Five-Year Outcomes from a Prospective Study on the Safety and Efficacy of Phasix-ST Mesh Use at the Hiatus During Paraesophageal Hernia Repair.

INTRODUCTION: Laparoscopic paraesophageal hernia (PEH) repair has a high hernia recurrence rate. The aim of this study was to assess the 5-year hernia recurrence rate after PEH repair using a combination of bioresorbable mesh and advanced surgical techniques to address tension as needed in a prospective group of patients. METHODS: In 2016 a prospective database was established for 50 patients undergoing primary, elective PEH repair with a new bioresorbable mesh (Phasix-ST). Intra-operatively, tension was addressed with Collis gastroplasty and / or diaphragm relaxing incisions as needed. All 50 patients from the initial study were tracked and asked to return for objective follow-up. Recurrence was considered present for any hernia > 2 cm in size. RESULTS: Objective follow-up was obtained in 27 of the original 50 patients (54%) at a median of 5.25 years after their PEH repair. Prior to the 5-year follow-up, 5 patients had a known recurrent hernia. Objective evaluation at 5 years identified an additional 3 recurrences, for a total recurrence rate of 25% (8/32 patients). The hernia recurrence rate in patients with a Collis gastroplasty was significantly lower compared to those without a Collis (7% vs 54%, p=0.008). Two patients underwent re-operation for hernia recurrence. No patient had a mesh infection or mesh erosion. CONCLUSION: The combination of Phasix-ST mesh and tension reducing techniques during PEH repair led to a 25% hernia recurrence rate at 5 years. The addition of a Collis gastroplasty led to significantly fewer hernia recurrences and is indicative of the potential for esophageal shortening in many patients with a PEH. The long-term safety and efficacy of Phasix-ST mesh in combination with surgical technique for PEH repair is confirmed.

Updated Markov Model to Determine Optimal Management Strategy for Patients with Paraesophageal Hernia and Symptoms, Cameron Ulcer, or Comorbid Conditions.

BACKGROUND: The current paradigm of watchful waiting (WW) in people 65 years or older with an asymptomatic paraesophageal hernia (PEH) is based on a now 20-year-old Markov analysis. Recently, we have shown that elective laparoscopic hernia repair (ELHR) provides an increase in life-years (L-Ys) compared with WW in most healthy patients aged 40 to 90 years. However, elderly patients often have comorbid conditions and may have complications from their PEH such as Cameron lesions. The aim of this study was to determine the optimal strategy, ELHR or WW, in these patients. STUDY DESIGN: A Markov model with updated variables was used to compare L-Ys gained with ELHR vs WW in hypothetical people with any type of PEH and symptoms, Cameron lesions, and/or comorbid conditions. RESULTS: In men and women aged 40 to 90 years with PEH-related symptoms and/or Cameron lesions, ELHR led to an increase in L-Ys over WW. The presence of comorbid conditions impacted life expectancy overall, but ELHR remained the preferred approach in all but 90-year-old patients with symptoms but no Cameron lesions. CONCLUSIONS: Using a Markov model with updated values for key variables associated with management options for patients with a PEH, we showed that life expectancy was improved with ELHR in most men and women aged 40 to 90 years, particularly in the presence of symptoms and/or Cameron lesions. Comorbid conditions increase the risk for surgery, but ELHR remained the preferred strategy in the majority of symptomatic patients. This model can be used to provide individualized management guidance for patients with a PEH.

Missed Opportunities: the Timing and Frequency of Screening Colonoscopy in Patients That Develop Esophageal Adenocarcinoma.

INTRODUCTION: Screening colonoscopy (SC) is widely accepted and has been shown to decrease the rate of colorectal cancer death. Guidelines and acceptance of screening for Barrett's esophagus (BE) are less established despite the fact that esophageal adenocarcinoma (EA) remains the fastest increasing cancer in the USA. The aim of this study was to assess the timing and frequency of SC in patients ultimately found to have EA and to evaluate the presence of symptoms and risk factors that might have prompted an esophagogastroduodenoscopy (EGD) and potentially earlier diagnosis of the EA. METHODS: A retrospective chart review was performed to identify all patients who were referred to a single center with esophageal cancer between July 2016 and November 2022. Patients with any histology other than adenocarcinoma were excluded. RESULTS: There were 221 patients referred with EA. Of these, a SC had been done prior to the diagnosis of EA in 108 patients (49%): 96 men and 12 women. A total of 203 SC had been done (range 1-7 per patient), and 47% of patients had more than 1 SC. The median interval from the last SC to the diagnosis of EA was 2.9 years. At the time of SC, gastroesophageal reflux disease (GERD) symptoms or chronic acid suppression medication use was reported by 81% of patients, and 80% had an American Society of Gastrointestinal Endoscopy (ASGE) indication for a screening EGD. Only 19 patients (18%) that had a SC had an EGD at any time prior to the diagnosis of EA, and in these patients, 74% had erosive esophagitis or BE. The EA in most patients was stage III or IV and associated with lymph node metastases. CONCLUSIONS: Nearly one-half of patients ultimately diagnosed with EA had one or more SCs, and most of these patients had GERD symptoms, were using acid suppression medications or had an ASGE indication for a screening EGD. Despite this, only 18% had an EGD prior to the EA diagnosis. The addition of an EGD at the time of SC in these patients may have allowed the detection of BE or EA at an early, endoscopically curable stage and represents a missed opportunity to intervene in the natural history of this disease.

Tumor differentiation impacts response to neoadjuvant therapy and survival in patients with esophageal adenocarcinoma.

OBJECTIVE: The current staging system for esophageal adenocarcinoma only considers tumor grade in early tumors. The aim of this study was to evaluate the impact of tumor differentiation on response to neoadjuvant chemoradiotherapy and survival in patients with locally advanced esophageal adenocarcinoma. METHODS: This was a multi-institution retrospective review of all patients with esophageal cancer who underwent neoadjuvant chemoradiotherapy followed by esophagectomy from January 2010 to December 2017. Response to neoadjuvant therapy and survival was compared between patients with well- or moderately differentiated (G1/2) tumors versus poorly differentiated (G3) tumors. RESULTS: There were 550 patients, 485 men (88.2%) and 65 women. The median age was 61 years, and the tumor was G1/2 in 288 (52.4%) and G3 in 262 patients. Overall clinical stage before neoadjuvant therapy was similar between groups. Pathologic complete response (pCR) was found in 87 patients (15.8%). The frequency of pCR was similar between groups, but residual disease in the esophagus and lymph nodes was significantly more likely with G3 tumors. Median follow-up was 63 months and absolute survival, overall survival, and disease-free survival were all significantly worse in patients with G3 tumors. Further, even with pCR, patients with G3 tumors had significantly worse survival. CONCLUSIONS: This study showed that response to neoadjuvant therapy was not affected by tumor differentiation. However, poor differentiation was associated with worse survival compared with patients with G1/2 tumors, even among those with pCR. These results suggest that poor differentiation should be considered as an added risk factor for clinical staging in patients with locally advanced esophageal adenocarcinoma.

Diaphragmatic relaxing incisions for complex hiatal reconstruction: longer-term follow-up confirms safety, efficacy and rare complications.

BACKGROUND: Tension is an important factor in hernia repairs. Relaxing incisions to reduce tension are common with ventral hernia repairs, and techniques for relaxing incisions also exist for the hiatus. The aim of this study was to update our original experience with a diaphragm relaxing incision (DRI) in a larger group of patients with longer follow-up. METHODS: A retrospective chart review was performed to identify all patients who had a DRI between August 2016 and September 2021 during hiatal hernia repair. All DRI defects were repaired with permanent mesh remote from the esophagus. Objective follow-up was with chest x-ray, upper GI series (UGI) or both. RESULTS: Seventy-three patients had a total of 79 DRI (right in 63, left in 4, and bilateral in 6 patients), during a primary (n = 52) or redo (n = 21) hiatal hernia repair. Concomitant Collis gastroplasty was used in 38 patients (52%). A single intra-operative complication occurred where the right crus tore during a right DRI. At a median of 15 months, 78% of patients had objective follow-up. There was one hernia through a repaired right DRI (1.2%). No patient had evidence of diaphragm paralysis and there were no mesh infections. The 1-year hernia recurrence rate in these patients was 3.9%. CONCLUSIONS: A DRI can be done safely with minimal risk of intra- or post-operative complications. There was a low rate of herniation through the defect when repaired with permanent mesh. No patient developed a mesh infection despite concomitant Collis gastroplasty in 52% of patients, and there was no evidence of diaphragm paralysis on imaging studies. Further, the low rate of hiatal hernia recurrence suggests efficacy of a DRI to reduce crural closure tension. These excellent outcomes should encourage use of a DRI in patients with a difficult hiatus during hernia repair.

Iatrogenic Injury During Intraoperative Transesophageal Echocardiography: Implications for Medical Equipment Storage.

BACKGROUND: Medical equipment failure is an underappreciated source of iatrogenesis. The authors report a successful root cause analysis and action (RCA2) to improve compliance and decrease risks to patients during cardiac anesthesia care. METHODS: A quality and safety team of five content experts performed an RCA2 after an iatrogenic injury with transesophageal echocardiogram (TEE) probe insertion. The team used a fishbone diagram to identify causes and performed a Gemba walk to discuss probability of the different causes with key stakeholders. The team reviewed hospital policies and procedures as well as manufacturer manuals regarding best practices for maintenance and storage of TEE probes. The team created a corrective action plan centered on purchasing larger TEE storage cabinets, education of those who handle TEE probes, and implementing standard operating procedures. Effectiveness of the intervention was evaluated by analyzing frequency of TEE probe maintenance. RESULTS: The study period ranged from July 2016 to June 2021. TEE probes required maintenance 51 times, of which 40 (78.4%) occurred prior to the larger storage cabinet purchase, and 11 (21.6%) afterward. The number of TEE probes requiring maintenance per quarter was 4.4 (standard deviation [SD] 2.5) during the preintervention period and 1.0 (SD 1.0) during the postintervention period (mean difference 3.4, 95% confidence interval 1.0-5.9, p = 0.0006). CONCLUSION: An extensive RCA2 resulting in a corrective action plan centered on compliance with manufacturer recommendations for storage of TEE probes resulted in fewer maintenance requests, which decreased the risk of iatrogenic patient injury from TEE probe failure during cardiac anesthesia care.

Tractography-Based Modeling Explains Treatment Outcomes in Patients Undergoing Deep Brain Stimulation for Obsessive-Compulsive Disorder.

BACKGROUND: Deep brain stimulation (DBS) is an established and expanding therapy for treatment-refractory obsessive-compulsive disorder. Previous work has suggested that a white matter circuit providing hyperdirect input from the dorsal cingulate and ventrolateral prefrontal regions to the subthalamic nucleus could be an effective neuromodulatory target. METHODS: We tested this concept by attempting to retrospectively explain through predictive modeling the ranks of clinical improvement as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) in 10 patients with obsessive-compulsive disorder who underwent DBS to the ventral anterior limb of internal capsule with subsequent programming uninformed by the putative target tract. RESULTS: Rank predictions were carried out using the tract model by a team that was completely uninvolved in DBS planning and programming. Predicted Y-BOCS improvement ranks significantly correlated with actual Y-BOCS improvement ranks at the 6-month follow-up (r = 0.75, p = .013). Predicted score improvements correlated with actual Y-BOCS score improvements (r = 0.72, p = .018). CONCLUSIONS: Here, we provide data in a first-of-its-kind report suggesting that normative tractography-based modeling can blindly predict treatment response in DBS for obsessive-compulsive disorder.

Concept mapping sociocultural aspects of cervical cancer prevention among African American women.

Introduction: For African American women in Houston, cervical cancer mortality is disproportionate to their racial and ethnic counterparts. Most notably, lack of human papillomavirus (HPV) screening and vaccination as well as late diagnosis increase cervical cancer mortality. However, cervical cancer is largely preventable. While previous research has identified a few social determinants that are specifically related to cervical cancer (e.g., education, income, neighborhood), there may be a host of additional social and cultural factors that contribute to a lack of preventative behavior. Methods: The present study used concept mapping to explore sociocultural determinants of cervical cancer prevention beliefs among young African American women. N = 15 African American women, ages 18-25, participated in a group concept mapping session focused on cervical cancer knowledge, beliefs about women's health, and how their social environment and culture play a role in their conceptualization of cervical cancer prevention. Discussion: Five overarching concepts emerged: (1) Screening, (2) Support System, (3) Cervical Cancer 101 (knowledge), (4) Fatalism, and (5) Ease of Prevention. Conclusion: The present study highlights the use of concept mapping for prevention science, particularly in exploratory studies for understanding cervical cancer screening barriers, avenues for intervention, and public health messaging. We discuss the findings and implications for public health research in cervical cancer prevention tailored for African American women.

Artifact characterization and mitigation techniques during concurrent sensing and stimulation using bidirectional deep brain stimulation platforms.

Bidirectional deep brain stimulation (DBS) platforms have enabled a surge in hours of recordings in naturalistic environments, allowing further insight into neurological and psychiatric disease states. However, high amplitude, high frequency stimulation generates artifacts that contaminate neural signals and hinder our ability to interpret the data. This is especially true in psychiatric disorders, for which high amplitude stimulation is commonly applied to deep brain structures where the native neural activity is miniscule in comparison. Here, we characterized artifact sources in recordings from a bidirectional DBS platform, the Medtronic Summit RC + S, with the goal of optimizing recording configurations to improve signal to noise ratio (SNR). Data were collected from three subjects in a clinical trial of DBS for obsessive-compulsive disorder. Stimulation was provided bilaterally to the ventral capsule/ventral striatum (VC/VS) using two independent implantable neurostimulators. We first manipulated DBS amplitude within safe limits (2-5.3 mA) to characterize the impact of stimulation artifacts on neural recordings. We found that high amplitude stimulation produces slew overflow, defined as exceeding the rate of change that the analog to digital converter can accurately measure. Overflow led to expanded spectral distortion of the stimulation artifact, with a six fold increase in the bandwidth of the 150.6 Hz stimulation artifact from 147-153 to 140-180 Hz. By increasing sense blank values during high amplitude stimulation, we reduced overflow by as much as 30% and improved artifact distortion, reducing the bandwidth from 140-180 Hz artifact to 147-153 Hz. We also identified artifacts that shifted in frequency through modulation of telemetry parameters. We found that telemetry ratio changes led to predictable shifts in the center-frequencies of the associated artifacts, allowing us to proactively shift the artifacts outside of our frequency range of interest. Overall, the artifact characterization methods and results described here enable increased data interpretability and unconstrained biomarker exploration using data collected from bidirectional DBS devices.

Intraoperative valence testing to adjudicate between ventral capsule/ventral striatum and bed nucleus of the stria terminalis target selection in deep brain stimulation for obsessive-compulsive disorder.

OBJECTIVE: Deep brain stimulation (DBS) is an accepted therapy for severe, treatment-refractory obsessive-compulsive disorder (trOCD). The optimal DBS target location within the anterior limb of the internal capsule, particularly along the anterior-posterior axis, remains elusive. Empirical evidence from several studies in the past decade has suggested that the ideal target lies in the vicinity of the anterior commissure (AC), either just anterior to the AC, above the ventral striatum (VS), or just posterior to the AC, above the bed nucleus of the stria terminalis (BNST). Various methods have been utilized to optimize target selection for trOCD DBS. The authors describe their practice of planning trajectories to both the VS and BNST and adjudicating between them with awake intraoperative valence testing to individualize permanent target selection. METHODS: Eight patients with trOCD underwent awake DBS with trajectories planned for both VS and BNST targets bilaterally. The authors intraoperatively assessed the acute effects of stimulation on mood, energy, and anxiety and implanted the trajectory with the most reliable positive valence responses and least stimulation-induced side effects. The method of intraoperative target adjudication is described, and the OCD outcome at last follow-up is reported. RESULTS: The mean patient age at surgery was 41.25 ± 15.1 years, and the mean disease duration was 22.75 ± 10.2 years. The median preoperative Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score was 39 (range 34-40). Two patients had previously undergone capsulotomy, with insufficient response. Seven (44%) of 16 leads were moved to the second target based on intraoperative stimulation findings, 4 of them to avoid strong negative valence effects. Three patients had an asymmetric implant (1 lead in each target). All 8 patients (100%) met full response criteria, and the mean Y-BOCS score reduction across the full cohort was 51.2% ± 12.8%. CONCLUSIONS: Planning and intraoperatively testing trajectories flanking the AC-superjacent to the VS anteriorly and to the BNST posteriorly-allowed identification of positive valence responses and acute adverse effects. Awake testing helped to select between possible trajectories and identify individually optimized targets in DBS for trOCD.

Decreased cocaine demand following contingency management treatment.

A hypothetical cocaine purchasing task (CocPT) was used to assess changes in cocaine demand in the context of contingency management (CM) treatment for cocaine use disorder (CUD). Participants (N = 89) were treatment-seeking individuals with CUD receiving 4 weeks of abstinence-based, high-magnitude CM. Treatment response (vs. non-response) was operationally defined as the submission of 6 consecutive cocaine-negative urine samples across two weeks. The CPT was assessed at baseline, week 2, and week 5. Demand data were well described by the exponentiated demand model, and baseline demand indices (Q0, Pmax, breakpoint, essential value) were significantly associated with self-report measures of cocaine use. The probability of being a zero-responder reporting zero cocaine consumption at all prices significantly increased over the course of treatment, and was greater among treatment responders vs. non-responders. Among non-zero demand data, decreases in Omax, Pmax, breakpoint, and essential value were observed over the course of CM treatment, favoring responders. To our knowledge, this is the first study to assess change in cocaine demand in the context of CM treatment targeting cocaine abstinence. Our results support the utility of cocaine demand as a measure for both identifying individuals with greater treatment need and tracking relapse risk over the course of treatment.

POEM: clinical outcomes beyond 5 years.

BACKGROUND: The short-term success of peroral endoscopic myotomy (POEM) is well documented but the durability of the operation is questioned. The aim of this study was to evaluate the clinical outcomes of the POEM procedure for esophageal motility disorders in a large cohort in which all patients had at least 5 years of follow-up. METHODS: All patients from a single center who underwent a POEM between October 2010 and September 2014 were followed for long-term clinical outcomes. Postoperative Eckardt symptom scores of short term and ≥ 5 years were collected through phone interview. Clinical success was defined as an Eckardt score < 3. Overall success was defined as Eckardt score < 3 and freedom from additional interventions. RESULTS: Of 138 patients, 100 patients were available for follow-up (mean age 56, 52% male). The indication for operation was achalasia in 94. The mean follow-up duration was 75 months (range: 60-106 months). Dysphagia was improved in 91% of patients. Long-term overall success was achieved in 79% of patients (80% of achalasia patients, 67% of DES patients). Preoperative mean Eckardt score was 6. At 6 months, it was 1, and at 75 months, it was 2 (p = 0.204). Five-year freedom from intervention was 96%. Overall, 7 patients had additional treatments: 1 balloon dilation (35 mm), 4 laparoscopic Heller myotomy, and 2 redo POEM at a mean of 51 months post-POEM. Ninety-three percent expressed complete satisfaction with POEM. CONCLUSION: A multitude of studies has shown the early benefits of POEM. Here, we show that nearly 80% of patients report clinical success with no significant decrement in symptom scores between their short- and long-term follow-up. Clearly POEM is an effective option for achalasia with durable long-term treatment efficacy.

Initial development of a brief assessment of cocaine demand.

Cocaine demand is a behavioral economic measure assessing drug reward value and motivation to use drug. The purpose of the current study was to develop a brief assessment of cocaine demand (BACD). Results from the BACD were compared with self-report measures of cocaine use. Participants consisted of treatment-seeking individuals with cocaine use disorder (N = 22). Results revealed that indices of brief demand were significantly associated with various self-report measures of cocaine use. Overall, these results support the utility of a BACD for assessing cocaine demand.

A Case Report: The CSF Characteristics of HaNDL Syndrome.

BACKGROUND: Headache and Neurologic Deficits with cerebrospinal fluid Lymphocytosis (HaNDL) is a rare and underdiagnosed syndrome that mimics recurrent stroke, migraine with aura, and encephalitis. OBJECTIVE: Describe the presentation, clinical characteristics, and cerebrospinal fluid (CSF) findings in a patient with HaNDL and provide insight into the importance of the recognition of this syndrome. METHODS: The authors describe a unique case of (HaNDL) during which the patient underwent three lumbar punctures over 26 days. RESULTS: The authors demonstrate the natural course of CSF characteristics of a patient with HaNDL, with rising and falling lymphocyte counts. Additionally, the authors provide an example of the clinical presentation of HaNDL, with episodic attacks over the course of 1 month of migraine headache, hemibody paresthesias, hemibody weakness, and encephalopathy. CONCLUSIONS: HaNDL is a headache syndrome mimicking viral encephalitis, migraine with aura, and recurrent cerebral ischemic events. While HaNDL is a diagnosis of exclusion, the syndrome's association with characteristic clinical and laboratory findings are important to recognize. Furthermore, a monophasic pattern of CSF lymphocytosis in HaNDL may be observed. IMPLICATIONS FOR NURSING: Increased recognition of this syndrome may help prevent unnecessary tests and treatments when patients present with recurrent episodes.

Baseline cocaine demand predicts contingency management treatment outcomes for cocaine-use disorder.

Cocaine use disorder (CUD) is a significant public health issue. Behavioral interventions such as contingency management (CM) have been demonstrated to be highly effective in promoting cocaine abstinence. However, identifying individual characteristics associated with cocaine relapse may help improve treatment outcomes. Cocaine demand is a behavioral economic measure that shares a scientific foundation with CM. In the current study, we assessed baseline cocaine demand using a hypothetical cocaine purchasing task. Participants (N = 58) consisted of treatment-seeking individuals with CUD. All participants received 1 month of CM treatment for cocaine abstinence, and treatment responders were defined as presenting 6 consecutive cocaine negative urine samples from thrice weekly clinic visits. Demand data were well described by the exponentiated demand model. Indices of demand (intensity of demand [Q0], elasticity [α]) were significantly associated with recent (last 30 days) cocaine use. Importantly, linear regression revealed that CM treatment nonresponders presented significantly higher Q0 (p = .025). Subsequent quantile regression analyses examining the relationship between CM treatment response and Q0 revealed statistically reliable effects of being a nonresponder across 3 of the lower percentiles (i.e., 15, 25, and 30). Overall, these findings provide further support for the utility of exponentiated demand model. To our knowledge, this is the first study to demonstrate an association between baseline demand and contingency management response and systematically extend the findings of prior demand research to a novel drug class, cocaine. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Calibration and validation of a microporous polyethylene passive sampler for quantitative estimation of illicit drug and pharmaceutical and personal care product (PPCP) concentrations in wastewater influent.

Wastewater-based epidemiology (WBE), the per capita normalised measurement of drugs, chemicals or metabolites in wastewater influent, relies on sampling and quantitative analysis to evaluate temporal and spatial trends of chemical consumption. Continuous, high-resolution, flow proportional composite sampling is optimal for accurate representations of chemical mass loads, but is rarely implemented, with conventional autosamplers providing relatively low frequency time or volume proportional samples. However, due to equipment or resource constraints at many wastewater treatment plants (WWTPs), even this may not be feasible. Passive sampling may provide an alternative sampling strategy. To investigate this, samplers comprising hollow, cylindrical Microporous Polyethylene Tubes (MPTs) containing polymeric sorbent phases of Strata-X and Strata-X in agarose were simultaneously deployed in a municipal WWTP influent stream. Samplers were extracted, analysed and evaluated for a range of illicit drugs and pharmaceuticals and personal care products (PPCPs) after 4, 7, 15, 21, and 29 day deployments. The MPT samplers were calibrated against 24-hour time proportional composite grab samples that were collected in parallel. Diffusion through the MPT governed uptake, reducing or eliminating the influence of external flow rates that may fluctuate unpredictably in a WWTP environment. Calibration data for six illicit drugs and fourteen PPCPs, including methamphetamine, benzoylecgonine, MDMA, codeine and carbamazepine, demonstrated linear accumulation in the samplers (R2 ≥ 0.84). Derived sampling rates for these analytes ranged from 0.25 to 17 mL d-1 for ibuprofen and verapamil, respectively. A validation study using this sampling rate data showed the MPT could effectively quantify concentrations (≥0.1 ng mL-1) of a range of amphetamine-type stimulants, opioids and metabolites as well as nicotine, accounting for 95% of the variance in parallel composite grab sample concentrations of these compounds. The MPT sampler shows promise for providing essential monitoring data for WBE, informing future intervention and research strategies.

Clonal hematopoiesis as determined by the HUMARA assay is a marker for acquired mutations in epigenetic regulators in older women.

Recent large cohort studies revealed that healthy older individuals harbor somatic mutations that increase their risk for hematologic malignancy and all-cause cardiovascular deaths. The majority of these mutations are in chromatin and epigenetic regulatory genes (CERGs). CERGs play a key role in regulation of DNA methylation (DNMT3A and TET2) and histone function (ASXL1) and in clonal proliferation of hematopoietic stem cells. We hypothesize that older women manifesting clonal hematopoiesis, defined here as a functional phenomenon in which a hematopoietic stem cell has acquired a survival and proliferative advantage, harbor a higher frequency of somatic mutations in CERGs. The human androgen receptor gene (HUMARA) assay was used in our study to detect the presence of nonrandom X inactivation in women, a marker for clonal hematopoiesis. In our pilot study, we tested 127 blood samples from women ≥65 years old without a history of invasive cancer or hematologic malignancies. Applying stringent qualitative criteria, we found that 26% displayed clonal hematopoiesis; 52.8% displayed polyclonal hematopoiesis; and 21.3% had indeterminate patterns (too close to call by qualitative assessment). Using Illumina MiSeq next-generation sequencing, we identified somatic mutations in CERGs in 15.2% of subjects displaying clonal hematopoiesis (three ASXL1 and two DNMT3A mutations with an average variant allele frequency of 15.7%, range: 6.3%-23.3%). In a more limited sequencing analysis, we evaluated the frequency of ASXL1 mutations by Sanger sequencing and found mutations in 9.7% of the clonal samples and 0% of the polyclonal samples. By comparing several recent studies (with some caveats as described), we determined the fold enrichment of detecting CERG mutations by using the HUMARA assay as a functional screen for clonal hematopoiesis. We conclude that a functional assay of clonal hematopoiesis is enriching for older women with somatic mutations in CERGs, particularly for ASXL1 and TET2 mutations and less so for DNMT3A mutations.

Etiology of unilateral neural hearing loss in children.

OBJECTIVE: Unilateral sensorineural hearing loss (SNHL) can be caused by a variety of lesions of the inner ear and central nervous system. An inner hair cell or neural site of pathology must be suspected when otoacoustic emissions (OAEs) are present, and inconsistent with audiologic data. We reviewed unilateral neural hearing loss (UNHL) in children, to better understand its etiology, clinical and audiologic features. DESIGN: Retrospective series. SETTING: Tertiary pediatric center. METHODS: From a database of 480 children with unilateral SNHL, 148 had OAE data. Patients with a neural pattern (present OAEs in the affected ear) were reviewed. OUTCOME MEASURES: Clinical course, audiologic data, imaging findings. RESULTS: Of 148 patients with OAE data, 11 (7.4%) had the unilateral neural phenotype. Most had stable, severe-to-profound loss in the affected ear. MRI determined an etiology in all 10 patients who received it. Absent cochlear nerves were remarkably common, being found in eight patients (73%). Tumors, previously unsuspected, were identified in the other two patients who received MRI. CONCLUSIONS: Cochlear nerve aplasia appears by far the most common cause of UNHL in children. As in adults, mass lesions must also be considered in children with unilateral SNHL with a neural pattern. As both lesions elude diagnosis on CT, MRI is the better modality for evaluating this condition.

Amplification considerations for children with minimal or mild bilateral hearing loss and unilateral hearing loss.

Children with minimal or mild bilateral hearing loss and unilateral hearing loss are at higher risk for academic, speech-language, and social-emotional difficulties than their normal hearing peers. The choice to fit infants with moderate or greater degrees of bilateral hearing loss has been standard practice for most clinicians, but for those with minimal or mild bilateral hearing loss or unilateral hearing loss, the fitting of hearing technology must be based on limited data. Evidence does not yet exist to support all the management decisions that an audiologist must make upon identifying an infant with minimal or mild bilateral hearing loss or unilateral hearing loss. It is not yet known which children are at the greatest risk for educational problems nor is it known if the provision of early amplification in this population will help a child avoid later difficulties. Some of these considerations and current hearing technology options for children with minimal or mild bilateral hearing loss or unilateral hearing loss are reviewed in this article.