Postherpetic granulomatous dermatitis occurring in the setting of immune checkpoint inhibitor therapy: A case report.

We report a case of a 72-year-old man presenting with a 2-month history of a persistent, painful rash of the chest, axilla, and back. He had a history of recently resolved varicella zoster virus reactivation in the same distribution of the current rash and metastatic malignant melanoma treated with nivolumab and ipilimumab. The histopathology was consistent with granulomatous dermatitis (GD), and a diagnosis of postherpetic isotopic response manifesting as GD was made. Given the paucity of reported cases of postherpetic GD in the setting of treatment with immune checkpoint inhibitors (ICIs), we discuss the clinicopathologic features of this case and potential mechanisms by which ICIs may contribute to the development of granulomatous disease.

Skin necrosis in spinal muscular atrophy: Case report and review of the literature.

Spinal muscular atrophy (SMA) type 0 is the most severe phenotype of SMA and is characterized by hypotonia, muscle weakness, and respiratory distress. Cutaneous necrosis, first described in an SMA mouse model, can occur in patients with severe disease; the use of targeted treatment versus supportive measures in the setting of skin necrosis is debated. We present a male infant with SMA type 0 with cutaneous necrosis of proximal and distal limbs who improved with supportive care. The seven previously reported cases of SMA skin necrosis are reviewed.

Injury Severity and Depressive Symptoms in a Post-acute Brain Injury Rehabilitation Sample.

This study explored the relationship between injury severity and depressive symptoms for treatment-seeking individuals with traumatic brain injury (TBI). The Mayo Classification System was used to classify TBI severity in 72 participants who completed the Patient Health Questionnaire at admission and at dismissal from rehabilitation. Patients with mild TBI reported more depressive symptoms than those with moderate or severe TBI at admission and at dismissal. Although injury severity groups differed by gender composition, gender had no effect on severity of depressive symptoms. All participants reported fewer depressive symptoms at dismissal from rehabilitation, including lower endorsement of dysphoria by discharge. Participants with mild TBI, however, continued to report depressive symptoms of a mild severity at dismissal, with residual problems with anhedonia. These findings underscore the benefit of interdisciplinary post-acute rehabilitation services for persons with TBI of any severity, including those with mild injury.

Altered Morphology and Immunohistochemical Characteristics in Metastatic Malignant Melanoma After Therapy With Vemurafenib.

Metastatic melanoma is traditionally diagnosed using classic morphologic features in addition to immunohistochemical studies. The authors report a case of metastatic malignant melanoma where both morphology and immunohistochemistry were altered after treatment. This 51-year-old patient presented with metastatic melanoma to the brain and axilla. Initially, both metastases showed classic morphology and diffuse staining with the pan-melanoma antibody cocktail. This cocktail is a combination of 3 antibodies commonly used to diagnose melanocytic neoplasms: Melan-A (MART-1), tyrosinase, and HMB-45. In combination, the cocktail is highly sensitive for detecting melanocytic neoplasms and is commonly used to diagnose metastatic melanoma. Her tumor was positive for the BRAF 1799T>A (V600E) mutation, and she was treated with BRAF inhibitor therapy (vemurafenib). However, the axillary tumor recurred after treatment with vemurafenib. The recurrent tumor showed a markedly different morphology and complete loss of staining with the pan-melanoma antibody cocktail. This loss of staining accompanied by the change in morphology was an observation not previously documented after therapy with vemurafenib. This case demonstrates a potential pitfall in the diagnosis of metastatic or recurrent malignant melanoma.

Incidence, clinical course, and predictors of prolonged recovery time following sport-related concussion in high school and college athletes.

Sport-related concussion (SRC) is typically followed by clinical recovery within days, but reports of prolonged symptoms are common. We investigated the incidence of prolonged recovery in a large cohort (n = 18,531) of athlete seasons over a 10-year period. A total of 570 athletes with concussion (3.1%) and 166 controls who underwent pre-injury baseline assessments of symptoms, neurocognitive functioning and balance were re-assessed immediately, 3 hr, and 1, 2, 3, 5, 7, and 45 or 90 days after concussion. Concussed athletes were stratified into typical (within 7 days) or prolonged (> 7 days) recovery groups based on symptom recovery time. Ten percent of athletes (n = 57) had a prolonged symptom recovery, which was also associated with lengthier recovery on neurocognitive testing (p < .001). At 45-90 days post-injury, the prolonged recovery group reported elevated symptoms, without deficits on cognitive or balance testing. Prolonged recovery was associated with unconsciousness [odds ratio (OR), 4.15; 95% confidence interval (CI) 2.12-8.15], posttraumatic amnesia (OR, 1.81; 95% CI, 1.00-3.28), and more severe acute symptoms (p < .0001). These results suggest that a small percentage of athletes may experience symptoms and functional impairments beyond the typical window of recovery after SRC, and that prolonged recovery is associated with acute indicators of more severe injury.

Measuring brain electrical activity to track recovery from sport-related concussion.

PRIMARY OBJECTIVE: To follow recovery from concussion in a sample of athletes using an electroencephalographic (EEG) index of quantitative brain activity developed previously on an independent Emergency Department (ED) sample of head-injured subjects with traumatic brain injury. METHODS AND PROCEDURES: EEG recordings from five frontal electrode sites were obtained on 59 injured athletes and 31 controls at the time of injury and at 8 and 45 days afterward. All subjects also completed standardized clinical assessment of post-concussion symptoms, postural stability and cognitive functioning at injury and 8 and 45 days post-injury. RESULTS: Abnormalities in clinical assessment measures were observed in injured subjects only at time of injury. Statistical analysis of brain electrical activity measures with the ED-based algorithm revealed significant differences between injured athletes vs controls at the time of injury and at day 8. Measures from the two groups did not differ on day 45. CONCLUSIONS: This study demonstrated that an algorithm of brain electrical activity developed on an independent sample of ED subjects with head injury is sensitive to the effects of sport-related concussion. Using this algorithm, abnormal features of brain electrical activity were detected in athletes with concussion at the time of injury and persisted beyond the point of recovery on clinical measures.

Electric-field-induced wetting and dewetting in single hydrophobic nanopores.

The behaviour of water in nanopores is very different from that of bulk water. Close to hydrophobic surfaces, the water density has been found to be lower than in the bulk, and if confined in a sufficiently narrow hydrophobic nanopore, water can spontaneously evaporate. Molecular dynamics simulations have suggested that a nanopore can be switched between dry and wet states by applying an electric potential across the nanopore membrane. Nanopores with hydrophobic walls could therefore create a gate system for water, and also for ionic and neutral species. Here, we show that single hydrophobic nanopores can undergo reversible wetting and dewetting due to condensation and evaporation of water inside the pores. The reversible process is observed as fluctuations between conducting and non-conducting ionic states and can be regulated by a transmembrane electric potential.

Estimating the diagnostic value of the trail making test for suboptimal effort in acquired brain injury rehabilitation patients.

This investigation explored the classification accuracy of Trail Making Test (TMT; Reitan & Wolfson, 1992) indices for suboptimal effort in a sample of non-litigious acquired brain injury patients seeking outpatient rehabilitation. Patients who exhibited optimal effort completed TMT A and B faster than suboptimal effort patients. Although TMT A time to completion demonstrated adequate sensitivity to suboptimal effort, positive predictive value was fair to poor unless the base rate of suboptimal effort was inflated to 40%. TMT B time to completion yielded poor sensitivity and positive predictive value for suboptimal effort. While TMT A time to completion appears to have some value as a validity indicator, no TMT validity indicator should replace more precise symptom validity tests during neuropsychological assessment.

Acute effects and recovery after sport-related concussion: a neurocognitive and quantitative brain electrical activity study.

OBJECTIVE: To investigate the clinical utility and sensitivity of a portable, automatic, frontal quantitative electroencephalographic (QEEG) acquisition device currently in development in detecting abnormal brain electrical activity after sport-related concussion. DESIGN: This was a prospective, non-randomized study of 396 high school and college football players, including cohorts of 28 athletes with concussion and 28 matched controls. All subjects underwent preseason baseline testing on measures of postconcussive symptoms, postural stability, and cognitive functioning, as well as QEEG. Clinical testing and QEEG were repeated on day of injury and days 8 and 45 postinjury for the concussion and control groups. MAIN OUTCOMES AND RESULTS: The injured group reported more significant postconcussive symptoms during the first 3 days postinjury, which resolved by days 5 and 8. Injured subjects also performed poorer than controls on neurocognitive testing on the day of injury, but no differences were evident on day 8 or day 45. QEEG studies revealed significant abnormalities in electrical brain activity in the injured group on day of injury and day 8 postinjury, but not on day 45. CONCLUSIONS: Results from the current study on clinical recovery after sport-related concussion are consistent with early reports indicating a typical course of full recovery in symptoms and cognitive dysfunction within the first week of injury. QEEG results, however, suggest that the duration of physiological recovery after concussion may extend longer than observed clinical recovery. Further study is required to replicate and extend these findings in a larger clinical sample, and further demonstrate the utility of QEEG as a marker of recovery after sport-related concussion.

An integrated review of recovery after mild traumatic brain injury (MTBI): implications for clinical management.

The diagnosis and treatment of mild traumatic brain injury (MTBI)have historically been hampered by an incomplete base of scientific evidence to guide clinicians. One question has been most elusive to clinicians and researchers alike: What is the true natural history of MTBI? Fortunately, the science of MTBI has advanced more in the last decade than in the previous 50 years, and now reaches a maturity point at which the science can drive an evidence-based approach to clinical management. In particular, technological advances in functional neuroimaging have created a powerful bridge between the clinical and basic science of MTBI in humans. Collectively, findings from clinical, basic science, and functional neuroimaging studies now establish a foundation on which to build integrative theories and testable hypotheses around a comprehensive model of MTBI recovery. We review the current scientific literature on postconcussion symptom recovery, neuropsychological outcome, and neurophysiological healing after MTBI. Special emphasis is placed on how the new evidence base can help guide clinicians in the evaluation and management of military-related MTBI.

Nonequilibrium 1/f noise in rectifying nanopores.

We report a single rectifying conically shaped nanopore system with ion current fluctuations whose 1/f noise characteristics observed at low frequencies are voltage dependent. Switching the voltage polarity allows one to switch between a system that produces equilibrium and nonequilibrium 1/f ion current fluctuations. The nonequilibrium fluctuations in the high-conductance state of the device are characterized by exponential dependence of the normalized power spectrum on voltage. The asymmetric 1/f noise is found characteristic for rectifying polymer nanopores and absent in pores with Ohmic current-voltage curves.

Nanoprecipitation-assisted ion current oscillations.

Nanoscale pores exhibit transport properties that are not seen in micrometre-scale pores, such as increased ionic concentrations inside the pore relative to the bulk solution, ionic selectivity and ionic rectification. These nanoscale effects are all caused by the presence of permanent surface charges on the walls of the pore. Here we report a new phenomenon in which the addition of small amounts of divalent cations to a buffered monovalent ionic solution results in an oscillating ionic current through a conical nanopore. This behaviour is caused by the transient formation and redissolution of nanoprecipitates, which temporarily block the ionic current through the pore. The frequency and character of ionic current instabilities are regulated by the potential across the membrane and the chemistry of the precipitate. We discuss how oscillating nanopores could be used as model systems for studying nonlinear electrochemical processes and the early stages of crystallization in sub-femtolitre volumes. Such nanopore systems might also form the basis for a stochastic sensor.

Effort issues in post-acute outpatient acquired brain injury rehabilitation seekers.

Recent findings suggest that compromised patient effort occurs in nonlitigious settings, but the nature and base rate of suboptimal effort in these settings remains poorly understood. In the treatment-seeking, acquired brain injury, outpatient rehabilitation sample included in this investigation, 21.8% of the patients scored below recommended cutting scores for suboptimal effort on the Test of Memory Malingering (TOMM). Disability status was the only variable explored in this study to be associated with suboptimal effort. It should be noted, however, that the proportion of patients on disability was large in both the optimal and suboptimal effort groups, suggesting that failure on the TOMM may not be a specific predictor of disability status in this sample. Importantly, performance on the TOMM was unrelated to age, education, time from injury to evaluation, and injury severity. Depression and anxiety were also shown to be unrelated to TOMM performance in this rehabilitation sample. As expected, performance on neurocognitive testing was significantly lower in the suboptimal effort group. This study suggests that reduced effort occurs outside forensic settings, is related to neuropsychometric performance, and urges further research into effort across various settings.

Calcium-induced voltage gating in single conical nanopores.

We examine time signals of ion current through single conically shaped nanopores in the presence of sub-millimolar concentrations of calcium ions. We show that calcium induces voltage-dependent ion current fluctuations in time in addition to the previously reported negative incremental resistance (Nano Lett. 2006, 6, 473-477). These current fluctuations occur on the millisecond time scale at voltages at which the effect of negative incremental resistance was observed. We explain the fluctuations as results of transient binding of calcium ions to carboxyl groups on the pore walls that cause transient changes in electric potential inside a conical nanopore. We support this explanation by recordings of ion current in the presence of manganese ions that bind to carboxyl groups 3 orders of magnitude more tightly than calcium ions. The system of a single conical nanopore with calcium ions is compared to a semiconductor device of a unijunction transistor in electronic circuits. A unijunction transistor also exhibits negative incremental resistance and current instabilities.

Cognitive measures predict pathologic Alzheimer disease.

BACKGROUND: Neuropsychologic testing is often used to infer neuropathologic processes, but clinicopathologic correlations for individual cognitive measures are based on a small number of published studies. OBJECTIVE: To examine the usefulness of the age- and education-adjusted Mayo Cognitive Factor Scales (MCFS) obtained at participants' initial assessments for predicting the presence or absence of pathologic Alzheimer disease (AD). DESIGN: This was a longitudinal study of a cohort of elderly patients with and without cognitive complaints who were followed up until death. Mayo Cognitive Factor Scales age- and education-adjusted standard scores from the participants' initial evaluations were used to calculate classification accuracy statistics for neuropathologic AD diagnosis obtained approximately 6 years after testing. Subjects with non-AD diagnoses or substantial non-AD-related changes were excluded from the study. SETTING: Academic medical center. PARTICIPANTS: One hundred two participants were evaluated clinically and underwent neuropathologic examination at autopsy. All were part of the Mayo Clinic Alzheimer's Disease Patient Registry or Alzheimer Disease Research Center. RESULTS: All Mayo Cognitive Factor Scale scores were significantly correlated with AD criteria. Logistic regression modeling including Mayo Cognitive Factor Scales Verbal Comprehension and Retention indices revealed high positive predictive value with moderate sensitivity and specificity for pathologic AD. CONCLUSION: Neuropsychologic test scores at initial evaluations were predictive of pathologic AD.

Negative incremental resistance induced by calcium in asymmetric nanopores.

Single polymer nanopores with permanent surface charges act as rectifiers of ionic current. The pores are tapered cones with narrow openings of several nanometers and wide openings of approximately 1 mum. The pores are cation-selective, and in symmetric solutions of potassium chloride they rectify the flow of potassium ions from the small opening toward the wide opening. Millimolar concentrations of calcium reverse the rectification, and a negative incremental resistance is observed. These observations can be interpreted by a model containing flashing ratchets.

Detecting symptom- and test-coached simulators with the test of memory malingering.

The ability of the Test of Memory Malingering (TOMM; Tombaugh, 1996) to detect feigned-memory impairment was explored. The TOMM was administered to three groups: (a) a control group instructed to perform optimally, (b) a symptom-coached group instructed to feign memory problems after being educated about traumatic brain injury symptomatology, and (c) a test-coached group instructed to feign memory problems after being educated about test-taking strategies to avoid detection. The recommended cutoff scores (Tombaugh, 1996) on Trial 2 and the Retention Trial produced overall classification accuracy rates of 96%, with high levels of sensitivity and specificity. Although the symptom-coached group performed more poorly on the TOMM relative to the test-coached group, the test was equally sensitive in detecting suboptimal effort across the different coaching paradigms.