Objective Evidence That Nerve Decompression Surgery Reduces Neuropathic DFU Recurrence Risk to Less than 5%

Significance: Despite 20 years of research and new treatment methods, diabetic foot ulcer (DFU) remains a common problem with frequent recurrences and complications. Recent Advances: There are reports that nerve decompression (ND) surgery has been observed to produce significantly fewer DFU recurrences than standard of care (SOC). The explanation of this apparent superiority has not been understood. Critical Issues: Microcirculation is understood to be involved in diabetic peripheral neuropathy (DPN) and DFU. There is an underappreciation of the participation in DPN of entrapment neuropathy (EN) due to nerve swelling and impingement in fibro-osseous tunnels. Reducing c-fiber compression in EN by ND generates recovery of subepidermal capillary flow. ND studies have found improved neuromuscular function and epidermal microcirculation phenomena, including chronic capillary ischemia (CCI) and pressure-induced vasodilatation (PIV). There is no current therapy recommended for impaired microcirculation. Clinical and animal evidence has demonstrated that release of locally compressed peripheral nerves improves the epidermal microcirculation which is under sympathetic control. Future Directions: Using epineurolysis to relieve nerve compressions is a physiology-based therapeutic intervention and provides the scientific foundation clarifying how ND reduces DFU recurrence risk. Incorporating ND with current SOC treatments could improve DFU recurrence risk, hard-to-heal ulcers, neuroischemic wounds, amputation risk, and the resulting costs to society. More studies using ND for DFU, especially evidence-based medicine Level I studies, are needed to confirm these preliminary outcomes.

Choosing wisely in burn care.

BACKGROUND: The Choosing Wisely Campaign was launched in 2012 and has been applied to a broad spectrum of disciplines in almost thirty countries, with the objective of reducing unnecessary or potentially harmful investigations and procedures, thus limiting costs and improving outcomes. In Canada, patients with burn injuries are usually initially assessed by primary care and emergency providers, while plastic or general surgeons provide ongoing management. We sought to develop a series of Choosing Wisely statements for burn care to guide these practitioners and inform suitable, cost-effective investigations and treatment choices. METHODS: The Choosing Wisely Canada list for Burns was developed by members of the Canadian Special Interest Group of the American Burn Association. Eleven recommendations were generated from an initial list of 29 statements using a modified Delphi process and SurveyMonkey™. RESULTS: Recommendations included statements on avoidance of prophylactic antibiotics, restriction of blood products, use of adjunctive analgesic medications, monitoring and titration of opioid analgesics, and minimizing 'routine' bloodwork, microbiology or radiological investigations. CONCLUSIONS: The Choosing Wisely recommendations aim to encourage greater discussion between those involved in burn care, other health care professionals, and their patients, with a view to reduce the cost and adverse effects associated with unnecessary therapeutic and diagnostic procedures, while still maintaining high standards of evidence-based burn care.

Acute Improvement in Intraoperative EMG During Common Fibular Nerve Decompression in Patients with Symptomatic Diabetic Sensorimotor Peripheral Neuropathy: EMG and Clinical Attribute Interrelations.

STUDY AIMS: Electromyographic (EMG) recordings of the fibularis longus and tibialis anterior muscles were performed intraoperatively during nerve decompression (ND) of the common fibular nerve (CFN) in patients with symptomatic diabetic sensorimotor peripheral neuropathy. Patient demographics and clinical attributes were compared against changes in EMG after ND and analyzed for possible correlations. METHODS: Intraoperative changes in CFN EMG were analyzed for correlations against sex, age, body mass index (BMI), hemoglobin A1c (A1c), and type and duration of diabetes. RESULTS: Statistically significant changes were found between EMG changes and patient attributes, but no individual correlations were established. Significant EMG improvement was observed for both men and women (p < 0.0001 and p < 0.05, respectively), age groups (4th decade: p < 0.05; 5th decade: p < 0.05; 6th decade: p < 0.01; 7th decade: p < 0.005), diabetes duration (0-9 years: p = 0.002; 10-19 years: p = 0.002; 20-29 years: p = 0.03), and for type 1 and 2 diabetes (type 1: p < 0.005; type 2: p < 0.001). EMG improvement was greater in patients with the highest BMI levels (30-34.9: p = 0.014; 35-39.9: p = 0.013; > 39.9: p = 0.043), and highest A1c levels (> 6.4%; p < 0.0001). CONCLUSION: Although long-term clinical studies are needed, these results provide insight into which patients might benefit most from this surgery. These results also suggest that surgical ND can produce an acute improvement in nerve function for both men and women, for people with type 1 and 2 diabetes, and across a wide range of ages, BMI, A1c levels, and disease duration.

Mechanical Allodynia Predicts Better Outcome of Surgical Decompression for Painful Diabetic Peripheral Neuropathy.

BACKGROUND: To determine the role of mechanical allodynia (MA) in predicting good surgical outcome for painful diabetic peripheral neuropathy (DPN). MATERIALS AND METHODS: Data of 192 patients with painful DPN were collected in this study, with 148 surgical patients and 44 patients in the control group. Both groups were further divided into subgroups based on the presence of MA on admission. Clinical evaluations including the visual analog scale (VAS), the Hospital Anxiety and Depression Scale (HADS), nerve conduction velocity (NCV), and high-resolution ultrasonography (cross-sectional area, CSA) were performed preoperatively and postoperatively. RESULTS: The levels of VAS and HADS and the results of NCV and CSA were improved in the surgical group (p < 0.05). In the surgical subgroups, pain reduction, psychiatric amelioration, improvement in NCVs, and the restoration of the CSA were observed in patients with signs of MA (p < 0.05), whereas only pain reduction, psychiatric amelioration, and restoration of the CSA were noted in patients without signs of MA (p > 0.05). Furthermore, better pain reduction was achieved in patients with MA when compared with those without MA (p < 0.05). CONCLUSIONS: MA is proved to be a reliable predictor of good surgical outcome for painful DPN.

Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole-exome sequencing on five families in which second- and third-degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes. Among these, a novel private missense C1143F variant in the second intracellular loop of the voltage-gated sodium channel NaV1.7, encoded by the SCN9A gene, was identified in one family. Through electrophysiological analysis, we show that NaV1.7C1143F exhibits partial loss-of-function effects, resulting in slower recovery from inactivation and decreased excitability in cultured cortical neurons. Furthermore, for the same intracellular loop of NaV1.7, we found an excess of rare variants in a case-control variant-burden study. Functional analysis of one of these variants, M932L/V991L, also demonstrated reduced firing in cortical neurons. However, although this variant is rare in Caucasians, it is frequent in Latino population, suggesting that genetic background can alter its effects on phenotype. Although the involvement of the SCN1A and SCN2A genes encoding NaV1.1 and NaV1.2 channels in de novo ASD has previously been demonstrated, our study indicates the involvement of inherited SCN9A variants and partial loss-of-function of NaV1.7 channels in the etiology of rare familial ASD.

Nerve decompression and neuropathy complications in diabetes: Are attitudes discordant with evidence?

External neurolysis of the nerve at fibro-osseous tunnels has been proprosed to treat or prevent signs, symptoms, and complications in the lower extremity of diabetes patients with sensorimotor polyneuropathy. Nerve decompression is justified in the presence of symptomatic compressed nerves in the several fibro-osseous tunnels of the extremities, which are known to be frequent in diabetes. Quite a body of literature has accumulated reporting results after such nerve decompression in the leg, describing pain relief and sensibility improvement, as well as balance recovery, diabetic foot ulcer prevention, curtailed ulcer recurrence risk, and amputation avoidance. Historical academic hesitance to endorse surgical treatments for pain and numbness in diabetes was based primarily on the early retrospective reports' potential for bias and placebo effects, and that the hypothetical basis for surgery lies outside the traditional etiology paradigm of length-dependent axonopathy. This reticence is here critiqued in view of recent studies using objective, measured outcome protocols which nullify such potential confounders. Pain relief is now confirmed with Level 1 studies, and Level 2 prospective information suggests protection from initial diabetic foot ulceration and most neuropathic ulcer recurrences. In view of the potential for nerve decompression to be useful in addressing some of the more difficult, expensive, and life altering complications of diabetic neuropathy, this secondary compression thesis and operative treatment methodology may deserve reassessment.

Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner.

Statins are widely prescribed to lower plasma low-density lipoprotein (LDL) cholesterol levels. They also modestly reduce plasma triglyceride (TG), an independent cardiovascular disease risk factor, in most people. The mechanism and inter-individual variability of TG statin response is poorly understood. We measured statin-induced gene expression changes in lymphoblastoid cell lines derived from 150 participants of a simvastatin clinical trial and identified 23 genes (false discovery rate, FDR=15%) with expression changes correlated with plasma TG response. The correlation of insulin-induced gene 1 (INSIG1) expression changes with TG response (rho=0.32, q=0.11) was driven by men (interaction P=0.0055). rs73161338 was associated with INSIG1 expression changes (P=5.4 × 10-5) and TG response in two statin clinical trials (P=0.0048), predominantly in men. A combined model including INSIG1 expression level and splicing changes accounted for 29.5% of plasma TG statin response variance in men (P=5.6 × 10-6). Our results suggest that INSIG1 variation may contribute to statin-induced changes in plasma TG in a sex-specific manner.

Transcriptomic variation of pharmacogenes in multiple human tissues and lymphoblastoid cell lines.

Variation in the expression level and activity of genes involved in drug disposition and action ('pharmacogenes') can affect drug response and toxicity, especially when in tissues of pharmacological importance. Previous studies have relied primarily on microarrays to understand gene expression differences, or have focused on a single tissue or small number of samples. The goal of this study was to use RNA-sequencing (RNA-seq) to determine the expression levels and alternative splicing of 389 Pharmacogenomics Research Network pharmacogenes across four tissues (liver, kidney, heart and adipose) and lymphoblastoid cell lines, which are used widely in pharmacogenomics studies. Analysis of RNA-seq data from 139 different individuals across the 5 tissues (20-45 individuals per tissue type) revealed substantial variation in both expression levels and splicing across samples and tissue types. Comparison with GTEx data yielded a consistent picture. This in-depth exploration also revealed 183 splicing events in pharmacogenes that were previously not annotated. Overall, this study serves as a rich resource for the research community to inform biomarker and drug discovery and use.

Acute Improvement in Intraoperative EMG Following Common Fibular Nerve Decompression in Patients with Symptomatic Diabetic Sensorimotor Peripheral Neuropathy: 1. EMG Results.

Background and Study Aims Electromyographic (EMG) recordings of the fibularis longus (FL) and tibialis anterior (TA) muscles were performed intraoperatively during common fibular nerve (CFN) nerve decompression (ND) in patients with symptomatic diabetic sensorimotor peripheral neuropathy (DSPN) and clinical nerve compression. Materials and Methods Forty-six legs in 40 patients underwent surgical ND by external neurolysis; FL and TA muscles were monitored intraoperatively. Evoked EMGs were recorded just prior to and within 1 minute after ND. Results Thirty-eight legs (82.6%) demonstrated EMG improvement 1 minute after ND. Sixty muscles (31 FL, 29 TA) were monitored, with 44 (73.3%) improving in EMG amplitude. Mean change in EMG amplitude represented a 73.6% improvement (p < 0.0001). Changes in EMG amplitudes correlated with visual analog scale pain improvement (p = 0.03). Conclusion This is the first report of acute changes in objective EMG responses during ND of CFN in DSPN patients and demonstrates that patients with symptomatic DSPN and clinical nerve entrapment have latent but functional axons that surgical ND can improve immediately.

Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short-rib polydactyly type I, Saldino-Noonan type.

The short-rib polydactyly syndromes (SRPS) are autosomal recessively inherited, genetically heterogeneous skeletal ciliopathies. SRPS phenotypes were historically categorized as types I-IV, with type I first delineated by Saldino and Noonan in 1972. Characteristic findings among all forms of SRP include short horizontal ribs, short limbs and polydactyly. The SRP type I phenotype is characterized by a very small thorax, extreme micromelia, very short, poorly mineralized long bones, and multiple organ system anomalies. To date, the molecular basis of this most severe type of SRP, also known as Saldino-Noonan syndrome, has not been determined. We identified three SRP cases that fit the original phenotypic description of SRP type I. In all three cases, exome sequence analysis revealed compound heterozygosity for mutations in DYNC2H1, which encodes the main component of the retrograde IFT A motor, cytoplasmic dynein 2 heavy chain 1. Thus SRP type I, II, III and asphyxiating thoracic dystrophy (ATD), which also result from DYNC2H1 mutations. Herein we describe the phenotypic features, radiographic findings, and molecular basis of SRP type I.

Intra-Abdominal Hypertension and Abdominal Compartment Syndrome after Abdominal Wall Reconstruction: Quaternary Syndromes?

BACKGROUND AND AIMS: Reconstruction with reconstitution of the container function of the abdominal compartment is increasingly being performed in patients with massive ventral hernia previously deemed inoperable. This situation places patients at great risk of severe intra-abdominal hypertension and abdominal compartment syndrome if organ failure ensues. Intra-abdominal hypertension and especially abdominal compartment syndrome may be devastating systemic complications with systematic and progressive organ failure and death. We thus reviewed the pathophysiology and reported clinical experiences with abnormalities of intra-abdominal pressure in the context of abdominal wall reconstruction. MATERIAL AND METHODS: Bibliographic databases (1950-2015), websites, textbooks, and the bibliographies of previously recovered articles for reports or data relating to intra-abdominal pressure, intra-abdominal hypertension, and the abdominal compartment syndrome in relation to ventral, incisional, or abdominal hernia repair or abdominal wall reconstruction. RESULTS: Surgeons should thus consider and carefully measure intra-abdominal pressure and its resultant effects on respiratory parameters and function during abdominal wall reconstruction. The intra-abdominal pressure post-operatively will be a result of the new intra-peritoneal volume and the abdominal wall compliance. Strategies surgeons may utilize to ameliorate intra-abdominal pressure rise after abdominal wall reconstruction including temporizing paralysis of the musculature either temporarily or semi-permanently, pre-operative progressive pneumoperitoneum, permanently removing visceral contents, or surgically releasing the musculature to increase the abdominal container volume. In patients without complicating shock and inflammation, and in whom the abdominal wall anatomy has been so functionally adapted to maximize compliance, intra-abdominal hypertension may be transient and tolerable. CONCLUSIONS: Intra-abdominal hypertension/abdominal compartment syndrome in the specific setting of abdominal wall reconstruction without other complication may be considered as a quaternary situation considering the classification nomenclature of the Abdominal Compartment Society. Greater awareness of intra-abdominal pressure in abdominal wall reconstruction is required and ongoing study of these concerns is required.

Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension.

Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals from the unrelated families were found to have compound heterozygous mutations in GUCY1A3. MM041 was diagnosed with achalasia at 4 years of age, hypertension and MMD at 18 years of age. MM149 was diagnosed with MMD and hypertension at the age of 20 months. Both individuals carry one allele that is predicted to lead to haploinsufficiency and a second allele that is predicted to produce a mutated protein. Biochemical studies of one of these alleles, GUCY1A3 Cys517Tyr, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide (NO). GUCY1A3 missense and haploinsufficiency mutations disrupt NO signaling leading to MMD and hypertension, with or without achalasia.

Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections.

Marfan syndrome (MFS) due to mutations in FBN1 is a known cause of thoracic aortic aneurysms and acute aortic dissections (TAAD) associated with pleiotropic manifestations. Genetic predisposition to TAAD can also be inherited in families in the absence of syndromic features, termed familial TAAD (FTAAD), and several causative genes have been identified to date. FBN1 mutations can also be identified in FTAAD families, but the frequency of these mutations has not been established. We performed exome sequencing of 183 FTAAD families and identified pathogenic FBN1 variants in five (2.7%) of these families. We also identified eight additional FBN1 rare variants that could not be unequivocally classified as disease-causing in six families. FBN1 sequencing should be considered in individuals with FTAAD even without significant systemic features of MFS.

Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting.

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

Illustration of Cost Saving Implications of Lower Extremity Nerve Decompression to Prevent Recurrence of Diabetic Foot Ulceration.

The US diabetic foot ulcer (DFU) incidence is 3-4% of 22.3 million diagnosed diabetes cases plus 6.3 million undiagnosed, 858 000 cases total. Risk of recurrence after healing is 30% annually. Lower extremity multiple nerve decompression (ND) surgery reduces neuropathic DFU (nDFU) recurrence risk by >80%. Cost effectiveness of hypothetical ND implementation to minimize nDFU recurrence is compared to the current $6.171 billion annual nDFU expense. A literature review identified best estimates of annual incidence, recurrence risk, medical management expense, and noneconomic costs for DFU. Illustrative cost/benefit calculations were performed assuming widespread application of bilateral ND after wound healing to the nDFU problem, using Center for Medicare Services mean expense data of $1143/case for unilateral lower extremity ND. Calculations use conservative, evidence-based cost figures, which are contemporary (2012) or adjusted for inflation. Widespread adoption of ND after nDFU healing could reduce annual DFU occurrences by at least 21% in the third year and 24% by year 5, representing calculated cost savings of $1.296 billion (year 3) to $1.481 billion (year 5). This scenario proffers significant expense reduction and societal benefit, and represents a minimum 1.9× return on the investment cost for surgical treatment. Further large cost savings would require reductions in initial DFU incidence, which ND might achieve by selective application to advanced diabetic sensorimotor polyneuropathy (DSPN). By minimizing the contribution of recurrences to yearly nDFU incidence, ND has potential to reduce by nearly $1 billion the annual cost of DFU treatment in the United States.

Recurrent de novo mutations implicate novel genes underlying simplex autism risk.

Autism spectrum disorder (ASD) has a strong but complex genetic component. Here we report on the resequencing of 64 candidate neurodevelopmental disorder risk genes in 5,979 individuals: 3,486 probands and 2,493 unaffected siblings. We find a strong burden of de novo point mutations for these genes and specifically implicate nine genes. These include CHD2 and SYNGAP1, genes previously reported in related disorders, and novel genes TRIP12 and PAX5. We also show that mutation carriers generally have lower IQs and enrichment for seizures. These data begin to distinguish genetically distinct subtypes of autism important for aetiological classification and future therapeutics.

Design and anticipated outcomes of the eMERGE-PGx project: a multicenter pilot for preemptive pharmacogenomics in electronic health record systems.

We describe here the design and initial implementation of the eMERGE-PGx project. eMERGE-PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research Network, has three objectives: (i) to deploy PGRNseq, a next-generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1- to 3-year time frame across several clinical sites; (ii) to integrate well-established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record-based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site-specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.