Initial validation of the Mass. General Neuropathy Exam Tool (MAGNET) for evaluation of distal small-fiber neuropathy.

INTRODUCTION/AIMS: Diagnosis of small-fiber neuropathy (SFN) is hampered by its subjective symptoms and signs. Confirmatory testing is insufficiently available and expensive, so predictive examinations have value. However, few support the 2020 SFN consensus-case-definition requirements or were validated for non-diabetes neuropathies. Thus we developed the Massachusetts General Hospital Neuropathy Exam Tool (MAGNET) and measured diagnostic performance in 160 symptomatic patients evaluated for length-dependent SFN from any cause and 37 healthy volunteers. METHODS: We compared prevalences of abnormalities (vital signs, pupil responses, lower-limb appearance, pin, light touch, vibration and position sensitivity, great-toe strength, muscle stretch reflexes), and validated diagnostic performance against objective SFN tests: lower-leg skin-biopsy epidermal neurite densities and autonomic function testing (AFT). Sensitivity/specificity, feasibility, test-retest and inter-rater reliability, and convergence with the Utah Early Neuropathy Scale were calculated. RESULTS: Patients' ages averaged 48.5 ± 14.7 years and 70.6% were female. Causes of neuropathy varied, remaining unknown in 59.5%. Among the 46 with abnormal skin biopsies, the most prevalent abnormality was reduced pin sharpness at the toes (71.7%). Inter-rater reliability, test-retest reliability, and convergent validity excelled (range = 91.3-95.6%). Receiver operating characteristics comparing all symptomatic patients versus healthy controls indicated that a MAGNET threshold score of 14 maximized predictive accuracy for skin biopsies (0.74) and a 30 cut-off maximized accuracy for predicting AFT (0.60). Analyzing patients with any abnormal neuropathy-test results identified areas-under-the-curves of 0.87-0.89 for predicting a diagnostic result, accuracy = 0.80-0.89, and Youden's index = 0.62. Overall, MAGNET was 80%-85% accurate for stratifying patients with abnormal versus normal neuropathy test results. DISCUSSION: MAGNET quickly generates research-quality metrics during clinical examinations.

[The Indeterminate Place of Property]. / Der unbestimmte Ort des Eigentums: Ein theoretischer Zugang zum ambivalenten Verhältnis von Enteignung und demokratischer Rechtsstaat.

An increasing political contestation of the existing private-property order can currently be observed. With serious demands for expropriation, even outside marginalized splinter groups, a concept is returning that has largely disappeared from the focus of political theory. In this context, the article aims at a decidedly political-scientific examination of the legal institution of expropriation by locating the concept in the architecture of the democratic rule of law. Shifting between the poles of the constitutional guarantee of private property on the one hand and a potentiality of democratic contestation of the property order on the other, it is made clear that the concept of expropriation highlights the aporias of the democratic rule of law. The thesis is presented by means of a theoretical-historical contouring using the example of the intensive discussions on expropriation in the Weimar Republic and, in particular, with a more in-depth examination of the positions of Carl Schmitt and Otto Kirchheimer, which are subsequently figured as antipodes. While Schmitt seeks to make plausible a far-reaching rejection of expropriation potentials with a narrow concept of the rule of law, Kirchheimer focuses on an extensive interpretation of democratic power of disposition over the private-property order. The Weimar crisis years are examined as a kind of "laboratory" in order to profit from the extraordinary degree of crisis-induced searching and to work out a political science theoretical language for contemporary discussions of expropriation.

Automatic error control during forward flux sampling of rare events in master equation models.

Enhanced sampling methods, such as forward flux sampling (FFS), have great capacity for accelerating stochastic simulations of nonequilibrium biochemical systems involving rare events. However, the description of the tradeoffs between simulation efficiency and error in FFS remains incomplete. We present a novel and mathematically rigorous analysis of the errors in FFS that, for the first time, covers the contribution of every phase of the simulation. We derive a closed form expression for the optimally efficient count of samples to take in each FFS phase in terms of a fixed constraint on sampling error. We introduce a new method, forward flux pilot sampling (FFPilot), that is designed to take full advantage of our optimizing equation without prior information or assumptions about the phase weights and costs along the transition path. In simulations of both single and multidimensional gene regulatory networks, FFPilot is able to completely control sampling error. We then discuss how memory effects can introduce additional error when relaxation along the transition path is slow. This extra error can be traced to correlations between the FFS phases and can be controlled by monitoring the covariance between them. Finally, we show that, in sets of simulations with matched error, FFPilot is on the order of tens-to-hundreds of times faster than direct sampling and noticeably more efficient than previous FFS methods.

Biospark: scalable analysis of large numerical datasets from biological simulations and experiments using Hadoop and Spark.

Data-parallel programming techniques can dramatically decrease the time needed to analyze large datasets. While these methods have provided significant improvements for sequencing-based analyses, other areas of biological informatics have not yet adopted them. Here, we introduce Biospark, a new framework for performing data-parallel analysis on large numerical datasets. Biospark builds upon the open source Hadoop and Spark projects, bringing domain-specific features for biology. AVAILABILITY AND IMPLEMENTATION: Source code is licensed under the Apache 2.0 open source license and is available at the project website: https://www.assembla.com/spaces/roberts-lab-public/wiki/Biospark CONTACT: eroberts@jhu.eduSupplementary information: Supplementary data are available at Bioinformatics online.

Multi-Particle Tracking in Complex Plasmas Using a Simplified and Compact U-Net.

Detecting micron-sized particles is an essential task for the analysis of complex plasmas because a large part of the analysis is based on the initially detected positions of the particles. Accordingly, high accuracy in particle detection is desirable. Previous studies have shown that machine learning algorithms have made great progress and outperformed classical approaches. This work presents an approach for tracking micron-sized particles in a dense cloud of particles in a dusty plasma at Plasmakristall-Experiment 4 using a U-Net. The U-net is a convolutional network architecture for the fast and precise segmentation of images that was developed at the Computer Science Department of the University of Freiburg. The U-Net architecture, with its intricate design and skip connections, has been a powerhouse in achieving precise object delineation. However, as experiments are to be conducted in resource-constrained environments, such as parabolic flights, preferably with real-time applications, there is growing interest in exploring less complex U-net architectures that balance efficiency and effectiveness. We compare the full-size neural network, three optimized neural networks, the well-known StarDist and trackpy, in terms of accuracy in artificial data analysis. Finally, we determine which of the compact U-net architectures provides the best balance between efficiency and effectiveness. We also apply the full-size neural network and the the most effective compact network to the data of the PK-4 experiment. The experimental data were generated under laboratory conditions.

Assessment of the Suitability of Selected Linear Actuators for the Implementation of the Load-Adaptive Biological Principle of Redundant Motion Generation.

The load-adaptive behavior of the muscles in the human musculoskeletal system offers great potential for minimizing resource and energy requirements in many technical systems, especially in drive technology and robotics. However, the lack of knowledge about suitable technical linear actuators that can reproduce the load-adaptive behavior of biological muscles in technology is a major reason for the lack of successful implementation of this biological principle. In this paper, therefore, the different types of linear actuators are investigated. The focus is particularly on artificial muscles and rope pulls. The study is based on literature, on the one hand, and on two physical demonstrators in the form of articulated robots, on the other hand. The studies show that ropes are currently the best way to imitate the load-adaptive behavior of the biological model in technology. This is especially illustrated in the context of this paper by the discussion of different advantages and disadvantages of the technical linear actuators, where ropes, among other things, have a good mechanical and control behavior, which is very advantageous for use in an adaptive system. Finally, the next steps for future research are outlined to conclude how ropes can be used as linear actuators to transfer load-adaptive lightweight design into technical applications.

Cardiotoxicity risk factors with immune checkpoint inhibitors.

BACKGROUND: Checkpoint-inhibitor immunotherapies have had a profound effect in the treatment of cancer by inhibiting down-regulation of T-cell response to malignancy. The cardiotoxic potential of these agents was first described in murine models and, more recently, in numerous clinical case reports of pericarditis, myocarditis, pericardial effusion, cardiomyopathy, and new arrhythmias. The objective of our study was to determine the frequency of and associated risk factors for cardiotoxic events in patients treated with immune checkpoint inhibitors. METHODS: Medical records of patients who underwent immunotherapy with durvalumab, ipilimumab, nivolumab, and pembrolizumab at Wake Forest Baptist Health were reviewed. We collected retrospective data regarding sex, cancer type, age, and cardiovascular disease risk factors and medications. We aimed to identify new diagnoses of heart failure, atrial fibrillation, ventricular fibrillation/tachycardia, myocarditis, and pericarditis after therapy onset. To assess the relationship between CVD risk factors and the number of cardiac events, a multivariate model was applied using generalized linear regression. Incidence rate ratios were calculated for every covariate along with the adjusted P-value. We applied a multivariate model using logistic regression to assess the relationship between CVD risk factors and mortality. Odds ratios were calculated for every covariate along with the adjusted P-value. Adjusted P-values were calculated using multivariable regression adjusting for other covariates. RESULTS: Review of 538 medical records revealed the following events: 3 ventricular fibrillation/tachycardia, 12 pericarditis, 11 atrial fibrillation with rapid ventricular rate, 0 myocarditis, 8 heart failure. Significant risk factors included female gender, African American race, and tobacco use with IRR 3.34 (95% CI 1.421, 7.849; P = 0.006), IRR 3.39 (95% CI 1.141, 10.055; P = 0.028), and IRR 4.21 (95% CI 1.289, 13.763; P = 0.017) respectively. CONCLUSIONS: Our study revealed 34 significant events, most frequent being pericarditis (2.2%) and atrial fibrillation (2.0%) with strongest risk factors being female gender, African American race, and tobacco use. Patients who meet this demographic, particularly those with planned pembrolizumab treatment, may benefit from early referral to a cardio-oncologist. Further investigation is warranted on the relationship between CTLA-4 and PD-L1 expression and cardiac adverse events with ICIs, particularly for these subpopulations.

MCCE analysis of the pKas of introduced buried acids and bases in staphylococcal nuclease.

The pK(a)s of 96 acids and bases introduced into buried sites in the staphylococcal nuclease protein (SNase) were calculated using the multiconformation continuum electrostatics (MCCE) program and the results compared with experimental values. The pK(a)s are obtained by Monte Carlo sampling of coupled side chain protonation and position as a function of pH. The dependence of the results on the protein dielectric constant (ε(prot)) in the continuum electrostatics analysis and on the Lennard-Jones non-electrostatics parameters was evaluated. The pK(a)s of the introduced residues have a clear dependence on ε(prot,) whereas native ionizable residues do not. The native residues have electrostatic interactions with other residues in the protein favoring ionization, which are larger than the desolvation penalty favoring the neutral state. Increasing ε(prot) scales both terms, which for these residues leads to small changes in pK(a). The introduced residues have a larger desolvation penalty and negligible interactions with residues in the protein. For these residues, changing ε(prot) has a large influence on the calculated pK(a). An ε(prot) of 8-10 and a Lennard-Jones scaling of 0.25 is best here. The X-ray crystal structures of the mutated proteins are found to provide somewhat better results than calculations carried out on mutations made in silico. Initial relaxation of the in silico mutations by Gromacs and extensive side chain rotamer sampling within MCCE can significantly improve the match with experiment.

Comparison of Physical and Digital Treatment and Documentation of Uncomplicated Cystitis.

Introduction Symptomatic criteria have a diagnostic specificity of approximately 90% for uncomplicated cystitis. Today there are triage bots that can collect patient history and document simultaneously. Acute uncomplicated cystitis could potentially be managed digitally, due to the symptom-based approach to diagnosis, but no studies have yet validated this approach. Aim We determined the extent of criteria documentation and evaluated adherence to antibiotic recommendations in order to compare physical and digital patient consultations for uncomplicated cystitis. Materials and methods This cross-sectional study recruited sixteen 50-year-old women who presented with urinary symptoms to digital healthcare or to three primary physical healthcare facilities. The primary endpoint was the proportion of patients who had two or more documented criteria and received correct antibiotic treatment. Results In total, 307 patient visits were included in the study (278 in the digital arm and 40 in the physical arm). The proportion of patients who had two or more documented diagnostic criteria and correct treatment was significantly higher in the digital arm (96 vs 81.6 %, p < 0.001). The total proportion of patients who had fully documented diagnostic criteria did not differ significantly between the arms, however, the proportion with two or more documented criteria was significantly higher in the digital arm (95 vs 77.5%, p < 0.001). The proportion of treated patients who had documented exclusion of diagnostic complicating factors was higher in the digital arm (85.5 vs 0%, p < 0.001). Conclusions More patients with urinary tract infection (UTI) now seek digital healthcare providers who have similar or better adherence to antibiotic treatment recommendations and documentation.

Myocardial and reproductive system toxicity of SCH 351591, a selective phosphodiesterase-4 inhibitor, in CD-1 mice.

This report describes the findings of preclinical testing of SCH 351591, a selective phosphodiesterase 4 inhibitor, in CD-1 mice over a wide range of doses, in which the heart and reproductive organs of both sexes demonstrated toxic effects. Repeat-dose toxicity studies assessed 5, 15, 50, 100, 200, 400, and 800 mg/kg/day, orally by gavage, for one or three months. Findings included higher testes and ovary weights and lower uterus weights (> or =200 mg/kg), small ovaries/uterus (> or =400 mg/kg), and histopathologic changes of large corpora lutea and ovarian atrophy at 200 and 800 mg/kg, respectively. In addition, chronic myocardial inflammation of the heart base occurred at 100 mg/kg. Vaginal staging of the estrous cycle revealed persistent diestrus. There was no histopathologic correlate or morphometric change to explain higher testes weights. A pilot fertility and early embryonic developmental toxicity study assessing doses of 100, 200, 400, and 800 mg/kg/day produced complementary results. Females had prolonged or abnormal estrous cycles, fewer successful pregnancies, increased ovarian corpora lutea, and decreased size of live litters owing to fetal resorptions. Male fertility was not affected. However, males had a 25% increase in testes weights at all doses. The pharmacology of specific PDE4 isoenzymes may explain both the reproductive and cardiac findings.

A Call for Culturally Responsive Transformational Leadership in College Sport: An Anti-ism Approach for Achieving Equity and Inclusion.

A longstanding fact in college sports in the United States (U.S.) is the reality that inequities, inequalities, and discrimination have been major issues preventing institutions from fostering harmonious diversity and inclusion. Several reasons for these persistent outcomes include the prevalence of implicit bias, homologous reproduction, hegemonic, and toxic masculinity/patriarchy, colorblind racism, and abstract liberalism to name a few. In addition, multi-level factors (macro-, meso-, and micro-) also influence the existence and salience of negative organizational cultures and climates particularly for groups that are underrepresented and marginalized in society. Despite the fact several leadership styles have been enacted and numerous policy reforms have been adopted over the years, inequities in representation, occupational mobility, position retention, and quality of experiences persist along racial and gender lines. As a result, the purpose of this manuscript is to offer innovative transformational leadership approaches that incorporate anti-racism, anti-sexism, and culturally responsive stances toward achieving true equity and inclusiveness in sport. Using interdisciplinary theories such as the anti-racism framework and culturally responsive leadership, this manuscript presents a paradigm shift for college sport leadership with the intent of cultivating paramount experiences for people across diverse backgrounds.

Longitudinal Muscle and Myocellular Changes in Community-Dwelling Men Over Two Decades of Successful Aging-The ULSAM Cohort Revisited.

Participants of the population-based Uppsala longitudinal study of adult men (ULSAM) cohort reaching more than 88 years of age (survivors, S) were investigated at age 70, 82, and 88-90 and compared at 70 years with non-survivors (NS) not reaching 82 years. Body composition, muscle mass and muscle histology were remarkably stable over 18 years of advanced aging in S. Analysis of genes involved in muscle remodeling showed that S had higher mRNA levels of myogenic differentiation factors (Myogenin, MyoD), embryonic myosin (eMyHC), enzymes involved in regulated breakdown of myofibrillar proteins (Smad2, Trim32, MuRF1,) and NCAM compared with healthy adult men (n = 8). S also had higher mRNA levels of eMyHC, Smad 2, MuRF1 compared with NS. At 88 years, S expressed decreased levels of Myogenin, MyoD, eMyHC, NCAM and Smad2 towards those seen in NS at 70 years. The gene expression pattern of S at 70 years was likely beneficial since they maintained muscle fiber histology and appendicular lean body mass until advanced age. The expression pattern at 88 years may indicate a diminished muscle remodeling coherent with a decline of reinnervation capacity and/or plasticity at advanced age.

Muscle atrophy and regeneration associated with behavioural loss and recovery of function after sciatic nerve crush.

AIM: To resolve timing and coordination of denervation atrophy and the re-innervation recovery process to discern correlations indicative of common programs governing these processes. METHODS: Female Sprague-Dawley (SD) rats had a unilateral sciatic nerve crush. Based on longitudinal behavioural observations, the triceps surae muscle was analysed at different time points post-lesion. RESULTS: Crush results in a loss of muscle function and mass (-30%) followed by a recovery to almost pre-lesion status at 30 days post-crush (dpc). There was no loss of fibres nor any significant change in the number of nuclei per fibre but a shift in fibres expressing myosins I and II that reverted back to control levels at 30 dpc. A residual was the persistence of hybrid fibres. Early on a CHNR -ε to -γ switch and a re-expression of embryonic MyHC showed as signs of denervation. Foxo1, Smad3, Fbxo32 and Trim63 transcripts were upregulated but not Myostatin, InhibinA and ActivinR2B. Combined this suggests that the mechanism instigating atrophy provides a selectivity of pathway(s) activated. The myogenic differentiation factors (MDFs: Myog, Myod1 and Myf6) were upregulated early on suggesting a role also in the initial atrophy. The regulation of these transcripts returned towards baseline at 30 dpc. The examined genes showed a strong baseline covariance in transcript levels which dissolved in the response to crush driven mainly by the MDFs. At 30 dpc the naïve expression pattern was re-established. CONCLUSION: Peripheral nerve crush offers an excellent model to assess and interfere with muscle adaptions to denervation and re-innervation.

The mechanics of breathing in children with acute severe croup.

RATIONALE: The assessment of the severity of croup and response to therapy has remained a clinical one. Despite recognition of the importance of a reproducible and easily applicable method for objectively measuring severity, currently, no such technique exists. OBJECTIVES: We postulated that measurements of air flow and intrathoracic pressure changes in patients with severe croup would provide detailed information about the mechanics of breathing and the potential for the development of continuous bedside methods for objective monitoring of upper airway obstruction. METHODS: Twenty out of 21 eligible infants and children with severe upper airway obstruction from croup, and 5 control participants, were studied under light sedation utilizing face masks and nasogastric feeding tubes for flow and esophageal pressure measurements. MEASUREMENTS AND MAIN RESULTS: Children with croup had lower tidal volumes, but breathed faster, thus maintaining similar minute volumes to the controls. During inspiration, all but 2 croup patients (but no controls) displayed flow limitation. Area within the flow-volume curve was significantly decreased and minute ventilation for effort expended was nearly 4.5 times higher in croup patients than in controls. Peak-to-trough pleural pressure swings, pressure-rate product and pressure-time integral were also significantly higher than in controls (p<0.001) and returned to the normal range in the 9 patients who were subsequently intubated (p<0.001). CONCLUSIONS: Patients with severe croup maintain minute ventilation by means of huge increases in intrathoracic pressure changes. Inspiratory flow limitation is present. In future outcome studies, measurements of respiratory function that do not include intrathoracic pressure changes are unlikely to be effective measures of the severity of croup.

Algorithm based patient care protocol to optimize patient care and inpatient stay in head and neck free flap patients.

OBJECTIVE: To determine if rigid adherence (where medically appropriate) to an algorithm/checklist-based patient care pathway can reduce the duration of hospitalization and complication rates in patients undergoing head and neck reconstruction with free tissue transfer. METHODS: Study design was a retrospective case-control study of patients undergoing major head and neck cancer resections and reconstruction at a tertiary referral centre. The intervention was rigid adherence to a pre-existing care pathway including flow algorithms and multidisciplinary checklists incorporated into patient charting and care orders. 157 patients were enrolled prospectively and were compared to 99 patients in a historical cohort. Patient charts were reviewed and information related to the patient, procedure, and post-operative course was extracted. The two groups were compared for number of major and minor complications (using the Clavien-Dindo system) and length of stay in hospital. RESULTS: Comparing pre- and post-intervention groups, no significant difference was identified in duration of hospital stay (21.5 days vs. 20.5 days, p = 0.750), the rate of major complications was significantly higher in the pre-intervention cohort (25.3% vs. 14.0%, p = 0.031), the rate of minor complications was not significantly higher (34.3% vs 30.8%, p = 0.610). CONCLUSION: Rigid adherence to our patient care pathway, and improved charting techniques including flow algorithms and multidisciplinary checklists has improved patient care by showing a significant reduction in the rate of major complications.

Transcranial magnetic stimulation of the brain: guidelines for pain treatment research.

Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of noninvasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multiday repetitive transcranial magnetic stimulation (rTMS) can induce long-lasting, potentially therapeutic brain plasticity. Nearby ferromagnetic or electronic implants are contraindications. Adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. Transcranial magnetic stimulation devices are marketed for depression and migraine in the United States and for various indications elsewhere. Although multiple studies report that high-frequency rTMS of the motor cortex reduces neuropathic pain, their quality has been insufficient to support Food and Drug Administration application. Harvard's Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters and improve strategies for sham and double blinding. Subjects should have common well-characterized pain conditions amenable to motor cortex rTMS and studies should be adequately powered. They recommended standardized assessment tools (eg, NIH's PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (eg, IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion and exclusion criteria, baseline and posttreatment means and SD, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months after initiation with prespecified statistical analyses. Multigroup collaborations or registry studies may be needed for pivotal trials.

The etiology and outcome of pneumonia in human immunodeficiency virus-infected children admitted to intensive care in a developing country.

In developing countries, many human immunodeficiency virus (HIV)-infected children require intensive care unit (ICU) resources for pneumonia, but there is little information on the etiology of pneumonia or the impact of ICU intervention. OBJECTIVE: To compare the etiology and outcome of pneumonia in HIV-positive and seronegative children admitted to ICU. DESIGN: Prospective study. SETTING: Two pediatric ICUs linked to the University of Cape Town, South Africa. PATIENTS: Consecutive children admitted for pneumonia during 1998. MEASUREMENTS AND MAIN RESULTS: Clinical, demographic, ventilatory, and laboratory data were collected. Blood for testing was obtained. Induced sputum or nondirected bronchoalveolar lavage was performed for culture and Pneumocystis carinii identification; gastric lavage (GL) provided specimens for mycobacterial culture. Seventy-six children (21 [27.6%, 95% confidence interval {CI} = 18-39.1] HIV-positive) were enrolled. At admission, HIV infection was diagnosed in 15 of the 21 (71.4% [47.8-88.7]) HIV-positive patients. P. carinii pneumonia occurred in eight HIV-positive children (38% of HIV-infected patients) and one HIV-negative child. It was the acquired immunodeficiency syndrome (AIDS)-defining illness in seven children (47%). The incidence of bacteremia (15.3%) was similar in HIV-positive (15.8%) and HIV-negative children (15.1%), p =.94; Streptococcus pneumoniae and Staphylococcus aureus were the predominant isolates. Bacterial and viral isolates from sputum or bronchoalveolar lavage, including Mycobacterium tuberculosis in six (8%) children, did not differ by HIV status. Intermittent positive pressure ventilation was used in 8 of 21 (38%) HIV-positive children and 28 of 55 (51%) HIV-negative children, p =.32. Median days of intermittent positive pressure ventilation (3 [2-6]), ICU (5 [3-9.5]), and hospital (11 [7.5-19]) did not vary by HIV status. The in-hospital mortality rate for HIV-positive children (6 of 21 [28.6%]) was double that for seronegative patients (8 of 55[14.5%], relative risk [RR] 1.96 [0.77-4.99], p =.16). CONCLUSION: More than a quarter of children admitted to ICU for pneumonia in this geographic area are HIV-positive; most are diagnosed with HIV at admission. P. carinii pneumonia is a common AIDS indicator disease. HIV-infected children admitted with pneumonia had a worse outcome than seronegative children, a difference that is rendered statistically insignificant by the small sample size.

Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes.

OBJECTIVE: We tested the hypothesis that acquired small-fiber polyneuropathy (SFPN), previously uncharacterized in children, contributes to unexplained pediatric widespread pain syndromes. METHODS: Forty-one consecutive patients evaluated for unexplained widespread pain beginning before age 21 had medical records comprehensively analyzed regarding objective diagnostic testing for SFPN (neurodiagnostic skin biopsy, nerve biopsy, and autonomic function testing), plus histories, symptoms, signs, other tests, and treatments. Healthy, demographically matched volunteers provided normal controls for SFPN tests. RESULTS: Age at illness onset averaged 12.3 ± 5.7 years; 73% among this poly-ethnic sample were female (P = .001). Sixty-eight percent were chronically disabled, and 68% had hospitalizations. Objective testing diagnosed definite SFPN in 59%, probable SFPN in 17%, and possible SFPN in 22%. Only 1 of 41 had entirely normal SFPN test results. Ninety-eight percent of patients had other somatic complaints consistent with SFPN dysautonomia (90% cardiovascular, 82% gastrointestinal, and 34% urologic), 83% reported chronic fatigue, and 63% had chronic headache. Neurologic examinations identified reduced sensation in 68% and vasomotor abnormalities in 55%, including 23% with erythromelalgia. Exhaustive investigations for SFPN causality identified only history of autoimmune illnesses in 33% and serologic markers of disordered immunity in 89%. Treatment with corticosteroids and/or intravenous immune globulin objectively and subjectively benefited 80% of patients (12/15). CONCLUSIONS: More than half among a large series of patients with childhood-onset, unexplained chronic widespread pain met rigorous, multitest, diagnostic criteria for SFPN, which extends the age range of acquired SFPN into early childhood. Some cases appeared immune-mediated and improved with immunomodulatory therapies.

Non-invasive Transcranial Magnetic Stimulation (TMS) of the Motor Cortex for Neuropathic Pain-At the Tipping Point?

The term "neuropathic pain" (NP) refers to chronic pain caused by illnesses or injuries that damage peripheral or central pain-sensing neural pathways to cause them to fire inappropriately and signal pain without cause. Neuropathic pain is common, complicating diabetes, shingles, HIV, and cancer. Medications are often ineffective or cause various adverse effects, so better approaches are needed. Half a century ago, electrical stimulation of specific brain regions (neuromodulation) was demonstrated to relieve refractory NP without distant effects, but the need for surgical electrode implantation limited use of deep brain stimulation. Next, electrodes applied to the dura outside the brain's surface to stimulate the motor cortex were shown to relieve NP less invasively. Now, electromagnetic induction permits cortical neurons to be stimulated entirely non-invasively using transcranial magnetic stimulation (TMS). Repeated sessions of many TMS pulses (rTMS) can trigger neuronal plasticity to produce long-lasting therapeutic benefit. Repeated TMS already has US and European regulatory approval for treating refractory depression, and multiple small studies report efficacy for neuropathic pain. Recent improvements include "frameless stereotactic" neuronavigation systems, in which patients' head MRIs allow TMS to be applied to precise underlying cortical targets, minimizing variability between sessions and patients, which may enhance efficacy. Transcranial magnetic stimulation appears poised for the larger trials necessary for regulatory approval of a NP indication. Since few clinicians are familiar with TMS, we review its theoretical basis and historical development, summarize the neuropathic pain trial results, and identify issues to resolve before large-scale clinical trials.