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Terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase which in vitro adds deoxynucleotides to the 3' OH end of a primer without a template. This function and its distribution in bone marrow pre-T cells and thymocytes suggest a role for this enzyme in the development of the immune system. We measured TdT activity in thymus biopsy specimens of patients with immunodeficiency disease to gain possible insight into the biology of this enzyme and/or the pathogenesis of immune deficient states. Thymuses from four patients with severe combined immunodeficiency disease (SCID) and one with DiGeorge syndrome were assayed for enzyme activity with and without ATP, a specific inhibitor of TdT. In two patients with SCID, specific enzyme activity (pmol/0.5 g tissue) was 50 and 157%, respectively, of age and sex-matched controls; one patient had no enzyme activity. TdT activity in the only adenosine deaminase deficient patient was 23% and was not inhibited by ATP. Crude extract from the DiGeorge thymus had 42% activity, but was not tested with ATP. Purification of crude extracts by DEAE, phosphocellulose and oligodT chromatography was performed to determine if specific enzyme activity had been masked. After phosphocellulose chromatography, ATP noninhibitable activity was removed from one fraction pool in one patient, but not from a second pool. Two other patients had TdT activity in low salt eluates (0.05 M KCl) rather than where expected. Purification of these samples by oligodT chromatography resulted in specific enzyme activity comparable to age-matched controls. The known inhibition of TdT activity by ATP suggests that the nucleotides and deoxynucleotides which accumulate in lymphocytes in SCID may account for the abnormal TdT activity seen in these patient specimens. Examination of TdT activity in immunodeficient patients may allow delineation of this enzyme's biological function.

Terminal deoxynucleotidyl transferase activity was studied in 42 whole human thymuses of different ages (2 days to 70 years). The results indicate that enzyme activity is high perinatally, falls soon after birth, rises to maximal activity early in life, and falls thereafter. Enzyme activity in homologous thymocytes of 9 thymuses ranging from 2 days to 105 months was also determined. The relative enzyme activity (thymocyte/thymus) did not remain constant with age. These results suggest that age-related changes in thymus terminal transferase activity occur which do not reflect a simple coordinate regulation of thymocyte and non-thymocyte elements.

PURPOSE: To estimate the prevalence of chronic fatigue syndrome (CFS) and describe characteristics of other fatiguing illnesses in adolescents (aged 12 through 17 years). METHODS: We conducted a random digit dialing survey of the residents of Wichita, Kansas. Adults identified fatigued adolescents in the household and answered questions relating to the child's health. Selected adolescents were invited to attend a clinic with a parent/guardian. After clinical evaluation they were classified as CFS or another fatigue state as defined in the 1994 CFS definition. Annual telephone interviews and clinical evaluations monitored subjects' fatigue status. Data were analyzed using the Kruskal-Wallis test, the Mantel-Haenszel test, and the exact McNemar test. RESULTS: The survey contacted 34,018 households with 90,316 residents. Of 8586 adolescents, 138 had fatigue for > or =1 month and most (107 or 78%) had chronic fatigue (> or =6 months) at some point during the 3-year follow-up. Twenty-eight had exclusionary diagnoses. Thirty-one were considered to have a CFS-like illness and were invited for clinical evaluation. Eleven agreed to participate and none met the CFS case definition. The baseline weighted prevalence of CFS-like illness was 338 per 100,000. Significant differences existed between parental and adolescents' descriptions of illness. CONCLUSIONS: The prevalence of CFS among adolescents was considerably lower than among adults. Evaluation of CFS in adolescents must consider both parent and patient perception of fatigue and other illnesses that might explain the symptom complex. [ABSTRACT FROM AUTHOR]

Pain complaints (myalgia, arthralgia, headache, sore throat) are commonly associated with chronic fatigue syndrome (CFS), yet to date, these patients' responses to standardized measures of pain perception have not been investigated. Pain perception was measured by pressure dolorimeter and ice water cold pressor tests, and the McGill Pain Questionnaire among 15 female subjects with CFS, 11 subjects with Major Depression and 11 healthy controls. No differences were found between the groups for pain threshold or intolerance levels on the pressure dolorimeter and cold pressor tests. CFS and depressed subjects endorsed significantly more selfreported pain complaints than did control subjects. Although more pain complaints were predicted by greater somatization and lower health perceptions, pain threshold and intolerance were not associated with psychiatric symptoms or functional status. The study yielded some interesting preliminary observations related to variability in pain tolerance among CFS patients. These preliminary observations are discussed in terms of the need for future research and their potential implications for treatment and coping with the illness. [ABSTRACT FROM AUTHOR]

The latest strategies for treating symptoms of chronic fatigue syndrome include graduated exercise and cognitive behavior therapy. Meanwhile, the National Institutes of Health is committed to uncovering a biological cause for the syndrome. [ABSTRACT FROM AUTHOR]

Many pieces are still missing from the puzzle of chronic fatigue, but new diagnostic and management strategies are emerging. You can help with this troubling ailment, symptomatically and psychologically. Here's how. [ABSTRACT FROM AUTHOR]

End of life (EoL) and refractory symptom management is a growing clinical topic and there is minimal literature to support effective treatment strategies, especially in individuals with a substance use disorder or opioids and/or benzodiazepine tolerance. We report the successful use of phenobarbital for proportionate EoL sedation in a 57-year-old man with opioid use disorder (heroin) and metastatic urothelial carcinoma presenting to an acute care hospital with intractable back pain related to bone metastases. During his hospitalization, his daily opioid requirement exceeded 1 gram of morphine equivalent daily dose (MEDD) with suboptimal pain control. The patient's clinical course was complicated by active heroin withdrawal, psychosocial suffering, and disease progression. Despite use of high-dose opioids and benzodiazepines, pain and anxiety were poorly controlled. After an acute medical decompensation, a goals of care discussion was held with his family and a determination with informed consent was made to change patient status to do not attempt resuscitation and proportionate sedation with phenobarbital was initiated to target refractory pain and agitation. Phenobarbital was continued for approximately 15 hours before patient peacefully died. Findings from this case report demonstrate the successful use of phenobarbital in opioid use disorder and benzodiazepine tolerance with intractable pain.

Objective: To examine the measured contents of over-the-counter (OTC) and prescription (Rx) prenatal multivitamins and minerals (PMVMs) and compare the findings with the amounts reported on the nutrition labels. The findings were subsequently examined on the basis of cost and ability to adequately supplement dietary intake during pregnancy on the basis of The National Academies' dietary reference intakes (DRIs) and tolerable upper intake levels., Methods: This was an observational convenience sample of OTC and Rx PMVMs available through online retailers and retail pharmacies. The amounts of folic acid, vitamin B 6 , vitamin C, and choline were measured in triplicate using mass spectrometry., Results: Twenty OTC and 16 Rx PMVMs were evaluated. The average measured quantities of the vitamins were not statistically different from the mean reported quantities for OTC and Rx PMVMs. When a standard diet was combined with the labeled nutrition information, 95% of the OTC PMVMs and 88% of the Rx PMVMs met the DRIs for folic acid and vitamins B 6 and C. When a standard diet was combined with the actual measured PMVM quantities, 79% of the OTC PMVMs and 82% of the Rx PMVMs met the DRIs for folic acid and vitamins B 6 and C. The measured choline content, with and without diet considerations, did not meet the DRIs. No statistically significant difference was found for the adequacy of supplementation between the OTC and Rx PMVMs on the basis of cost., Conclusion: On the basis of a comparison of the measured and reported values for folic acid, vitamin C, vitamin B 6 , and choline, it seems that either OTC or Rx PMVMs at low or high cost can be recommended to supplement diets and meet the DRIs during pregnancy for these vitamins., (Copyright © 2021 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Compared to those without depression, acutely-ill patients with depression hospitalized for an infection usually have poor outcomes, including increased length of stay (LOS)., Purpose: The primary objective was to evaluate the LOS between patients receiving an anti-infective with and without any antidepressant use. Secondary objectives were to examine LOS based on acuity of care and age., Methods: Using a cross-sectional design, hospitalized adult patients who received anti-infective agents between January 1, 2017 and October 31, 2019 for ≥7 days were included. Univariate and multivariate analyses were conducted to determine statistical significance., Results: A total of 17,651 patient encounters were included in the study. Of all patient encounters, 5165 (29%) received antidepressants concurrently with anti-infectives, with mean age of 57 years ± 17.3. Patients receiving concurrent antidepressants experienced longer LOS compared with patients not receiving antidepressants [20 vs 16 days, 95% confident interval (CI): 3.98-5.18, p < 0.001]. Stratified by intensive care unit (ICU) admission during hospital encounters and age ≥ 65 years, patients receiving antidepressants had longer LOS (25 vs 18 days, CI: 5.63-8.61, p < 0.001, and 18 vs 15 days, CI: 2.39-4.04, p < 0.001, respectively). After controlling for gender and ethnicity, antidepressant use and ICU admission were independently associated with increased LOS., Conclusion: Patients who received both an antidepressant and an anti-infective agent had significantly increased LOS, including those in the ICU and in the elderly population. Future studies are needed to assess the impact of concomitant antidepressant use on mortality and other clinical outcomes in patients hospitalized with an infection., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The opioid epidemic is a public health crisis that continues to impact healthcare in the United States of America (USA). While changes in opioid prescribing have curbed the medical use of opioids, the increase in nonmedical use, largely driven by injection drug use (IDU), has contributed to the escalating incidence of opioid use disorder (OUD). Furthermore, IDU is associated with high-risk injection practices that can increase the risk of acquiring viral and bacterial infections. Here in this comprehensive review, we aimed to summarize the epidemiology and management of OUD, along with the screening and antimicrobial treatment of associated infections, specifically focused on human immunodeficiency virus, hepatitis C virus, skin and soft tissue infections, endocarditis, and osteomyelitis. Medication-assisted therapy (MAT) and infection guidelines from the USA will be presented.

Background: As the most commonly occurring form of mental illness worldwide, depression poses significant health and economic burdens to both the individual and community. Different types of depression pose different levels of risk. Individuals who suffer from mild forms of depression may recover without any assistance or be effectively managed by primary care or family practitioners. However, other forms of depression are far more severe and require advanced care by certified mental health providers. However, identifying cases of depression that require advanced care may be challenging to primary care providers and health care team members whose skill sets run broad rather than deep., Objective: This study aimed to leverage a comprehensive range of patient-level diagnostic, behavioral, and demographic data, as well as past visit history data from a statewide health information exchange to build decision models capable of predicting the need of advanced care for depression across patients presenting at Eskenazi Health, the public safety net health system for Marion County, Indianapolis, Indiana., Methods: Patient-level diagnostic, behavioral, demographic, and past visit history data extracted from structured datasets were merged with outcome variables extracted from unstructured free-text datasets and were used to train random forest decision models that predicted the need of advanced care for depression across (1) the overall patient population and (2) various subsets of patients at higher risk for depression-related adverse events; patients with a past diagnosis of depression; patients with a Charlson comorbidity index of ≥1; patients with a Charlson comorbidity index of ≥2; and all unique patients identified across the 3 above-mentioned high-risk groups., Results: The overall patient population consisted of 84,317 adult (aged ≥18 years) patients. A total of 6992 (8.29%) of these patients were in need of advanced care for depression. Decision models for high-risk patient groups yielded area under the curve (AUC) scores between 86.31% and 94.43%. The decision model for the overall patient population yielded a comparatively lower AUC score of 78.87%. The variance of optimal sensitivity and specificity for all decision models, as identified using Youden J Index, is as follows: sensitivity=68.79% to 83.91% and specificity=76.03% to 92.18%., Conclusions: This study demonstrates the ability to automate screening for patients in need of advanced care for depression across (1) an overall patient population or (2) various high-risk patient groups using structured datasets covering acute and chronic conditions, patient demographics, behaviors, and past visit history. Furthermore, these results show considerable potential to enable preventative care and can be easily integrated into existing clinical workflows to improve access to wraparound health care services., (©Suranga N Kasthurirathne, Paul G Biondich, Shaun J Grannis, Saptarshi Purkayastha, Joshua R Vest, Josette F Jones. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 22.07.2019.)

Background: Cancer registries systematically collect cancer-related data to support cancer surveillance activities. However, cancer data are often unavailable for months to years after diagnosis, limiting its utility., Objective: The objective of this study was to identify the barriers to rapid cancer reporting and identify ways to shorten the turnaround time., Methods: Certified cancer registrars reporting to the Indiana State Department of Health cancer registry participated in a semistructured interview. Registrars were asked to describe the reporting process, estimate the duration of each step, and identify any barriers that may impact the reporting speed. Qualitative data analysis was performed with the intent of generating recommendations for workflow redesign. The existing and redesigned workflows were simulated for comparison., Results: Barriers to rapid reporting included access to medical records from multiple facilities and the waiting period from diagnosis to treatment. The redesigned workflow focused on facilitating data sharing between registrars and applying a more efficient queuing technique while registrars await the delivery of treatment. The simulation results demonstrated that our recommendations to reduce the waiting period and share information could potentially improve the average reporting speed by 87 days., Conclusions: Knowing the time elapsing at each step within the reporting process helps in prioritizing the needs and estimating the impact of future interventions. Where some previous studies focused on automating some of the cancer reporting activities, we anticipate much shorter reporting by leveraging health information technologies to target this waiting period., (©Abdulrahman M Jabour, Brian E Dixon, Josette F Jones, David A Haggstrom. Originally published in JMIR Cancer (http://cancer.jmir.org), 01.03.2018.)

Experimental studies have revealed that phytoestrogens may modulate the risk of certain sites of cancer due to their structural similarity to 17β-estradiol. The present study investigates whether intake of these compounds may influence prostate cancer risk in human populations. During a median follow up of 11.5 years, 2,598 cases of prostate cancer (including 287 advanced cases) have been identified among 27,004 men in the intervention arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Dietary intake of phytoestrogens (excluding lignans) was assessed with a food frequency questionnaire. Cox proportional hazards regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for dietary isoflavones and coumestrol in relation to prostate cancer risk. After adjustment for confounders, an increased risk of advanced prostate cancer [HR (95% CI) for quintile (Q) 5 vs. Q1] was found for the dietary intake of total isoflavones [1.91 (1.25-2.92)], genistein [1.51 (1.02-2.22), daidzein [1.80 (1.18-2.75) and glycitein [1.67 (1.15-2.43)] (p-trend for all associations ≤0.05). For example, HR (95% CI) for comparing the Q2, Q3, Q4 and Q5 with Q1 of daidzein intake was 1.45 (0.93-2.25), 1.65 (1.07-2.54), 1.73 (1.13-2.66) and 1.80 (1.18-2.75), respectively (p-trend: 0.013). No statistically significant associations were observed between the intake of total isoflavones and individual phytoestrogens and non-advanced and total prostate cancer after adjustment for confounders. This study revealed that dietary intake of isoflavones was associated with an elevated risk of advanced prostate cancer., (© 2017 UICC.)

Circulating tumor cells (CTCs) are extremely rare cells found in blood of metastatic cancer patients. There is a need for inexpensive technologies for fast enrichment of CTCs from large blood volumes. Previous data showed that antibody-conjugated lipid shell immuno-microbubbles (MBs) bind and isolate cells from biological fluids by flotation. Here, blood-stable MBs targeted to several surface markers for isolation of breast tumor cells were developed. MBs coated with anti-human EpCAM antibodies showed efficient binding of EpCAM + breast cancer cell lines SKBR-3, MCF-7, and MDA-MB-453, whereas anti-human EGFR MBs showed binding of EpCAM LOW/NEGATIVE cell lines MDA-MB-231 and BT-549. Multitargeted anti-human EpCAM/EGFR MBs bound all cell lines with over 95% efficiency. Highly concentrated MB-bound tumor cells were collected in a microliter volume via an inverted vacuum-assisted harvesting setup. Using anti-EpCAM and/or anti-EpCAM/EGFR MBs, an efficient (70-90%) recovery and fast (30min) isolation of the above-mentioned cells and cell clusters was achieved from 7.5mL of spiked human blood. Using anti-EpCAM MBs and anti-EpCAM/EGFR MBs, cytokeratin-positive, CD45-negative CTCs were detected in 62.5% (10/16) of patients with metastatic breast cancer and CTC clusters were detected in 41.7% (5/12) of CTC-positive samples. Moreover, in some samples MBs isolated cytokeratin positive, CD45 negative tumor-derived microparticles. None of these structures were detected in blood from non-epithelial malignancies. The fast and inexpensive multitargeted platform for batch isolation of CTCs can promote research and clinical applications involving primary tumors and metastases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Toilets contaminated with infectious organisms are a recognized contact disease transmission hazard. Previous studies indicate that toilet bowl water can remain contaminated for several flushes after the contamination occurs. This study characterized contamination persistence over an extended series of flushes using both indicator particles and viable bacteria. For this study, toilets were seeded with microbe-size microbial surrogates and with Pseudomonas fluorescens or Clostridium difficile bacteria and flushed up to 24 times. Bowl water samples collected after seeding and after each flush indicated the clearance per flush and residual bowl water contaminant concentration. Toilets exhibited 3 + log10 contaminant reductions with the first flush, only 1-2 logs with the second flush, and less than 1 log thereafter. Contamination still was present 24 flushes post contamination. Clearance was modeled accurately by a two-stage exponential decay process. This study shows that toilet bowl water will remain contaminated many flushes after initial contamination, posing a risk of recurring environmental contamination and associated infection incidence.

There is a lack of alignment between and within the competencies and skills required by health informatics (HI) related jobs and those present in academic curriculum frameworks. This study uses computational topic modeling for gap analysis of career needs vs. curriculum objectives. The seven AMIA-CAHIIM-accepted core knowledge domains were used to categorize a corpus of HI-related job postings (N = 475) from a major United States-based job posting website. Computational modeling-generated topics were created and then compared and matched to the seven core knowledge domains. The HI-defining core domain, representing the intersection of health, technology and social/behavioral sciences matched only 45.9% of job posting content. Therefore, the authors suggest that bidirectional communication between academia and industry is needed in order to better align educational objectives to the demands of the job market.

Introduction: Over a million adults in the U.S. are affected by chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME). A debilitating illness, ME/CFS is accompanied by profound fatigue that is not relieved by rest and affects daily activities. Symptoms include postexertional malaise, cognitive problems, unrefreshing sleep, and pain. This course provides tools to teach medical, physician assistant, and nursing students to recognize, diagnose, and manage patients with ME/CFS., Methods: The student is expected to view the provider-to-provider video and the PowerPoint slide curriculum, which describe the steps for evaluation. The video depicts two physicians conferring about ME/CFS and addresses the challenges of making a diagnosis. The slide curriculum shows the different ME/CFS symptoms and case definitions and how to apply them using a case study. Medical, physician assistant, and nursing students were recruited to evaluate the course and viewed it either online or in a campus education center., Results: Results showed that students met learning objectives and showed increases from pre- to posttest evaluation in their understanding of the difficulties of diagnosing ME/CFS and managing the illness. In addition to knowledge, student attitudes towards ME/CFS changed, with more empathy towards patients and the awareness that ME/CFS requires frequent communication and reevaluation of patients' symptoms., Discussion: Strategies of how to manage ME/CFS for the patient and manage time constraints during visits with ME/CFS patients are discussed., Competing Interests: None to report.

BACKGROUND: Central cancer registries collect tumor-related data to monitor incidence rates and support population- based research. One concern with using registry data for research is timeliness of reporting. Timeliness has been recognized as an important data characteristic by both the Centers for Disease Control and Prevention and the National Academy of Medicine. Yet, few studies in the United States have systematically measured timeliness. The purpose of this study is to evaluate timeliness in cancer-case reporting to a state population-based cancer registry. METHOD: Using the Indiana State Department of Health Cancer Registry, 66,395 breast, colorectal, and lung cancer diagnoses recorded during the years 2001–2009 were examined for timeliness. Timeliness was measured from the date the cancer was diagnosed to when the data were available at the state registry. Differences over time and among the 3 cancer types were examined. RESULT: Timeliness of reporting improved since 2003. Mean reporting time ranged from 426 days in 2003 to 253 days in 2009. We found significant difference in reporting time between the 3 cancer types. CONCLUSION: Timeliness of reporting has improved over time. Advances in health information technologies may have contributed to this improvement. However, achieving even more timely reporting for research purposes and care intervention may require moving away from traditional reporting methods.

Background: Sacral neuromodulation (SNM) is a treatment option for intractable fecal incontinence. The mechanism of action is unclear, however, increasing evidence for afferent somatosensory effects exists. This study's aim was to elucidate effects of acute SNM on the cerebral cortex in a rodent model of pudendal nerve injury., Methods: The effects of 14 Hz and 2 Hz SNM on sensory cortical activation were studied. In 32 anesthetized rats, anal canal evoked potentials (EPs) were recorded over the primary somatosensory cortex. Pudendal nerve injury was produced by 1-hour inflation of two intra-pelvic balloons. Four groups were studied: balloon injury, balloon injury plus either 14 Hz or 2 Hz SNM, sham operation. Immunohistochemistry for the neural plasticity marker polysialylated neural cell adhesion molecule (PSA-NCAM) positive cells (numerical density and location) in the somatosensory cortex was performed., Key Results: Anal EP amplitudes diminished during balloon inflation; 14 Hz SNM restored diminished anal EPs to initial levels and 2 Hz SNM to above initial levels. Evoked potential latencies were prolonged during balloon inflation. The numerical density of PSA-NCAM positive cells increased in the SNM groups, but not in sham or balloon injury without SNM. Stimulated cortices showed clusters of PSA-NCAM positive cells in layers II, IV, and V. Post SNM changes were similar in both SNM groups., Conclusions & Inferences: Sacral neuromodulation augments anal representation in the sensory cortex and restores afferent pathways following injury. PSA-NCAM positive cell density is increased in stimulated cortices and positive cells are clustered in layers II, IV, and V., (© 2016 John Wiley & Sons Ltd.)

Background: Multiple case definitions are in use to identify chronic fatigue syndrome (CFS). Even when using the same definition, methods used to apply definitional criteria may affect results. The Centers for Disease Control and Prevention (CDC) conducted two population-based studies estimating CFS prevalence using the 1994 case definition; one relied on direct questions for criteria of fatigue, functional impairment and symptoms (1997 Wichita; Method 1), and the other used subscale score thresholds of standardized questionnaires for criteria (2004 Georgia; Method 2). Compared to previous reports the 2004 CFS prevalence estimate was higher, raising questions about whether changes in the method of operationalizing affected this and illness characteristics., Methods: The follow-up of the Georgia cohort allowed direct comparison of both methods of applying the 1994 case definition. Of 1961 participants (53 % of eligible) who completed the detailed telephone interview, 919 (47 %) were eligible for and 751 (81 %) underwent clinical evaluation including medical/psychiatric evaluations. Data from the 499 individuals with complete data and without exclusionary conditions was available for this analysis., Results: A total of 86 participants were classified as CFS by one or both methods; 44 cases identified by both methods, 15 only identified by Method 1, and 27 only identified by Method 2 (Kappa 0.63; 95 % confidence interval [CI]: 0.53, 0.73 and concordance 91.59 %). The CFS group identified by both methods were more fatigued, had worse functioning, and more symptoms than those identified by only one method. Moderate to severe depression was noted in only one individual who was classified as CFS by both methods. When comparing the CFS groups identified by only one method, those only identified by Method 2 were either similar to or more severely affected in fatigue, function, and symptoms than those only identified by Method 1., Conclusions: The two methods demonstrated substantial concordance. While Method 2 classified more participants as CFS, there was no indication that they were less severely ill or more depressed. The classification differences do not fully explain the prevalence increase noted in the 2004 Georgia study. Use of standardized instruments for the major CFS domains provides advantages for disease stratification and comparing CFS patients to other illnesses.

Background: Sacral nerve stimulation has become a first line treatment for fecal incontinence, however, its effect on the motor function of the anorectum is uncertain. The aim of this study was to apply acute lumbosacral nerve stimulation in an animal model and to determine its effect on the external and internal anal sphincter forces, the rectoanal inhibitory and excitatory reflexes, and the slow wave frequency of the internal anal sphincter., Methods: Lumbosacral nerve stimulation was applied to 16 nulliparous female rats. A novel in vivo preparation was designed to allow simultaneous monitoring of external and internal anal sphincter forces. The effect of rectal distension on the two anal sphincters was also studied., Key Results: Lumbosacral nerve stimulation delivered at either S1 or L6 in rodents did not affect sphincter forces, rectoanal reflexes or slow wave frequency of anal canal smooth muscle., Conclusions & Inferences: The absence of effect on the motor pathways of continence suggests that the mechanism of action is predominantly on sensory feedback mechanisms from the anorectum, thereby increasing cortical awareness of the pelvic floor., (© 2015 John Wiley & Sons Ltd.)

Background: Advancements in information technology (IT) and its increasingly ubiquitous nature expand the ability to engage patients in the health care process and motivate health behavior change., Objective: Our aim was to systematically review the (1) impact of IT platforms used to promote patients' engagement and to effect change in health behaviors and health outcomes, (2) behavior theories or models applied as bases for developing these interventions and their impact on health outcomes, (3) different ways of measuring health outcomes, (4) usability, feasibility, and acceptability of these technologies among patients, and (5) challenges and research directions for implementing IT platforms to meaningfully impact patient engagement and health outcomes., Methods: PubMed, Web of Science, PsycINFO, and Google Scholar were searched for studies published from 2000 to December 2014. Two reviewers assessed the quality of the included papers, and potentially relevant studies were retrieved and assessed for eligibility based on predetermined inclusion criteria., Results: A total of 170 articles met the inclusion criteria and were reviewed in detail. Overall, 88.8% (151/170) of studies showed positive impact on patient behavior and 82.9% (141/170) reported high levels of improvement in patient engagement. Only 47.1% (80/170) referenced specific behavior theories and only 33.5% (57/170) assessed the usability of IT platforms. The majority of studies used indirect ways to measure health outcomes (65.9%, 112/170)., Conclusions: In general, the review has shown that IT platforms can enhance patient engagement and improve health outcomes. Few studies addressed usability of these interventions, and the reason for not using specific behavior theories remains unclear. Further research is needed to clarify these important questions. In addition, an assessment of these types of interventions should be conducted based on a common framework using a large variety of measurements; these measurements should include those related to motivation for health behavior change, long-standing adherence, expenditure, satisfaction, and health outcomes.

For centuries, cadaveric dissection has been the touchstone of anatomy education. It offers a medical student intimate access to his or her first patient. In contrast to idealized artisan anatomical models, it presents the natural variation of anatomy in fine detail. However, a new teaching construct has appeared recently in which artificial cadavers are manufactured through three-dimensional (3D) printing of patient specific radiological data sets. In this article, a simple powder based printer is made more versatile to manufacture hard bones, silicone muscles and perfusable blood vessels. The approach involves blending modern approaches (3D printing) with more ancient ones (casting and lost-wax techniques). These anatomically accurate models can augment the approach to anatomy teaching from dissection to synthesis of 3D-printed parts held together with embedded rare earth magnets. Vascular simulation is possible through application of pumps and artificial blood. The resulting arteries and veins can be cannulated and imaged with Doppler ultrasound. In some respects, 3D-printed anatomy is superior to older teaching methods because the parts are cheap, scalable, they can cover the entire age span, they can be both dissected and reassembled and the data files can be printed anywhere in the world and mass produced. Anatomical diversity can be collated as a digital repository and reprinted rather than waiting for the rare variant to appear in the dissection room. It is predicted that 3D printing will revolutionize anatomy when poly-material printing is perfected in the early 21st century., (© 2015 American Association of Anatomists.)

Background: Normal defaecation involves activation of anorectal mechanoreceptors responsive to pressure and stretch. The aim of this study was to develop selective anal and rectal mucosal light-touch stimulation suitable for measurement of cortical evoked potentials (EPs) in order to explore the sensory arm of these pathways., New Method: A novel device was manufactured to deliver selective rectal and/or anal light-touch stimulation using a shielded inter-dental brush mounted on a rotating stepper motor (1Hz, 1ms, 15° rotation). Resultant somatosensory EPs recorded with a 32-channel cortical multi-electrode array were compared to those elicited by electrical anorectal stimulation (2mm anal plug electrode [1Hz, 1ms, 10V])., Results: Eighteen anaesthetized female Wistar rats (body mass 180-250g) were studied. Electrical and mechanical stimulation provoked similar maximal response amplitudes (electrical anorectal 39.0μV[SEM 5.5], mechanical anal 42.2μV[8.1], mechanical rectal 45.8μV[9.0]). Response latency was longer following mechanical stimulation (electrical anorectal 8.8ms[0.5], mechanical anal 16.4ms[1.1], mechanical rectal 18.3ms[2.5]). The extent of activated sensory cortex was smaller for mechanical stimulation. Sensory inferior rectal nerve activity was greater during anal compared to rectal mechanical in a subgroup of 4 rats. Evoked potentials were reproducible over 40min in a subgroup of 9 rats., Comparison With Existing Methods: Cortical EPs are typically recorded in response to non-physiological electrical stimuli. The use of a mechanical stimulus may provide a more localized physiological method of assessment., Conclusions: To the authors' knowledge these are the first selective brush-elicited anal and rectal EPs recorded in animals and provide a physiological approach to testing of anorectal afferent pathways., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Sacral nerve stimulation (SNS) was originally developed in the field of urinary incontinence. Without adaptation, it was subsequently applied to treat faecal incontinence. SNS has now become a first line therapy for this socially disabling condition, however the mechanism of action is unknown. This review examines the evidence for stimulation parameters currently used for SNS in humans and considers the potential electrophysiological effects of changing these parameters. However, without a proper understanding of the physiology of SNS, changing stimulation parameters remains empirical., (Copyright © 2014 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Introduction: This study was initiated because it was noted that the peripheral nerves of Trembler-J mice (a model of human Charcot-Marie-Tooth disease) appear to lack normal striations., Methods: We performed confocal microscopy of whole sciatic nerves and tested the effect of axial stress on impulse conduction., Results: We found that the axons of mutant mice were longer than those of the wild-type (1.55 mm of axon/mm length of nerve vs. 1.28 mm/mm respectively). This axonal elongation altered the helical nerve striations (bands of Fontana). As nerves were stretched axially, the conduction distance became correspondingly shorter. The effect on latency was significantly greater in the more coiled nerves of Trembler-J mice (P = 0.038)., Conclusions: The finding that mice with a mutated peripheral myelin protein 22 (PMP22) possess excessively long axons may be related to the excess Schwann cell numbers found in this disorder., (© 2014 Wiley Periodicals, Inc.)

Background: A behavioural animal model of faecal continence and/or incontinence would be of value in experimental studies of the mechanisms by which sacral neuromodulation can effect continence mechanisms in humans., Aim: The aim of this behavioural study was to establish whether the rat, an obligate coprophagic species, exhibits patterns of faecal continence., Methods: Standard rat cages were modified to consist of a food and drink area, a nesting area and an empty latrine area. Three floor pressure pads were connected to hour meters to record the time spent in each area over the course of 4 days. The door to the latrine was open for 2 days and closed for another 2 days to create a physical barrier that could only be surmounted by climbing over a partition., Results: In the first 2 days, most faecal pellets (74 ± 20 %; p < 0.0001) were deposited in the latrine and this was not changed by door closure (81 ± 13 %). Door closure had no effect per se on pellet output (p = 0.99), nor did it alter the place preference for defaecation (p = 0.17, two factor ANOVA). Rats spent less time in the latrine area accounting for 23 and 13 % of total time before and after the door was closed, respectively. Normal and infrared videography showed that the place preference for pellets was not due to pellet collection for coprophagic purposes., Conclusions: The rat demonstrates place preference for defaecation and may drop pellets to mark remote boundaries. This simple method may prove useful in future animal studies of neuropathic faecal incontinence and refinement of neuromodulation interventions that lack placebo effects.

Chronic intermittent hypoxia (CIH) in animal models has been shown to result in hypertension and elevation of sympathetic nervous system activity. Sympathetically mediated vasoconstriction is believed to be the primary mechanism underpinning CIH-induced hypertension; however, the potential contribution of the heart is largely overlooked. We sought to determine the contribution of cardiac output (CO) and lumbar sympathetic control of the hindlimb circulation to CIH-induced hypertension. Male Wistar rats (n = 64) were exposed to 2 weeks of CIH [cycles of 90 s hypoxia (5% O2 nadir) and 210 s normoxia] or normoxia for 8 h day(-1). Under urethane anaesthesia, CIH-treated animals developed hypertension (81.4 ± 2.2 versus 91.6 ± 2.4 mmHg; P < 0.001), tachycardia (397 ± 8 versus 445 ± 7 beats min(-1); P < 0.001) and an increased haematocrit (42.4 ± 0.4 versus 45.0 ± 0.4%; P < 0.001). Echocardiography revealed that CIH exposure increased the CO [19.3 ± 1.7 versus 25.8 ± 2.6 ml min(-1) (100 g)(-1); P = 0.027] with no change in total peripheral resistance (4.93 ± 0.49 versus 4.17 ± 0.34 mmHg ml(-1) min(-1); P = 0.123). Sympathetic ganglionic blockade revealed that sympathetic control over blood pressure was not different (-27.7 ± 1.6 versus -32.3 ± 2.9 mmHg; P = 0.095), and no chronic vasoconstriction was found in the hindlimb circulation of CIH-treated animals (39.4 ± 2.5 versus 38.0 ± 2.4 μl min(-1) mmHg(-1); P = 0.336). Lumbar sympathetic control over the hindlimb circulation was unchanged in CIH-treated animals (P = 0.761), although hindlimb arterial sympathetic density was increased (P = 0.012) and vascular sensitivity to phenylephrine was blunted (P = 0.049). We conclude that increased CO is sufficient to explain the development of CIH-induced hypertension, which may be an early adaptive response to raise O2 flow. We propose that sustained elevated cardiac work may ultimately lead to heart failure., (© 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.)

Background: Sacral nerve stimulation (SNS) is now well established as a treatment for fecal incontinence (FI) resistant to conservative measures and may also have utility in the management of chronic constipation; however, mechanism of action is not fully understood. End organ effects of SNS have been studied in both clinical and experimental settings, but interpretation is difficult due to the multitude of techniques used and heterogeneity of reported findings. The aim of this study was to systematically review available evidence on the mechanisms of SNS in the treatment of FI and constipation., Methods: Two systematic reviews of the literature (performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses framework) were performed to identify manuscripts pertaining to (a) clinical and (b) physiological effects of SNS during the management of hindgut dysfunction., Key Results: The clinical literature search revealed 161 articles, of which 53 were deemed suitable for analysis. The experimental literature search revealed 43 articles, of which nine were deemed suitable for analysis. These studies reported results of investigative techniques examining changes in cortical, gastrointestinal, colonic, rectal, and anal function., Conclusions & Inferences: The initial hypothesis that the mechanism of SNS was primarily peripheral motor neurostimulation is not supported by the majority of recent studies. Due to the large body of evidence demonstrating effects outside of the anorectum, it appears likely that the influence of SNS on anorectal function occurs at a pelvic afferent or central level., (© 2014 John Wiley & Sons Ltd.)

Introduction: Although sacral neuromodulation (SNM) is an established treatment for faecal incontinence, stimulation parameters have been derived empirically and only one frequency (14 Hz) is employed clinically. The aim of this study was to test a range of stimulation frequencies to establish an optimal frequency of SNM for maximum augmentation of anal canal cortical evoked potentials (EPs) in an animal model., Methods: In female Wistar rats, anal canal EPs were recorded over the primary somatosensory cortex using a flexible multielectrode array, and the effect of SNM was studied. SNM was applied at 0·1-100 Hz and a frequency response curve plotted. The data were fitted to a quadratic equation., Results: The magnitude of potentiation of anal canal EPs caused by SNM depended significantly on stimulation frequency (P < 0·001). The frequency-potentiation relationship was parabolic in form, with a clear optimum at 2 Hz. The SNM must be applied for at least 3 min. The theoretical maximal potentiation predicted by the model was not found to be statistically different to actual data recorded (P = 0·514-0·814). The response depended on stimulation amplitude in an 'all-or-nothing' fashion. EPs were augmented when the SNM intensity was 0·5 times the motor threshold to tail twitch or greater, but values below this intensity failed to affect the EPs., Conclusion: The effect of SNM in this animal model is governed principally by frequency, with an optimum of 2 Hz. If animal data can be translated to humans, optimization of SNM frequency may offer a clinically relevant improvement in the efficacy of SNM. Surgical relevance Sacral neuromodulation (SNM) for faecal incontinence currently employs stimulation parameters that have been derived empirically and may not be optimal. This study used an animal model of SNM and focused on its acute effect on anal canal cortical evoked potentials (EPs). It was found that SNM potentiated EPs, with a clear optimum at a frequency of 2 Hz. If this finding is applicable to the mechanism of action of human SNM, this suggests that there may be a clinically relevant improvement by reducing stimulus frequency from its typical value of 14 Hz to 2 Hz., (© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation. Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation. In order to directly test the hypothesis of decreased basal ganglia function in CFS, we used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward-processing (monetary gambling) task in a community sample of 59 male and female subjects, including 18 patients diagnosed with CFS according to 1994 CDC criteria and 41 non-fatigued healthy controls. For each subject, the average effect of winning vs. losing during the gambling task in regions of interest (ROI) corresponding to the caudate nucleus, putamen, and globus pallidus was extracted for group comparisons and correlational analyses. Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects. These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.

Sustained hypoxia is a dominant feature of respiratory disease. Despite the clinical significance, the effects of sustained hypoxia on the form and function of respiratory muscle during development are relatively underexplored. Wistar rats were exposed to 1 week of sustained hypoxia (ambient pressure 450 mmHg) or normoxia at various time points during development. Sternohyoid and diaphragm muscle contractile and endurance properties were assessed in vitro. Muscle succinate dehydrogenase and myosin heavy chain composition were determined. The role of reactive oxygen species in hypoxia-induced muscle remodelling was assessed. Sustained hypoxia increased sternohyoid muscle force and fatigue in early but not late development, effects that persisted after return to normoxia. Hypoxia-induced sternohyoid muscle fatigue was not attributable to fibre type transitions or to a decrease in oxidative capacity. Chronic supplementation with the superoxide scavenger tempol did not prevent hypoxia-induced sternohyoid muscle fatigue, suggesting that mechanisms unrelated to oxidative stress underpin hypoxia-induced maladaptation in sternohyoid muscle. Sustained hypoxia had no effect on diaphragm muscle fatigue. We conclude that there are critical windows during development for hypoxia-induced airway dilator muscle maladaptation. Sustained hypoxia-induced impairment of upper airway muscle endurance may persist into later life. Upper airway muscle dysfunction could have deleterious consequences for the control of pharyngeal airway calibre in vivo.

We describe a death in a 15-mo-old girl who developed a varicella-like rash 20 d after varicella vaccination that lasted for 2 mo despite acyclovir treatment. The rash was confirmed to be due to vaccine-strain varicella-zoster virus (VZV). This is the first case of fatal varicella due to vaccine-strain VZV reported from the United States. The patient developed severe respiratory complications that worsened with each new crop of varicella lesions; vaccine-strain VZV was detected in the bronchial lavage specimen. Sepsis and multi-organ failure led to death. The patient did not have a previously diagnosed primary immune deficiency, but her failure to thrive and repeated hospitalizations early in life (starting at 5 mo) for presumed infections and respiratory compromise treated with corticosteroids were suggestive of a primary or acquired immune deficiency. Providers should monitor for adverse reactions after varicella vaccination. If severe adverse events develop, acyclovir should be administered as soon as possible. The possibility of acyclovir resistance and use of foscarnet should be considered if lesions do not improve after 10 d of treatment (or if they become atypical [e.g., verrucous]). Experience with use of varicella vaccine indicates that the vaccine has an excellent safety profile and that serious adverse events are very rare and mostly described in immunocompromised patients. The benefit of vaccination in preventing severe disease and mortality outweigh the low risk of severe events occurring after vaccination.

We sought to test the hypothesis that chronic intermittent hypoxia (CIH)-a feature of sleep-disordered breathing in humans-impairs reflex recruitment of the genioglossus (GG, pharyngeal dilator) during obstructive airway events. Adult male Wistar rats were exposed to 20 cycles of normoxia and hypoxia (5% O2 at nadir) per hour, 8h a day for 7 days (CIH, N=7). The sham group (N=7) were exposed to normoxia in parallel. Following gas treatments, rats were anesthetized with an i.p. injection of urethane (1.5g/kg; 20%, w/v). Fine concentric needle electrodes were inserted into the GG and the costal diaphragm. Discriminated GG motor unit potentials and whole electromyograph (EMG), together with arterial blood pressure and arterial O2 saturation, were recorded during quiet basal breathing and during nasal airway occlusion. Airway occlusion significantly increased GG EMG activity in all animals; but there was no difference in the reflex response to airway occlusion between sham and CIH-treated animals (+105±22% vs. +105±17%, mean±SEM for area under the curve of integrated GG EMG, % increase from baseline, p=0.99). Occluded breaths were characterized by a significant increase in the firing frequency of phasically active units and the recruitment of large motor units that were quiescent under basal conditions. Though there are reports of impaired control of the upper airway following CIH in the rat, we conclude that reflexly evoked motor discharge to the GG is not affected by 7 days of CIH, a paradigm that we have shown increases apnea index in sleeping rats., (© 2014 Elsevier B.V. All rights reserved.)