depending on youths' level of need after adjusting for sociodemographic and treatment factors. The relationship to caregiver-reported clinical outcomes was also examined. Using administrative data and cross-sectional surveys from a stratified random sample of 1124 caregivers of youths ages 5-20 within a statewide system, adjusted analyses indicated caregivers of youths with the most intensive needs were significantly less likely to report receiving care that embodied SOC principles, with deficits on six of nine items. Youths whose services embodied SOC principles experienced significantly greater improvement in caregiver-reported functioning even after adjusting for level of need. Results highlight disparities in SOC principles for youths with intensive needs and the need for policy and intervention development to improve care for this population., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although microsuture neurorrhaphy is the accepted clinical standard treatment for severed peripheral nerves, this technique requires microsurgical proficiency and still often fails to provide adequate nerve approximation for effective regeneration. Entubulation utilizing commercially available conduits may enhance the technical quality of the nerve coaptation and potentially provide a proregenerative microenvironment, but still requires precise suture placement. We developed a sutureless nerve coaptation device, Nerve Tape ® , that utilizes Nitinol microhooks embedded within a porcine small intestinal submucosa backing. These tiny microhooks engage the outer epineurium of the nerve, while the backing wraps the coaptation to provide a stable, entubulated repair. In this study, we examine the impact of Nerve Tape on nerve tissue and axonal regeneration, compared with repairs performed with commercially available conduit-assisted or microsuture-only repairs. Eighteen male New Zealand white rabbits underwent a tibial nerve transection, immediately repaired with (1) Nerve Tape, (2) conduit plus anchoring sutures, or (3) four 9-0 nylon epineurial microsutures. At 16 weeks postinjury, the nerves were re-exposed to test sensory and motor nerve conduction, measure target muscle weight and girth, and perform nerve tissue histology. Nerve conduction velocities in the Nerve Tape group were significantly better than both the microsuture and conduit groups, while nerve compound action potential amplitudes in the Nerve Tape group were significantly better than the conduit group only. Gross morphology, muscle characteristics, and axon histomorphometry were not statistically different between the three repair groups. In the rabbit tibial nerve repair model, Nerve Tape offers similar regeneration efficacy compared with conduit-assisted and microsuture-only repairs, suggesting minimal impact of microhooks on nerve tissue.

In vivo tracking of white matter fibres catalysed a modern perspective on the pivotal role of brain connectome disruption in neuropsychological deficits. However, the examination of white matter integrity in neurological patients by diffusion-weighted magnetic resonance imaging bears conceptual limitations and is not widely applicable, as it requires imaging-compatible patients and resources beyond the capabilities of many researchers. The indirect estimation of structural disconnection offers an elegant and economical alternative. For this approach, a patient's structural lesion information and normative connectome data are combined to estimate different measures of lesion-induced structural disconnection. Using one of several toolboxes, this method is relatively easy to implement and is even available to scientists without expertise in fibre tracking analyses. Nevertheless, the anatomo-behavioural statistical mapping of structural brain disconnection requires analysis steps that are not covered by these toolboxes. In this paper, we first review the current state of indirect lesion disconnection estimation, the different existing measures, and the available software. Second, we aim to fill the remaining methodological gap in statistical disconnection-symptom mapping by providing an overview and guide to disconnection data and the statistical mapping of their relationship to behavioural measurements using either univariate or multivariate statistical modelling. To assist in the practical implementation of statistical analyses, we have included software tutorials and analysis scripts., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To reduce health care facility-onset (HCFO) Clostridioides difficile infection (CDI) incidence by improving diagnostic stewardship and reducing the inappropriate testing of C difficile assays., Patients and Methods: A multidisciplinary team conducted a quality improvement initiative from January 1, 2020, through March 31, 2021. Clostridioides difficile infection and inappropriate testing were identified via electronic health records using predefined criteria related to stool quantity/caliber, confounding medications, and laboratory data. An intervention bundle was designed including (1) provider education, (2) implementation of an appropriate testing algorithm, (3) expert review of C difficile orders, and (4) batch testing of assays to facilitate review and cancellation if inappropriate., Results: Compared with a baseline period from January to September 2020, implementation of our intervention bundle from December 2020 to March 2021 resulted in an 83.6% reduction in inappropriate orders tested and a 41.7% reduction in HCFO CDI incidence., Conclusion: A novel prevention bundle improved C difficile diagnostic stewardship and HCFO CDI incidence by reducing testing of inappropriate orders. Such initiatives targeting HCFO CDI may positively affect patient safety and hospital reimbursement., (© 2021 The Authors.)

Recent resting-state functional MRI studies in stroke patients have identified two robust biomarkers of acute brain dysfunction: a reduction of inter-hemispheric functional connectivity between homotopic regions of the same network, and an abnormal increase of ipsi-lesional functional connectivity between task-negative and task-positive resting-state networks. Whole-brain computational modelling studies, at the individual subject level, using undirected effective connectivity derived from empirically measured functional connectivity, have shown a reduction of measures of integration and segregation in stroke as compared to healthy brains. Here we employ a novel method, first, to infer whole-brain directional effective connectivity from zero-lagged and lagged covariance matrices, then, to compare it to empirically measured functional connectivity for predicting stroke versus healthy status, and patient performance (zero, one, multiple deficits) across neuropsychological tests. We also investigated the accuracy of functional connectivity versus model effective connectivity in predicting the long-term outcome from acute measures. Both functional and effective connectivity predicted healthy from stroke individuals significantly better than the chance-level; however, accuracy for the effective connectivity was significantly higher than for functional connectivity at 1- to 2-week, 3-month and 1-year post-stroke. Predictive functional connections mainly included those reported in previous studies (within-network inter-hemispheric and between task-positive and -negative networks intra-hemispherically). Predictive effective connections included additional between-network links. Effective connectivity was a better predictor than functional connectivity of the number of behavioural domains in which patients suffered deficits, both at 2-week and 1-year post-onset of stroke. Interestingly, patient deficits at 1-year time-point were better predicted by effective connectivity values at 2 weeks rather than at 1-year time-point. Our results thus demonstrate that the second-order statistics of functional MRI resting-state activity at an early stage of stroke, derived from a whole-brain effective connectivity, estimated in a model fitted to reproduce the propagation of neuronal activity, has pertinent information for clinical prognosis., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: The purpose of this feasibility study was to assess whether combined intermittent theta burst suppression (iTBS) applied to the ipsilesional hemisphere and modified constraint-induced aphasia therapy (mCIAT) are safe and logistically feasible within the time interval associated with iTBS induced long-term potentiation in patients with post-stroke aphasia. We also wanted to determine whether combining priming with iTBS and CIAT improves language functions after treatment., Methods: Twelve participants received fMRI (semantic decision/tone decision task) and neuropsychological testing of language skills at three time points - before starting the iTBS/mCIAT intervention (T1), immediately after completing 2-week long course of intervention (T2), and at 3-months follow-up (T3). ITBS was applied to the individually determined fMRI language "hot spot" located in the left fronto-temporal regions., Results: There were no serious adverse events, and all mCIAT group therapy sessions (3-4 subjects each) were initiated within 30 minutes of the first group subject receiving iTBS. Neuropsychological assessments of language showed a significant effect of session on Western Aphasia Battery aphasia quotient (WAB-AQ; p = 0.04) and spontaneously correct responses on Boston Naming Test (BNT; p = 0.002), with improvement noted at T2 (p = 0.002) and T3 (p = 0.05) versus T1. FMRI showed significant changes between all timepoints. Post-hoc correlations showed associations between improvements in WAB-AQ from T2 to T3 and decreased BOLD signal in left inferior parietal lobe, and improvements in BNT from T1 to T3 with decreased signal in right inferior frontal gyrus., Conclusion: This study shows feasibility and safety for combining behavioral and neurostimulation interventions for chronic post-stroke aphasia. Observed changes in linguistic measures were relatively small. However, they were statistically significant and associated with parallel changes observed in the neuroimaging. Our findings support further development and testing of the combined mCIAT and iTBS protocol and comparisons to either CIAT/mCIAT or iTBS applied alone for the treatment of post-stroke aphasia.

This study sought to determine if the site of graduate medical training or other factors impact the length of institutional employment. Physician hires for the home institution were catalogued from January 1, 1996, through December 31, 2006. In analyzing the 253 physician hires, we found no statistically significant advantage in employee retention associated with hiring "one's own" or with U.S. medical school graduates.

Background: In anterior cruciate ligament (ACL) reconstruction, an interference device achieves soft-tissue graft fixation by radially compressing the graft against the bone., Purpose: The objective of this study was to measure the radial force generated by different interference devices and evaluate the effect of this radial force on the pullout strength of graft-device constructs., Study Design: Controlled laboratory study., Methods: A resultant force (F(R)) was used as a representative measure of the total radial force generated. Bovine tendons were fixated in either synthetic bone or porcine tibia using one of following devices: (1) RCI titanium screw, (2) PEEK screw, (3) IntraFix sheath-and-screw device, and (4) ExoShape sheath-and-insert device. F(R) was measured while each device was inserted into synthetic bone mounted on a test machine (n=5 for each device). In a subsequent test series, graft-device constructs were loaded to failure at 50mm/min. The pullout strength was measured as the ultimate load before failure (n=10 for each device)., Results: The F(R) values generated during insertion into synthetic bone were 777 ± 86N, 865 ± 140N, 1313 ± 198N, and 1780 ± 255N for the RCI screw, PEEK screw, IntraFix, and ExoShape, respectively. The pullout strengths in synthetic bone for the RCI screw, PEEK screw, IntraFix and ExoShape were 883 ± 125N, 716 ± 249N, 1147 ± 142N, and 1233 ± 190N, respectively., Conclusions: These results suggest that the F(R) generated during interference fixation affects the pullout strength with sheath-based devices providing superior F(R) compared with interference screws. The use of synthetic bone was validated by comparing the pullout strengths to those when tested in porcine tibia., Clinical Relevance: These results could be valuable to a surgeon when determining the best fixation device to use in the clinical setting., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Studies performed to quantify the pullout strength of suture anchors have not adequately defined the basic device parameters that control monotonic pullout. The bearing area of a suture anchor can be used to understand and predict anchor pullout strength in a soft-bone model. First, conical-shaped test samples were varied in size and shape and tested for pullout in 5, 8, and 10 pcf sawbone models. Next, bearing area and pullout strength relationships developed from the test samples were validated against nine commercially available suture anchors, including the Mitek QuickAnchor and SpiraLok, Opus Magnum(2), ArthroCare ParaSorb, and Arthrex BioCorkscrew. The samples showed a direct correlation between bearing area and pullout strength. Increased insertion depth was a secondary condition that also increased pullout strength. The pullout strength for the suture anchors followed the predicted trends of conical devices based on their individual bearing areas. For the 5 and 8 pcf models, only two and three devices, respectively, fell outside the predicted pullout strength range by more than a standard deviation. The use of a synthetic sawbone model was validated against the pullout strength of an Arthrex Corkscrew in five fresh-frozen cadaver humeral heads. The bearing area of a suture anchor can be used to predict the pullout strength independent of design in a soft-bone model. This work helps provide a foundation to understand the principles that affect the pullout strength of suture anchors., (Copyright 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Enterotoxigenic strains of Bacteriodes fragilis (ETBF) have recently been found to be associated with diarrheal illness in Apache and Bangladeshi children. This study was conducted to define the role of ETBF in diarrhea of children in an urban setting. Fecal specimens from 991 children with diarrhea and 581 asymptomatic age-matched controls were cultured for B. fragilis (BF). The isolates were tested for enterotoxin production using a human colonic epithelial cell line. BF was isolated from 318 (32.1%) of the patients and 123 (21.2%) of the controls (p < 0.001). In children < 1 year old which comprised about 50% of both patients and controls, the BF isolation rates were comparable (26.5% vs 25.7%; p = 0.812), contrasting with the significant difference in isolation rates for children > or = 1 year (37.6% vs 16.5%; p = < 0.001). Overall, ETBF were identified in 4.4% of patients and 3.1% of controls (p = 0.2). However, ETBF were significantly associated with diarrheal disease in children 1-5 years (5.4% vs 1.8%; p = 0.033) and 1-10 years (4.8% vs 1.5%; p = 0.021) in age. ETBF were isolated the year round and comprised 14.4% and 15% of the BF isolated from the patients and controls, respectively, suggesting that part of the indigenous BF are inherently enterotoxin producers. In this study, BF and ETBF were associated with diarrheal illness in children 1-10 years old.

Chronic hemodialysis (HD) leads to significant losses of carnitine from plasma and muscle. Because L-carnitine is important in the production of energy from fatty acid oxidation (FAO) in muscle, we examined the role of carnitine replacement by administering therapeutic doses of intravenous carnitine to 14 male patients receiving HD. Placebo or carnitine was given 2 g i.v. 3 times weekly for 6 months in a double-blind manner. To evaluate long-term toxicity of carnitine, all patients subsequently received 1 g i.v. carnitine for 10 months. Patients were rated for muscle strength each week. After 6 months, definite improvement in strength occurred in 4 of 7 carnitine-treated patients and in none of 7 controls. During the subsequent 10 months of carnitine administration, no adverse effects were noted and muscle strength improved in 9 of 14 patients. Muscle biopsy was performed in 13 patients before and after the first 6 months of treatment and in 6 healthy controls. FAO and carnitine were measured in each muscle biopsy. FAO was significantly lower in both carnitine- and placebo-treated HD patients compared to healthy controls. Although carnitine therapy increased the muscle concentration of carnitine 3-fold in muscle of HD patients, muscle FAO did not increase significantly and never reached the level of healthy controls. Muscle histopathology and ultrastructure were not specific for HD myopathy. Carnitine may be useful in treating some patients with muscle weakness related to HD.

The single-dose pharmacokinetics of two dosages of imipenem-cilastatin (1:1), 10 and 25 mg/kg, were studied in ten children. Plasma concentrations, half-lives, and areas under the curve of both imipenem and cilastatin was significantly greater at the 25 mg/kg dosage but the half-lives and clearances of the two drugs were similar to each other only at the larger dose. After a 25 mg/kg dose, the mean peak and trough (6 hr) plasma concentrations of imipenem were 78.8 and 0.68 micrograms/ml, respectively, and the half-lives of imipenem and cilastatin were 1.12 and 0.97 hr, respectively. Urinary excretion of imipenem was 43-47% during the 6 hr following administration of either dosage. No clinical or laboratory toxicity was noted. A 25 mg/kg dose of imipenem-cilastatin maintains serum concentrations of imipenem above the minimum inhibitory concentration (MIC) of potential pathogens for 4-6 hr and seems appropriate for multiple-dose studies. Our data suggest that a minimum dosage, greater than 10 mg/kg, of cilastatin may be required to prolong the half-life of imipenem to adult values.

A retrospective study of 6 years (1981-1987) experience with clinical specimens of pediatric patients submitted for identification of respiratory viruses was undertaken to determine the prevalence of multiple viral isolates and to assess the impact of dual infections on severity of clinical disease. Respiratory Syncytial Virus (RSV), the most frequently identified agent, was detected in cell culture and/or by immunofluorescence (IF) in 666 of 2,415 specimens examined. A second virus was isolated in cell cultures from 51 of the 666 specimens (7.6%). Cytomegalovirus, rhinoviruses, adenoviruses, influenza and parainfluenza viruses, echoviruses, vaccine strain polio viruses, and herpes simplex virus were identified with RSV. The diagnosis of a dual viral infection would have been missed in 37 of 51 instances (79%) had rapid diagnosis for RSV been employed without inoculation of cell cultures. Demographics and clinical presentations were similar in patients with dual infections or RSV alone. A case-control study comparing patients with dual isolates and patients with RSV alone to determine the effect of multiple viral infections on severity of disease revealed no significant difference. The combined use of rapid methods and isolation in culture provides more complete viral diagnosis and could have an impact on the choice of antiviral agents and the institution of appropriate infection control measures.