Assessment, management, and rehabilitation of traumatic peripheral nerve injuries for non-surgeons.

Electrodiagnostic evaluation is often requested for persons with peripheral nerve injuries and plays an important role in their diagnosis, prognosis, and management. Peripheral nerve injuries are common and can have devastating effects on patients' physical, psychological, and socioeconomic well-being; alongside surgeons, electrodiagnostic medicine specialists serve a central function in ensuring patients receive optimal treatment for these injuries. Surgical intervention-nerve grafting, nerve transfers, and tendon transfers-often plays a critical role in the management of these injuries and the restoration of patients' function. Increasingly, nerve transfers are becoming the standard of care for some types of peripheral nerve injury due to two significant advantages: first, they shorten the time to reinnervation of denervated muscles; and second, they confer greater specificity in directing motor and sensory axons toward their respective targets. As the indications for, and use of, nerve transfers expand, so too does the role of the electrodiagnostic medicine specialist in establishing or confirming the diagnosis, determining the injury's prognosis, recommending treatment, aiding in surgical planning, and supporting rehabilitation. Having a working knowledge of nerve and/or tendon transfer options allows the electrodiagnostic medicine specialist to not only arrive at the diagnosis and prognosticate, but also to clarify which nerves and/or muscles might be suitable donors, such as confirming whether the branch to supinator could be a nerve transfer donor to restore distal posterior interosseous nerve function. Moreover, post-operative testing can determine if nerve transfer reinnervation is occurring and progress patients' rehabilitation and/or direct surgeons to consider tendon transfers.

The 27-gene IO score is associated with efficacy of PD-1/L1 inhibitors independent of FGFR expression in a real-world metastatic urothelial carcinoma cohort.

Multiple targeted therapeutics have been approved by the FDA for mUC, including immune checkpoint inhibitors (ICIs) and more recently targeted agents for both FGFR and Nectin-4. FGFR3-aberrant and Nectin-4 expressing cells have been associated with an immunosuppressed phenotype. Given that less than half of all patients respond to these agents as monotherapies and less than 20% are eligible to receive salvage therapy, effective personalized treatment plans are critical. Typical biomarkers for ICIs such as PD-L1 and TMB have not been definitive in mUC, yet a biomarker-driven optimization of first-line therapy and subsequent sequencing have the potential to achieve higher and more durable response rates. The IO score is a 27-gene tumor immune microenvironment (TIME) classifier that has been associated with the clinical benefits of ICIs in multiple cancer types, including mUC. This study demonstrates that the IO score was associated with both progression-free survival (PFS) and overall survival (OS) in a real-world cohort of mUC patients treated with ICIs. Furthermore, the IO score was independent of and provided information incremental to TMB. Interestingly, the IO score predicted benefit in patients with high FGFR expression, despite conflicting data regarding response rates among the FGFR aberrant population. Taken together, these results demonstrate that the IO score assessment of the TIME is associated with a clinical benefit from ICI therapy and that this novel biomarker may inform therapeutic sequencing decisions in mUC, potentially improving outcomes for this notoriously difficult-to-treat disease.

Geographic variation in 5-year mortality following HIV diagnosis: implications for clinical interventions.

Characterizing spatial distribution of HIV outcomes is vital for targeting interventions to areas most at risk. We performed spatial analysis to identify geographic clusters and factors associated with mortality in KwaZulu-Natal, South Africa. We utilized Sizanani trial (NCT01188941) data, which enrolled participants August 2010-January 2013 and obtained vital status at 5.8 (IQR 5.0-6.4) years of follow-up. We mapped geocoded addresses to 2011 Census-defined small area layer (SAL) centroids, used Kulldorff's spatial scan statistic to identify mortality clusters, and compared socio-demographic factors for SALs within and outside mortality clusters. We assigned 1,143 participants living with HIV (260 [23%] of whom died during follow-up) to 677 SALs. One lower mortality cluster (n = 90, RR = 0.23, p = 0.022) was identified near a hospital outside Durban. SALs in the cluster were younger (24y vs 25y, p < 0.001); had fewer bedrooms/household (3 vs 4, p < 0.001); had more females (52% vs 51%, p = 0.013) and residents with no schooling past age 20 (4% vs 3%, p < 0.001) or no education at all (4% vs 3%, p < 0.001); had fewer residents with income >3,200 ZAR/month (5% vs 9%, p < 0.001); and had reduced access to piped water (p < 0.001), refuse disposal (p < 0.001), and toilets (p < 0.001). Targeted interventions may improve outcomes in areas with similar characteristics.

The hand diagram: A novel outcome measure following supercharged end-to-side anterior interosseous nerve to ulnar nerve transfer in severe compressive ulnar neuropathy.

BACKGROUND: With advances in the surgical management for severe ulnar neuropathy with the introduction of the super charged-end-to-side (SETS) anterior interosseous nerve (AIN) to ulnar nerve transfer, a simple and reliable outcome measure is required. There is currently not "one" standardized outcome measure used to represent and compare results. PURPOSE: To present the abduction hand diagram as a "novel", reproducible, and simple outcome measure for patients with severe ulnar neuropathy. STUDY DESIGN: Retrospective case series. METHODS: Nine patients with severe entrapment/compressive ulnar neuropathy at the elbow were reviewed. Clinical parameters included preoperative and postoperative abduction tracings, Medical Research Grade (MRC) muscle strength, key pinch strength, Disability of the Hand Arm and Shoulder (DASH) score, and crossed finger test. Electrodiagnostic data included change in compound muscle action potentials (CMAP) amplitude of the first dorsal interosseous (FDI), and abductor digiti minimi (ADM). Summary statistics were used for demographic and clinical data. RESULTS: Average follow-up was 22.8 ± 9.3 months. At 18-months of follow up, 44% had ADM MRC grade 3 strength or higher, mean key pinch strength improved to 72 ± 19.3%, and mean DASH was 33 ± 28.7. There was a mean increase of 16.7 ± 9.1 mm and 31.5 ± 12 mm in total and summed hand abduction tracing measurements respectively. CONCLUSIONS: Hand abduction tracings are a quantitative outcome measure to follow recovery over time for intrinsic hand function and can be used in patients with severe ulnar neuropathy following surgical intervention.

Treating hypothyroidism is not always easy: When to treat subclinical hypothyroidism, TSH goals in the elderly, and alternatives to levothyroxine monotherapy.

The majority of patients with hypothyroidism feel better when levothyroxine treatment restores thyroid-stimulating hormone (TSH) concentrations to normal. Increasingly, a significant minority of patients remain symptomatic and are dissatisfied with their treatment. Overzealous treatment of symptomatic patients with subclinical hypothyroidism may contribute to dissatisfaction among hypothyroidism patients, as potential hypothyroid symptoms in patients with minimal hypothyroidism rarely respond to treatment. Thyroid hormone prescriptions have increased by 30% in the United States in the last decade. The diagnosis of subclinical hypothyroidism should be confirmed by repeat thyroid function tests ideally obtained at least 2 months later, as 62% of elevated TSH levels may revert to normal spontaneously. Generally, treatment is not necessary unless the TSH exceeds 7.0-10 mIU/L. In double-blinded randomized controlled trials, treatment does not improve symptoms or cognitive function if the TSH is less than 10 mIU/L. While cardiovascular events may be reduced in patients under age 65 with subclinical hypothyroidism who are treated with levothyroxine, treatment may be harmful in elderly patients with subclinical hypothyroidism. TSH goals are age dependent, with a 97.5 percentile (upper limit of normal) of 3.6 mIU/L for patients under age 40, and 7.5 mIU/L for patients over age 80. In some hypothyroid patients who are dissatisfied with treatment, especially those with a polymorphism in type 2 deiodinase, combined treatment with levothyroxine and liothyronine may be preferred.

Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients.

BACKGROUND: The IO Score is a 27-gene immuno-oncology (IO) classifier that has previously predicted benefit to immune checkpoint inhibitor (ICI) therapy in triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). It generates both a continuous score and a binary result using a defined threshold that is conserved between breast and lung. Herein, we aimed to evaluate the IO Score's binary threshold in ICI-naïve TCGA bladder cancer patients (TCGA-BLCA) and assess its clinical utility in metastatic urothelial cancer (mUC) using the IMvigor210 clinical trial treated with the ICI, atezolizumab. METHODS: We identified a list of tumor immune microenvironment (TIME) related genes expressed across the TCGA breast, lung squamous and lung adenocarcinoma cohorts (TCGA-BRCA, TCGA-LUSQ, and TCGA-LUAD, 939 genes total) and then examined the expression of these 939 genes in TCGA-BLCA, to identify patients as having high inflammatory gene expression. Using this as a test of classification, we assessed the previously established threshold of IO Score. We then evaluated the IO Score with this threshold in the IMvigor210 cohort for its association with overall survival (OS). RESULTS: In TCGA-BLCA, IO Score positive patients had a strong concordance with high inflammatory gene expression (p < 0.0001). Given this concordance, we applied the IO Score to the ICI treated IMvigor210 patients. IO Score positive patients (40%) had a significant Cox proportional hazard ratio (HR) of 0.59 (95% CI 0.45-0.78 p < 0.001) for OS and improved median OS (15.6 versus 7.5 months) compared to IO Score negative patients. The IO Score remained significant in bivariate models combined with all other clinical factors and biomarkers, including PD-L1 protein expression and tumor mutational burden. CONCLUSION: The IMvigor210 results demonstrate the potential for the IO Score as a clinically useful biomarker in mUC. As this is the third tumor type assessed using the same algorithm and threshold, the IO Score may be a promising candidate as a tissue agnostic marker of ICI clinical benefit. The concordance between IO Score and inflammatory gene expression suggests that the classifier is capturing common features of the TIME across cancer types.

Association of a novel 27-gene immuno-oncology assay with efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapies represent a major advance in treating a variety of advanced-stage malignancies. Nevertheless, only a subset of patients benefit, even when selected based on approved biomarkers such as PD-L1 and tumor mutational burden. New biomarkers are needed to maximize the therapeutic ratio of these therapies. METHODS: In this retrospective cohort, we assessed a 27-gene RT-qPCR immuno-oncology (IO) gene expression assay of the tumor immune microenvironment and determined its association with the efficacy of ICI therapy in 67 advanced-stage NSCLC patients. The 27-gene IO test score (IO score), programmed cell death ligand 1 immunohistochemistry tumor proportion score (PD-L1 TPS), and tumor mutational burden (TMB) were analyzed as continuous variables for response and as binary variables for one-year progression free survival. The threshold for the IO score was prospectively set based upon a previously described training cohort. Prognostic implications of the IO score were evaluated in a separate cohort of 104 advanced-stage NSCLC patients from The Cancer Genome Atlas (TCGA) who received non-ICI therapy. RESULTS: The IO score was significantly different between responders or non-responders (p = 0.007) and associated with progression-free survival (p = 0.001). Bivariate analysis established that the IO score was independent of PD-L1 TPS and TMB in identifying patients benefiting from ICI therapy. In a separate cohort of late-stage NSCLC patients from TCGA, the IO score was not prognostic of outcome from non-ICI-treated patients. CONCLUSIONS: This study is the first application of this 27-gene IO RT-qPCR assay in a clinical cohort with outcome data. IO scores were significantly associated with response to ICI therapy and prolonged progression-free survival. Together, these data suggest the IO score should be further studied to define its role in informing clinical decision-making for ICI treatment in NSCLC.

Comparison of long-term antithyroid drugs versus radioactive iodine or surgery for Graves' disease: A review of the literature.

BACKGROUND: The management of Graves' disease (GD) in the US is shifting towards increased use of anti-thyroid drugs (ATD). If patients fail to achieve remission after a standard course of therapy of 12-18 months, long-term treatment with ATD (≥24 months) may be chosen over definitive therapy with radioiodine (RAI) or surgery. Clinicians will need to contrast this strategy to ablative therapies as they help patients in decision making. SUMMARY: Review of the literature illustrates that long-term ATD delivers euthyroidism with minimal complications, low financial cost and with an advantageous profile regarding quality of life (QoL) and other biological outcomes. CONCLUSIONS: Long-term ATD is a viable alternative to ablative therapies in the management of GD offering advantages across multiple patient centred outcomes. Decision making must factor differences in this approach compared to ablative therapies and ultimately be tailored to individualized patient situations.

Postoperative management and rehabilitation after the supercharged end-to-side anterior interosseous nerve to ulnar motor nerve transfer: A report of 3 cases.

INTRODUCTION: Compressive ulnar neuropathy at the elbow is the second most common compressive neuropathy. Nerve transfers are used for severe ulnar neuropathies as a means of facilitating recovery. Hand therapy and rehabilitation after nerve transfers have not been extensively explored. PURPOSE OF THE STUDY: The aim of this repeated case study was to describe the responses, functional outcome, and neuromuscular health of three participants after the supercharged end-to-side (SETS) anterior interosseous nerve (AIN) to ulnar motor nerve transfer do describe the hand therapy and recovery of 3 cases reflecting different recovery potential mediators, trajectories, and outcomes. STUDY DESIGN: Repeated case study. METHODS: Three participants of similar age (76-80 years) that had severe ulnar neuropathy who underwent surgical treatment including a SETS AIN to ulnar motor nerve surgery were purposively selected from an ongoing clinical trial, based on their response to the surgical and the rehabilitation intervention (large, moderate, and small improvements). Clinical evaluations included measuring range of motion, strength testing, and clinical tests (ie, Egawa's sign) and, subjective assessment of rehabilitation adherence., Quick Disability of Arm, Shoulder and Hand and decomposition-based quantitative electromyography were performed at >23 months to evaluate patients. RESULTS: All the three participants completed the surgical and hand therapy interventions, demonstrating a variable course of recovery and functional outcomes. The Quick Disability of Arm, Shoulder and Hand scores (>23 months) for participants A, B, and C were 68, 30, and 18, respectively. The person with the least improvement had idiopathic Parkinson's disease, dyslipidemia, history of depression, and gout. Comparison across cases suggested that the comorbidities, longer time from neuropathy to the surgical intervention, and psychosocial barriers to exercise and rehabilitation adherence influenced the recovery process. The participants with the best outcomes demonstrated improvements in his lower motor neurons or motor unit counts (109 and 18 motor units in the abductor digiti minimi (ADM) and first dorsal interosseous, respectively) and motor unit stability (39.5% and 37.6% near-fiber jiggle in the ADM and first dorsal interosseous, respectively). The participant with moderate response to the interventions had a motor unit count of 93 for the ADM muscle. We were unable to determine motor unit counts and measurements from the participant with the poorest outcomes due to his physical limitations. CONCLUSIONS: SETS AIN to ulnar motor nerve followed by multimodal hand therapy provides measurable improvements in neurophysiology and function, although engagement in hand therapy and outcomes appear to be mediated by comorbid physical and psychosocial health.

Trends in immediate breast reconstruction and radiation after mastectomy: A population study.

In the last decade, there has been an increase in women undergoing immediate breast reconstruction (IBR) at the time of mastectomy. Recent literature suggests a shift in practice: Surgeons are becoming more comfortable with IBR in the setting of possible postoperative adjuvant radiotherapy, despite the known complications. This study sought to investigate, at a population level, the patient and surgeon characteristics associated with the use of IBR and which of these factors were predictive of adjuvant radiotherapy. This retrospective population-based cohort study included all adult women who underwent mastectomy in the province of Ontario from 2007 to 2014. The Canadian Institute for Health Information (CIHI) administrative data base was used to generate patient demographic and clinical data. The Ontario Health Insurance Plan (OHIP) data base was used to elicit surgeon characteristics including clinical experience and volume of practice dedicated to breast surgery. Outcome variables included reconstruction concurrent with mastectomy, alloplastic vs autologous reconstruction, and use of radiation. A total of 25 861 patients underwent mastectomy and 2972 had IBR (11.5%). The rate of IBR after mastectomy increased over time from 7.2% in 2007 to 17.2% in 2014 (P < .001). There was also an increase in the proportion of patients with IBR who received radiation over the time period, from 19.4% in 2007 to 28.2% in 2014 (P = .003). In the first regression analysis, IBR was associated with younger patient age, residing in closer proximity to cancer clinics, absence of malignant breast disease (ie, prophylactic mastectomy), having a younger surgeon performing the mastectomy, and receiving care at a teaching hospital. A second analysis showed that patient variables predictive of radiation after IBR were a younger age and a more advanced cancer stage and no variables specific to surgeon or institution were predictive of radiation in patients with IBR. A significant increase in the rate of IBR as well as the use of radiation occurred over the 7-year study period. Multiple patient and surgeon factors were associated with IBR. Variables associated with radiation in IBR were harder to predict. Given the increase in the use of radiation in IBR, further research is needed to look at long-term outcomes in these patients at the population level.

Subclinical tuberculosis among adults with HIV: clinical features and outcomes in a South African cohort.

BACKGROUND: Subclinical tuberculosis is an asymptomatic disease phase with important relevance to persons living with HIV. We describe the prevalence, clinical characteristics, and risk of mortality for HIV-infected adults with subclinical tuberculosis. METHODS: Untreated adults with HIV presenting for outpatient care in Durban, South Africa were screened for tuberculosis-related symptoms and had sputum tested by acid-fast bacilli smear and tuberculosis culture. Active tuberculosis and subclinical tuberculosis were defined as having any tuberculosis symptom or no tuberculosis symptoms with culture-positive sputum. We evaluated the association between tuberculosis disease category and 12-month survival using Cox regression, adjusting for age, sex, and CD4 count. RESULTS: Among 654 participants, 96 were diagnosed with active tuberculosis disease and 28 with subclinical disease. The median CD4 count was 68 (interquartile range 39-161) cells/mm3 in patients with active tuberculosis, 136 (72-312) cells/mm3 in patients with subclinical disease, and 249 (125-394) cells/mm3 in those without tuberculosis disease (P < 0.001). The proportion of smear positive cases did not differ significantly between the subclinical (29%) and active tuberculosis groups (14%, P 0.08). Risk of mortality was not increased in individuals with subclinical tuberculosis relative to no tuberculosis (adjusted hazard ratio 0.84, 95% confidence interval 0.26-2.73). CONCLUSIONS: Nearly one-quarter of tuberculosis cases among HIV-infected adults were subclinical, which was characterized by an intermediate degree of immunosuppression. Although there was no significant difference in survival, anti-tuberculous treatment of subclinical cases was common. TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov , NCT01188941 (August 26, 2010).

Insecticide resistance monitoring of house fly populations from the United States.

Insecticide resistance in house fly populations is a major problem faced by livestock producers worldwide. A survey of insecticide resistance levels and pyrethroid resistance allele frequencies in the United States was conducted in 2008-09, but little is known about how resistance levels have changed over the last 10 years. In addition, new target-site pyrethroid resistance alleles that confer high levels of resistance have been recently identified in the voltage-sensitive sodium channel, and their frequencies in field populations are unknown. Our aim in this study was to reassess the resistance status of house flies from select locations in the United States by examining resistance levels against commonly used insecticides and frequencies of known resistance alleles. House flies were collected from animal production facilities in five different states between 2016 and 2018. Resistance levels to three insecticides (permethrin, tetrachlorvinphos, and methomyl), representing three classes of insecticides (pyrethroids, organophosphates and carbamates) varied geographically and were lowest in the population collected from New Mexico, intermediate in the population collected from Utah, and greatest in the population from Kansas. The recently identified 1B pyrethroid resistance allele increased dramatically in frequency compared to previous reports, most notably in populations from Kansas and Maryland, indicating that it may already be widespread around the United States. Based on comparison with historical data, the population collected from Kansas represents one of the most highly permethrin resistant populations ever sampled. If the alleles responsible for this level of resistance spread, pyrethroids may be of limited use for house fly control in the United States in the near future.

Treatment of Cervical Spondylotic Amyotrophy With Nerve Transfers.

Cervical spondylotic amyotrophy is characterized by severe, proximal upper extremity weakness including an inability to abduct the shoulder and flex the elbow. Treatment using both medical and surgical decompression approaches has produced variable results. This paper reports the use of nerve transfers (spinal accessory to suprascapular, flexor carpi ulnaris fascicle of ulnar to biceps motor branch, radial nerve branch to triceps to axillary) to restore shoulder and elbow function in a case of unilateral cervical spondylotic amyotrophy involving C5 and C6 myotomes. Evidence of regeneration was observed on electromyography as well as clinically at 5 months postoperatively. At 3 years after surgery, recovery of elbow flexion and shoulder abduction was Medical Research Council grade 4/5 with improved external rotation and considerably improved patient-rated Disabilities of the Arm, Shoulder and Hand scores. We propose that nerve transfers be considered along with other reconstruction modalities in the treatment of cervical spondylotic amyotrophy.

Death-associated Protein Kinase-1 Expression and Autophagy in Chronic Lymphocytic Leukemia Are Dependent on Activating Transcription Factor-6 and CCAAT/Enhancer-binding Protein-ß.

Expression of DAPK1, a critical regulator of autophagy and apoptosis, is lost in a wide variety of tumors, although the mechanisms are unclear. A transcription factor complex consisting of ATF6 (an endoplasmic reticulum-resident factor) and C/EBP-ß is required for the IFN-γ-induced expression of DAPK1 IFN-γ-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-ß are obligatory for the formation of this transcriptional complex. We report that defects in this pathway fail to control growth of chronic lymphocytic leukemia (CLL). Consistent with these observations, IFN-γ and chemotherapeutics failed to activate autophagy in CLL patient samples lacking ATF6 and/or C/EBP-ß. Together, these results identify a molecular basis for the loss of DAPK1 expression in CLL.

Performance of claims-based algorithms for identifying incident thyroid cancer in commercial health plan enrollees receiving antidiabetic drug therapies.

BACKGROUND: Thyroid cancer incidence is increasing in the United States (US) and many other countries. The objective of this study was to develop and evaluate algorithms using administrative medical claims data for identification of incident thyroid cancer. METHODS: This effort was part of a prospective cohort study of adults initiating therapy on antidiabetic drugs and used administrative data from a large commercial health insurer in the US. Patients had at least 6 months of continuous enrollment prior to initiation during 2009-2013, with follow-up through March, 2014 or until disenrollment. Potential incident thyroid cancers were identified using International Classification of Diseases, 9th Revision (ICD-9) diagnosis code 193 (malignant neoplasm of the thyroid gland). Medical records were adjudicated by a thyroid cancer specialist. Several clinical variables (e.g., hospitalization, treatments) were considered as predictors of case status. Positive predictive values (PPVs) and 95% confidence intervals (CIs) were calculated to evaluate the performance of two primary algorithms. RESULTS: Charts were requested for 170 patients, 150 (88%) were received and 141 (80%) had sufficient information to adjudicate. Of the 141 potential cases identified using ≥1 ICD-9 diagnosis code 193, 72 were confirmed as incident thyroid cancer (PPV of 51% (95% CI 43-60%)). Adding the requirement for thyroid surgery increased the PPV to 68% (95% CI 58-77%); including the presence of other therapies (chemotherapy, radio-iodine therapy) had no impact. When cases were required to have thyroid surgery during follow-up and ≥2 ICD-9 193 codes within 90 days of this surgery, the PPV was 91% (95% CI 81-96%); 62 (82%) of the true cases were identified and 63 (91%) of the non-cases were removed from consideration by the algorithm as potential cases. CONCLUSIONS: These findings suggest a significant degree of misclassification results from relying only on ICD-9 diagnosis codes to detect thyroid cancer. An administrative claims-based algorithm was developed that performed well to identify true incident thyroid cancer cases.

Functional cyclic AMP response element in the breast cancer resistance protein (BCRP/ABCG2) promoter modulates epidermal growth factor receptor pathway- or androgen withdrawal-mediated BCRP/ABCG2 transcription in human cancer cells.

Phosphorylated cyclic-AMP (cAMP) response element binding protein (p-CREB) is a downstream effector of a variety of important signaling pathways. We investigated whether the human BCRP promoter contains a functional cAMP response element (CRE). 8Br-cAMP, a cAMP analogue, increased the activity of a BCRP promoter reporter construct and BCRP mRNA in human carcinoma cells. Epidermal growth factor receptor (EGFR) pathway activation also led to an increase in p-CREB and in BCRP promoter reporter activity via two major downstream EGFR signaling pathways: the phosphotidylinositol-3-kinase (PI3K)/AKT pathway and the mitogen-activated protein kinase (MAPK) pathway. EGF treatment increased the phosphorylation of EGFR, AKT, ERK and CREB, while simultaneously enhancing BCRP mRNA and functional protein expression. EGF-stimulated CREB phosphorylation and BCRP induction were diminished by inhibition of EGFR, PI3K/AKT or RAS/MAPK signaling. CREB silencing using RNA interference reduced basal levels of BCRP mRNA and diminished the induction of BCRP by EGF. Chromatin immunoprecipitation assays confirmed that a putative CRE site on the BCRP promoter bound p-CREB by a point mutation of the CRE site abolished EGF-induced stimulation of BCRP promoter reporter activity. Furthermore, the CREB co-activator, cAMP-regulated transcriptional co-activator (CRTC2), is involved in CREB-mediated BCRP transcription: androgen depletion of LNCaP human prostate cancer cells increased both CREB phosphorylation and CRTC2 nuclear translocation, and enhanced BCRP expression. Silencing CREB or CRTC2 reduced basal BCRP expression and BCRP induction under androgen-depletion conditions. This novel CRE site plays a central role in mediating BCRP gene expression in several human cancer cell lines following activation of multiple cancer-relevant signaling pathways.

Nerve transfers and neurotization in peripheral nerve injury, from surgery to rehabilitation.

Peripheral nerve injury (PNI) and recent advances in nerve reconstruction (such as neurotization with nerve transfers) have improved outcomes for patients suffering peripheral nerve trauma. The purpose of this paper is to bridge the gap between the electromyographer/clinical neurophysiologist and the peripheral nerve surgeon. Whereas the preceding literature focuses on either the basic science behind nerve injury and reconstruction, or the surgical options and algorithms, this paper demonstrates how electromyography is not just a 'decision tool' when deciding whether to operate but is also essential to all phases of PNI management including surgery and rehabilitation. The recent advances in the reconstruction and rehabilitation of PNI is demonstrated using case examples to assist the electromyographer to understand modern surgical techniques and the unique demands they ask from electrodiagnostic testing.

ACTIVE SURVEILLANCE FOR PAPILLARY THYROID MICROCARCINOMA: NEW CHALLENGES AND OPPORTUNITIES FOR THE HEALTH CARE SYSTEM.

OBJECTIVE: The dramatic increase in papillary thyroid carcinoma (PTC) is primarily a result of early diagnosis of small cancers. Active surveillance is a promising management strategy for papillary thyroid microcarcinomas (PTMCs). However, as this management strategy gains traction in the U.S., it is imperative that patients and clinicians be properly educated, patients be followed for life, and appropriate tools be identified to implement the strategy. METHODS: We review previous active surveillance studies and the parameters used to identify patients who are good candidates for active surveillance. We also review some of the challenges to implementing active surveillance protocols in the U.S. and discuss how these might be addressed. RESULTS: Trials of active surveillance support nonsurgical management as a viable and safe management strategy. However, numerous challenges exist, including the need for adherence to protocols, education of patients and physicians, and awareness of the impact of this strategy on patient psychology and quality of life. The Thyroid Cancer Care Collaborative (TCCC) is a portable record keeping system that can manage a mobile patient population undergoing active surveillance. CONCLUSION: With proper patient selection, organization, and patient support, active surveillance has the potential to be a long-term management strategy for select patients with PTMC. In order to address the challenges and opportunities for this approach to be successfully implemented in the U.S., it will be necessary to consider psychological and quality of life, cultural differences, and the patient's clinical status.