Allopurinol use leading to xanthine nephrolithiasis in pediatric tumor lysis syndrome: a case series.

Tumor lysis syndrome (TLS) is a life-threatening metabolic disorder caused by massive tumor lysis. Allopurinol, a xanthine oxidase inhibitor, is initiated during chemotherapy to prevent hyperuricemia and subsequent acute kidney injury (AKI). We report two cases of xanthine nephrolithiasis during TLS in newly diagnosed hematologic malignancy patients receiving prophylactic allopurinol. Allopurinol use likely promoted xanthine crystallization, stone formation, and AKI.

High variability in cardiac education and experiences during United States paediatric critical care fellowships.

BACKGROUND: Paediatric cardiac critical care continues to become more sub-specialised, and many institutions have transitioned to dedicated cardiac ICUs. Literature regarding the effects of these changes on paediatric critical care medicine fellowship training is limited. OBJECTIVE: To describe the current landscape of cardiac critical care education during paediatric critical care medicine fellowship in the United States and demonstrate its variability. METHODS: A review of publicly available information in 2021 was completed. A supplemental REDCap survey focusing on cardiac ICU experiences during paediatric critical care medicine fellowships was e-mailed to all United States Accreditation Council of Graduate Medical Education-accredited paediatric critical care medicine fellowship programme coordinators/directors. Results are reported using inferential statistics. RESULTS: Data from 71 paediatric critical care medicine fellowship programme websites and 41 leadership responses were included. Median fellow complement was 8 (interquartile range: 6, 12). The majority (76%, 31/41) of programmes had a designated cardiac ICU. Median percentage of paediatric critical care medicine attending physicians with cardiac training was 25% (interquartile range: 0%, 69%). Mandatory cardiac ICU time was 16 weeks (interquartile range: 13, 20) with variability in night coverage and number of other learners present. A minority of programmes (29%, 12/41) mandated other cardiac experiences. Median CHD surgical cases per year were 215 (interquartile range: 132, 338). When considering the number of annual cases per fellow, programmes with higher case volume were not always associated with the highest case number per fellow. CONCLUSIONS: There is a continued trend toward dedicated cardiac ICUs in the United States, with significant variability in cardiac training during paediatric critical care medicine fellowship. As the trend toward dedicated cardiac ICUs continues and practices become more standardised, so should the education.

COVID-19-associated apnea and circumoral cyanosis in a 3-week-old.

BACKGROUND: Data regarding coronavirus disease 2019 (COVID-19) cases and outcomes in infants are sparse compared to older pediatric and adult populations. CASE PRESENTATION: We present a three-week-old full-term male with a history of mild hypoxic ischemic encephalopathy (HIE) who was admitted as an inpatient twice for episodes of apnea and perioral cyanosis. The patient tested positive for COVID-19 and negative for other common respiratory viruses at both admissions. CONCLUSIONS: To our knowledge, this is the first report of apnea and perioral cyanosis associated with COVID-19 in an infant. This case highlights a previously undocumented COVID-19 presentation and suggests that even mildly symptomatic infants warrant viral diagnostic testing in an effort to prevent further spread of the disease.

A Randomized Controlled Trial of Positioning for Lumbar Puncture in Young Infants.

OBJECTIVE: The lateral and sitting positions are those most widely used to perform lumbar puncture (LP) in infants. This study sought to compare LP success rates by position. Secondary outcomes were successful LP on the first attempt and rates of procedural complications. METHODS: Infants aged 1 to 90 days undergoing LP in our pediatric emergency department between June 1, 2012 and October 31, 2013 were randomized to 1 position or the other. Successful LP was defined as collection of cerebrospinal fluid with a red blood cell count of less than 10,000 cells/mm on either of the first 2 attempts. Electronic medical records were reviewed for patient information, cerebrospinal fluid results, and procedural complications. Providers completed a questionnaire detailing their previous LP experience and technique. Primary results were analyzed using the intention-to-treat principle. RESULTS: We enrolled 168 infants. Of 167 with data eligible for analysis, 82 (49%) were randomized to the lateral position. There was no statistically significant difference in LP success rate between the lateral (77%, 63/82) and sitting (72%, 61/85) positions (difference, 5.1%; 95% confidence interval, -8.2%-18.3%). There were no significant differences in success on the first LP attempt or the rates of procedural complications. CONCLUSIONS: Among infants 1 to 90 days of age, this study found no difference in LP success between the lateral and sitting positions.

Treatment outcomes with cefazolin versus oxacillin for deep-seated methicillin-susceptible Staphylococcus aureus bloodstream infections.

Clinical preference for a semisynthetic penicillin (oxacillin or nafcillin) over cefazolin for deep-seated methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections (BSI) perseveres despite limited data to support this approach. A retrospective cohort study of patients treated for MSSA BSI with either oxacillin or cefazolin was performed across two medical centers in Chicago, IL. The outcome measures included documented in-hospital treatment failure, all-cause in-hospital mortality, duration of MSSA BSI, and incidence of documented adverse events. Of 161 patients with MSSA BSI, 103 (64%) received cefazolin, and 58 (36%) received oxacillin. The identified sources of BSI were central line (37.9%), osteoarticular (18%), and skin and soft tissue (17.4%). Patients with endocarditis (29/52 [44.2%]) and other deep-seated infections (23/52 [55.8%]) were classified under the subset of deep-seated infections (52/161 [32.3%]). Multivariate models found deep-seated infection (adjusted odds ratio [aOR], 4.52; 95% confidence interval [CI], 1.23 to 16.6; P = 0.023), metastatic disease (aOR, 4.21; 95% CI, 1.13 to 15.7; P = 0.033), and intensive care unit (ICU) onset of infection (aOR, 4.80; 95% CI, 1.26 to 18.4; P = 0.022) to be independent risk factors for in-hospital treatment failure. Treatment group was not an independent predictor of failure (aOR, 3.76; 95% CI, 0.98 to 14.4; P = 0.053). The rates of treatment failure were similar among cefazolin-treated (5/32 [15.6%]) and oxacillin-treated (4/20 [20.0%]) patients (P = 0.72) in the subset of deep-seated infections. Mortality was observed in 1 (1%) and 3 (5.2%) cases of cefazolin- and oxacillin-treated patients, respectively (P = 0.13). Cefazolin was not associated with higher rates of treatment failure and appears to be an effective alternative to oxacillin for treatment of deep-seated MSSA BSI.

Diffuse Desquamating Rash Following Exposure to Vancomycin-Impregnated Bone Cement.

OBJECTIVE: To describe a case of systemic desquamating dermatitis following implantation of vancomycin antibiotic-laden cement (ABLC) in a patient with prior history of Stevens-Johnson (SJS) reaction to vancomycin. CASE SUMMARY: A 59-year-old man with a history of SJS reaction to systemic vancomycin and recurrent methicillin-susceptible Staphylococcus aureus prosthetic knee infection developed a painful, blistering rash after implantation of bone cement that had been mixed with 2 g of vancomycin. He was started empirically on steroids by his primary care provider and had desquamation about 1 week later. DISCUSSION: Systemic absorption of antibiotics from ABLC has been well documented in the literature. Reports of systemic toxicity are rare, and none have described systemic allergic reactions to vancomycin. This patient's prior episode of SJS was diagnosed at another academic medical center 6 years ago, and records are unavailable. Following low-level reexposure to vancomycin, he developed a diffuse painful desquamating rash. Application of the Naranjo nomogram yielded a score of 8 (probable adverse reaction). Although he did not experience fever, sore throat, or mucous membrane involvement to fulfill classic features of SJS, we believe that his severe rash represented a less-severe form of a systemic hypersensitivity reaction to vancomycin. CONCLUSION: Antibiotics contained in ABLC are systemically absorbed, though at low levels, and have been associated with systemic toxicities. Antibiotics to which a patient has had a potentially life-threatening reaction should not be used in ABLC. Particular attention should be paid to an individual's antibiotic allergy history prior to implantation of any ABLC.

Analysis of infant lumbar puncture success rates: sitting flexed versus lateral flexed positions.

OBJECTIVES: The primary objective was to determine whether the sitting flexed position yields higher success rates of obtaining cerebrospinal fluid (CSF) for culture. The secondary objectives were to determine whether the sitting flexed position yields higher success rates of obtaining the following: CSF for cell count, non-traumatic CSF, and CSF on the first attempt. METHODS: The study investigator performed a retrospective chart review of infants 0 to 365 days of age who had a lumbar puncture (LP) performed from January 1 to December 31 of 2010. Data on the LP position and the number of attempts were abstracted from procedure notes. Twenty-one LPs were excluded because of incomplete data on LP position and/or number of attempts. Spinal fluid count results were obtained from electronic medical records. Non-traumatic LPs were defined in 2 categories: CSF red blood cell counts of 500 cells per cubic millimeter or less and 10,000 cells per cubic millimeter or less. RESULTS: One hundred thirty-two LPs were included: 30 sitting flexed and 102 lateral flexed. There were no differences in success rates between positions for the primary objective of obtaining CSF for culture and the secondary study objectives of obtaining CSF for cell count and non-traumatic CSF. A significant secondary objective was that operators who performed the LP in the sitting flexed position were more likely to obtain CSF on the first attempt (odds ratio, 2.74; confidence interval, 1.17-6.45). CONCLUSIONS: The sitting flexed position was as successful as the lateral flexed position in the primary objective of obtaining CSF for culture and the secondary objectives of obtaining CSF for cell count and non-traumatic CSF. For the secondary objective of obtaining CSF on the first attempt, the sitting flexed position was associated with a higher rate of obtaining CSF on the first attempt in infants younger than 12 months.

Valacyclovir or valganciclovir for cytomegalovirus prophylaxis: A randomized controlled trial in adult and pediatric kidney transplant recipients.

BACKGROUND: Valganciclovir (valG), a cytomegalovirus (CMV) prophylactic agent, has dose-limiting side effects. The tolerability and effectiveness of valacyclovir (valA) as CMV prophylaxis is unknown. METHODS: We conducted a randomized, open-label, single-center trial of valA versus valG for all posttransplant CMV prophylaxis in adult and pediatric kidney recipients. Participants were randomly assigned to receive valA or valG. Primary endpoints were the incidence of CMV viremia and side-effect related drug reduction with secondary assessment of incidence of EBV viremia. RESULTS: Of the 137 sequential kidney transplant recipients enrolled, 26 % were positive and negative for CMV antibody in donor and recipient respectively. The incidence of CMV viremia (4 of 71 [6 %]; 8 of 67 [12 %] P = 0.23), time to viremia (P = 0.16) and area under CMV viral load time curve (P = 0.19) were not significantly different. ValG participants were significantly more likely to require side-effect related dose reduction (15/71 [21 %] versus 1/66 [2 %] P = 0.0003). Leukopenia was the most common reason for valG dose reduction and granulocyte-colony stimulating factor was utilized for leukopenia recovery more frequently (25 % in valG vs 5 % in valA: P = 0.0007). Incidence of EBV viremia was not significantly different. CONCLUSIONS: ValA has significantly less dose-limiting side effects than valG. In our study population, a significant increase in CMV viremia was not observed, in adults and children after kidney transplant, compared to valG. TRIAL REGISTRATION NUMBER: NCT01329185.

Educational and Patient Care Impacts of In Situ Simulation in Healthcare: A Systematic Review.

ABSTRACT: This systematic review was performed to assess the effectiveness of in situ simulation education. We searched databases including MEDLINE and Embase for studies comparing in situ simulation with other educational approaches. Two reviewers screened articles and extracted information. Sixty-two articles met inclusion criteria, of which 24 were synthesized quantitatively using random effects meta-analysis. When compared with current educational practices alone, the addition of in situ simulation to these practices was associated with small improvements in clinical outcomes, including mortality [odds ratio, 0.66; 95% confidence interval (CI), 0.55 to 0.78], care metrics (standardized mean difference, -0.34; 95% CI, -0.45 to -0.21), and nontechnical skills (standardized mean difference, -0.52; 95% CI, -0.99 to -0.05). Comparisons between in situ and traditional simulation showed mixed learner preference and knowledge improvement between groups, while technical skills showed improvement attributable to in situ simulation. In summary, available evidence suggests that adding in situ simulation to current educational practices may improve patient mortality and morbidity.

Body composition assessment after pediatric liver transplant.

BACKGROUND: Pediatric liver transplantation generally restores metabolic function; yet after transplantation, some children remain malnourished, have increased adiposity, and develop obesity. Measurement of body composition in the assessment of nutrition status could reduce adverse consequences in children. METHODS: Anthropometric measurements, multiple-frequency bioelectrical impedance analysis, air displacement plethysmography, and ultrasound measurements were conducted on children recruited from the liver transplant program at the University of Minnesota Masonic Children's Hospital. A cross-sectional study was conducted to describe the quality of weight gain in post-liver transplant children between the ages of 2 and 17 years using multiple assessment tools (air displacement plethysmography, multiple-frequency bioelectrical impedance analysis, and ultrasound) and to determine whether multiple-frequency bioelectrical impedance analysis and ultrasound accurately describe body composition and quality of weight gain. RESULTS: Mean percent body fat by air displacement plethysmography and multiple-frequency bioelectrical impedance analysis was 18.4% (±3.3) and 19.0% (±3.9), respectively (P > .99). There were insufficient data to examine the relationship between summed muscle and adipose thickness measures by ultrasound and percent body fat determined by air displacement plethysmography or multiple-frequency bioelectrical impedance analysis. CONCLUSION: Percent body fat, fat mass, and fat-free mass measures determined by air displacement plethysmography and multiple-frequency bioelectrical impedance analysis were not statistically different, which suggests the stand-on device used in this study could be a useful body composition assessment tool for the pediatric population.

Decline in Pediatric Shelf Examination Performance During COVID-19.

Background Medical student education has been impacted by the ongoing coronavirus 2019 (COVID-19) pandemic. Medical students were removed from clinical settings, and the censuses in pediatric hospitals decreased. While there have been studies starting to evaluate these effects on medical students training in surgical subspecialties, the literature in pediatrics is limited. Objective This study analyzed third-year medical students' National Board of Medical Examiners (NBME) Clinical Science Pediatrics Shelf Exam scores at the conclusion of their core pediatric clerkship. We compared the exam scores before COVID-19 pandemic to those during the pandemic. We hypothesized that the ongoing COVID-19 pandemic would have a negative impact on NBME shelf exam scores and that shelf exam failure rates would increase. Methods Institutional Review Board approval was obtained prior to initiation of this study. We conducted a retrospective review of medical student pediatric shelf exam scores from June 2017 to December 2020 from one large, single institution. We adjusted scores for block schedule timing and standardized them based on national norms published for the year prior. We compared two groups: those who completed their pediatric clerkship experiences before pandemic (predominantly in-person learning) vs. those who completed it during the pandemic (predominantly virtual learning). Groups were compared using chi-square and analysis-of-variance testing. Results We included 991 medical students, 772 before COVID-19 and 219 during COVID-19. Of these, 19 of 772 (2.5%) students failed the exam prior to COVID-19 compared to 19 of 219 (8.7%) during COVID-19 (p < 0.001). Students who completed their pediatric clerkship during COVID-19 were 3.77 times more likely to fail their end-of-clerkship NBME shelf exam (p < 0.001). Conclusions Students who completed their core pediatric clerkship in a predominantly virtual platform during the COVID-19 pandemic were significantly more likely to fail their end-of-clerkship NBME shelf exam. Increased failure rates may suggest issues with acquisition and retainment of pediatric medical knowledge throughout the clerkship, creating knowledge gaps in the foundation of their pediatric experience. Long-term effects of virtual learning platforms will need to be studied further.

Psychometric Testing of the Debriefing Assessment for Simulation in Healthcare (DASH) for Trainee-led, In Situ Simulations in the Pediatric Emergency Department Context.

OBJECTIVES: Effective trainee-led debriefing after critical events in the pediatric emergency department has potential to improve patient care, but debriefing assessments for this context have not been developed. This study gathers preliminary validity and reliability evidence for the Debriefing Assessment for Simulation in Healthcare (DASH) as an assessment of trainee-led post-critical event debriefing. METHODS: Eight fellows led teams in three simulated critical events, each followed by a video-recorded discussion of performance mimicking impromptu debriefings occurring after real clinical events. Three raters assessed the recorded debriefings using the DASH, and their feedback was collated. Data were analyzed using generalizability theory, Gwet's AC2, intraclass correlation coefficient (ICC), and coefficient alpha. Validity was examined using Messick's framework. RESULTS: The DASH instrument had relatively low traditional inter-rater reliability (Gwet's AC2 = 0.24, single-rater ICC range = 0.16-0.35), with 30% fellow, 19% rater, and 23% rater by fellow variance. DASH generalizability (G) coefficient was 0.72, confirming inadequate reliability for research purposes. Decision (D) study results suggest the DASH can attain a G coefficient of 0.8 with five or more raters. Coefficient alpha was 0.95 for the DASH. A total of 90 and 40% of items from Elements 1 and 4, respectively, were deemed "not applicable" or left blank. CONCLUSIONS: Our results suggest that the DASH does not have sufficient validity and reliability to rigorously assess debriefing in the post-critical event environment but may be amenable to modification. Further development of the tool will be needed for optimal use in this context.

Variation in COVID-19 Diagnosis by Zip Code and Race and Ethnicity in Indiana.

Objectives: To describe variations in coronavirus disease 2019 (COVID-19) diagnosis by zip code race and ethnicity in Indiana. Methods: Cross-sectional evaluation of subjects with SARS-CoV-2 at Indiana University Health. We performed two separate analyses, first evaluating likelihood of COVID-19 diagnosis by race (Caucasian, African American, Asian, or other) and ethnicity (Hispanic vs. non-Hispanic) in the cohort encompassing the entire state of Indiana. Subsequently, patient data was geolocated with zip codes in Marion County and the immediate surrounding counties, and descriptive statistical analyses were used to calculate the number of COVID-19 cases per 10,000 persons for each of these zip codes. Results: Indiana had a total of 3,892 positive COVID-19 cases from January 1 to April 30, 2020. The odds of testing positive for COVID-19 were four-fold higher in African Americans than non-African Americans (OR 4.58, 95% CI 4.25-4.94, P < 0.0001). Increased COVID-19 cases per 10,000 persons were seen in zip codes with higher percentage of African American (median infection rate of 17.4 per 10,000 population in zip codes above median % African American compared to 6.7 per 10,000 population in zip codes below median % African American, with an overall median infection rate 9.9 per 10,000 population, P < 0.0001) or Hispanic residents (median infection rate of 15.9 per 10,000 population in zip codes above median % Hispanic compared to 7.0 per 10,000 population in zip codes below median % Hispanic, overall median infection rate 9.6 per 10,000 population, P < 0.0001). Conclusions: Individuals from zip codes with higher percentages of African American, Hispanic, foreign-born, and/or residents living in poverty are disproportionately affected by COVID-19. Urgent work is needed to understand and address the disproportionate burden of COVID-19 in minority communities and when economic disparities are present.

A Case of Linezolid Induced Toxicity.

Adverse effects of linezolid are typically limited to diarrhea, nausea, and headache when shorter durations are used; however, as extended durations of linezolid therapy are increasingly more common, additional monitoring parameters should be considered in these patients. We describe a unique case of hypoglycemia, lactic acidosis, and pancreatitis related to an extended duration of linezolid therapy. A 52-year-old woman presented with altered mental status, abdominal pain, and hypotension following six weeks of linezolid and ertapenem therapy. Laboratory data revealed an initial blood glucose of 40 mg/dL and metabolic acidosis secondary to lactic acidosis. Finally, her abdominal pain on admission was likely related to an enlarged pancreas noted on computed tomography of her abdomen. Due to suspected linezolid toxicity, the patient received two intermittent hemodialysis sessions to remove linezolid and correct the metabolic acidosis. Given limited data on long-term monitoring of patients receiving extended durations of linezolid therapy, we suggest periodic monitoring of lactate, arterial blood gas, and blood glucose. If patients present with this triad of symptoms secondary to linezolid therapy, adverse effects should be treated with dextrose and intravenous thiamine while reserving hemodialysis for those with metabolic acidosis refractory to thiamine.

Developing Employment Environments Where Individuals with ASD Thrive: Using Machine Learning to Explore Employer Policies and Practices.

An online survey instrument was developed to assess employers' perspectives on hiring job candidates with Autism Spectrum Disorder (ASD). The investigators used K-means clustering to categorize companies in clusters based on their hiring practices related to individuals with ASD. This methodology allowed the investigators to assess and compare the various factors of businesses that successfully hire employees with ASD versus those that do not. The cluster analysis indicated that company structures, policies and practices, and perceptions, as well as the needs of employers and employees, were important in determining who would successfully hire individuals with ASD. Key areas that require focused policies and practices include recruitment and hiring, training, accessibility and accommodations, and retention and advancement.

Development of a 51-hospital Chicagoland regional antibiogram and comparison to local hospital and national surveillance data.

OBJECTIVE: To develop a regional antibiogram within the Chicagoland metropolitan area and to compare regional susceptibilities against individual hospitals within the area and national surveillance data. DESIGN: Multicenter retrospective analysis of antimicrobial susceptibility data from 2017 and comparison to local institutions and national surveillance data. SETTING AND PARTICIPANTS: The analysis included 51 hospitals from the Chicago-Naperville-Elgin Metropolitan Statistical Area within the state of Illinois. Overall, 18 individual collaborator hospitals provided antibiograms for analysis, and data from 33 hospitals were provided in aggregate by the Becton Dickinson Insights Research Database. METHODS: All available antibiogram data from calendar year 2017 were combined to generate the regional antibiogram. The final Chicagoland antibiogram was then compared internally to collaborators and externally to national surveillance data to assess its applicability and utility. RESULTS: In total, 167,394 gram-positive, gram-negative, fungal, and mycobacterial isolates were collated to create a composite regional antibiogram. The regional data represented the local institutions well, with 96% of the collaborating institutions falling within ±2 standard deviations of the regional mean. The regional antibiogram was able to include 4-5-fold more gram-positive and -negative species with ≥30 isolates than the median reported by local institutions. Against national surveillance data, 18.6% of assessed pathogen-antibiotic combinations crossed prespecified clinical thresholds for disparity in susceptibility rates, with notable trends for resistant gram-positive and gram-negative bacteria. CONCLUSIONS: Developing an accurate, reliable regional antibiogram is feasible, even in one of the largest metropolitan areas in the United States. The biogram is useful in assessing susceptibilities to less commonly encountered organisms and providing clinicians a more accurate representation of local antimicrobial resistance rates compared to national surveillance databases.

Intrathoracic hybrid lesion: an incidental finding in a patient with PHACE syndrome.

Hybrid lesions (HLs) are unique, congenital lung malformations with both cystic and solid components and vascular supply consistent with bronchopulmonary sequestration. Increase of HLs reported in recent literature suggest a common pathological mechanism occurring during embryogenesis, leading to occurrence of both malformations within a single lesion. Due to the unusual nature of HLs, gold standard approach for diagnosis is not very well-defined in the literature. We report a novel case of a 3-year-old girl with posterior fossa anomalies-haemangioma-arterial lesions-coarctation of the aorta-eye anomalies syndrome, who was found, on CT angiography, to have a previously missed HL diagnosis which was confirmed after surgical resection.

Chemical interactions between fibrosarcoma cancer cells and sensory neurons contribute to cancer pain.

In an experimental model of cancer pain, the hyperalgesia that occurs with osteolytic tumor growth is associated with the sensitization of nociceptors. We examined functional and molecular changes in small-diameter dorsal root ganglion (DRG) neurons to determine cellular mechanisms underlying this sensitization. The occurrence of a Ca2+ transient in response to either KCl (25 mM) or capsaicin (500 nM) increased in small neurons isolated from murine L3-L6 DRGs ipsilateral to fibrosarcoma cell tumors. The increased responses were associated with increased mRNA levels for the Ca2+ channel subunit alpha2delta1 and TRPV1 receptor. Pretreatment with gabapentin, an inhibitor of the alpha2delta1 subunit, blocked the increased response to KCl in vitro and the mechanical hyperalgesia in tumor-bearing mice in vivo. Similar increases in neuronal responsiveness occurred when DRG neurons from naive mice and fibrosarcoma cells were cocultured for 48 h. The CC chemokine ligand 2 (CCL2) may contribute to the tumor cell-induced sensitization because CCL2 immunoreactivity was present in tumors, high levels of CCL2 peptide were present in microperfusates from tumors, and treatment of DRG neurons in vitro with CCL2 increased the amount of mRNA for the alpha2delta1 subunit. Together, our data provide strong evidence that the chemical mediator CCL2 is released from tumor cells and evokes phenotypic changes in sensory neurons, including increases in voltage-gated Ca2+ channels that likely underlie the mechanical hyperalgesia in the fibrosarcoma cancer model. More broadly, this study provides a novel in vitro model to resolve the cellular and molecular mechanisms by which tumor cells drive functional changes in nociceptors.