Changes in older adults' life space during lung cancer treatment: A mixed methods cohort study.

BACKGROUND: Maintenance of function during cancer treatment is important to older adults. Characteristics associated with pretreatment life-space mobility and changes during non-small cell lung cancer (NSCLC) treatment remain unknown. METHODS: This mixed methods cohort study recruited adults age ≥65 with advanced NSCLC starting palliative chemotherapy, immunotherapy, and/or targeted therapy from a Comprehensive Cancer Center, Veterans Affairs, and safety-net clinic. Patients completed geriatric assessments including Life-Space Assessment (LSA) pretreatment and at 1, 2, 4, and 6 months after treatment initiation. LSA scores range from 0 to 120 (greater mobility); LSA <60 is considered restricted. We used mixed-effects models to examine pretreatment LSA, change from 0 to 1 month, and change from 1 to 6 months. A subgroup participated in semistructured interviews pretreatment and at 2 and 6 months to understand the patient experience of life-space change. For each interview participant, we created joint displays of longitudinal LSA scores juxtaposed with illustrative quotes. RESULTS: Among 93 patients, median age was 73 (range 65-94). Mean pretreatment LSA score was 67.1. On average, LSA declined 10.1 points from pretreatment to 1 month and remained stable at 6 months. Pretreatment LSA score was associated with several demographic, clinical, geriatric assessment, and symptom characteristics. LSA decline at 1 month was greater among patients with high anxiety (slope = -12.6 vs. -2.3, p = 0.048). Pretreatment body mass index <21 kg/m2 was associated with LSA improvement from 1 to 6 months (slope = 4.1 vs. -0.04, p = 0.003). Joint displays illustrated the impact of different life-space trajectories on patients' lives in their words. CONCLUSION: Older adults with NSCLC have low pretreatment life space with many developing restricted life space during treatment. Incorporating life-space assessments into clinical cancer care may help older adults concretely visualize how treatment might impact their daily function to allow for informed decision making and identify early changes in mobility to implement supportive interventions.

FACE-Q craniofacial module: Part 2 Psychometric properties of newly developed scales for children and young adults with facial conditions.

BACKGROUND: The FACE-Q Craniofacial Module is a patient-reported outcome measure designed for patients aged 8 to 29 years with conditions associated with a facial difference. In part 1, we describe the psychometric findings for the original CLEFT-Q scales tested in patients with cleft and noncleft facial conditions. The aim of this study was to examine psychometric performance of new FACE-Q Craniofacial Module scales. METHODS: Data were collected between December 2016 and December 2019 from patients aged 8 to 29 years with conditions associated with a visible or functional facial difference. Rasch measurement theory (RMT) analysis was used to examine psychometric properties of each scale. Scores were transformed from 0 (worst) to 100 (best) for tests of construct validity. RESULTS: 1495 participants were recruited with a broad range of conditions (e.g., birthmarks, facial paralysis, craniosynostosis, craniofacial microsomia, etc.) RMT analysis resulted in the refinement of 7 appearance scales (Birthmark, Cheeks, Chin, Eyes, Forehead, Head Shape, Smile), two function scales (Breathing, Facial), and an Appearance Distress scale. Person separation index and Cronbach alpha values met criteria. Three checklists were also formed (Eye Function, and Eye and Face Adverse Effects). Significantly lower scores on eight of nine scales were reported by participants whose appearance or functional difference was rated as a major rather than minor or no difference. Higher appearance distress correlated with lower appearance scale scores. CONCLUSION: The FACE-Q Craniofacial Module scales can be used to collect and compare patient reported outcomes data in children and young adults with a facial condition.

Discriminatory Power of Combinatorial Antigen Recognition in Cancer T Cell Therapies.

Precise discrimination of tumor from normal tissues remains a major roadblock for therapeutic efficacy of chimeric antigen receptor (CAR) T cells. Here, we perform a comprehensive in silico screen to identify multi-antigen signatures that improve tumor discrimination by CAR T cells engineered to integrate multiple antigen inputs via Boolean logic, e.g., AND and NOT. We screen >2.5 million dual antigens and ∼60 million triple antigens across 33 tumor types and 34 normal tissues. We find that dual antigens significantly outperform the best single clinically investigated CAR targets and confirm key predictions experimentally. Further, we identify antigen triplets that are predicted to show close to ideal tumor-versus-normal tissue discrimination for several tumor types. This work demonstrates the potential of 2- to 3-antigen Boolean logic gates for improving tumor discrimination by CAR T cell therapies. Our predictions are available on an interactive web server resource (antigen.princeton.edu).

CLEFT-Q: Detecting Differences in Outcomes among 2434 Patients with Varying Cleft Types.

BACKGROUND: Measuring the patient perspective is important in evaluating outcomes of cleft care. Understanding how treatment outcomes vary depending on cleft type may allow for better planning of treatments, setting of expectations, and more accurate benchmarking efforts. The CLEFT-Q is a patient-reported outcome measure for patients with cleft lip and/or palate. METHODS: The 12 CLEFT-Q scales measuring appearance (i.e., face, nose, nostrils, lips, cleft lip scar, teeth, and jaws), function (i.e., speech), and health-related quality of life (i.e., psychological, school, social, and speech-related distress) were field tested in a cross-sectional study in 30 centers in 12 countries. Patients with cleft lip and/or cleft palate aged 8 to 29 years were recruited from clinical settings. Differences in CLEFT-Q scores by cleft subtypes were evaluated using one-way analysis of variance or Kruskal-Wallis H tests, with Tukey or Dunn procedure with Bonferroni corrections post hoc analyses, respectively. Scores are presented using radar charts to visualize all outcomes simultaneously. RESULTS: The field test included 2434 patients. Scores on all CLEFT-Q scales varied significantly with cleft subtype. Patients with unilateral or bilateral cleft lip and/or palate scored lower on all appearance scales compared with patients with cleft palate or unilateral incomplete cleft lip. Scores on the speech function and speech-related distress scales decreased with each progressive group in the Veau classification. Patients with complete bilateral cleft lip and palate scored lowest on the social, school, and psychological scales. CONCLUSIONS: Patient-reported outcomes measured with the CLEFT-Q vary significantly with cleft type. Visualizing multiple outcomes simultaneously with radar charts allows for an understanding of a patient's overall status in a single graph.

Dornase Alfa Ototoxic Effects in Animals and Efficacy in the Treatment of Clogged Tympanostomy Tubes in Children: A Preclinical Study and a Randomized Clinical Trial.

Importance: Many treatments for clogged tympanostomy tubes (TTs) have been proposed, but none have met scientific rigor for safety and efficacy, including the popular empirical use of ototopical antibiotic drops. Dornase alfa, a recombinant molecule with the unique property of cleaving DNA, may be ideal in treating clogged TTs because both middle-ear effusion and the plug are abundant with DNA. Objective: To investigate the ototoxic effects of dornase alfa in a chinchilla model and its efficacy in a clinical trial in children with clogged TTs. Design, Setting, and Participants: The safety profiles of dornase alfa (full-strength and 1:10 strength) were evaluated in chinchilla middle ears using serial auditory brainstem response. The efficacy of ototopical dornase alfa (full-strength) was evaluated in children with clogged TTs in a prospective, single-blind randomized clinical trial. The animal study included 21 chinchillas and was conducted at Loma Linda University, Loma Linda, California, and the clinical trial was conducted at Children's Hospital Colorado, Aurora. A total of 40 children (50 ears with tubes) were enrolled. Interventions: In the animal study, chinchillas were assigned to 3 groups: controls (saline), full-strength dornase alfa, or 1:10 dornase alfa dilution. Children were randomly assigned to receive either topical dornase alfa or ofloxacin for clogged TT, 5 drops each ear twice a day for 7 days. Main Outcomes and Measures: Animal study: Auditory brainstem responses. Randomized trial of children participants: The primary outcome was patency of TT at day 14 assessed by otoscopy and tympanometry. Results: The chinchilla study showed similar auditory brainstem response degradation during a 6-hour period between the control (n = 5) and treatment groups (n = 21). In the clinical trial, a total of 40 clogged TTs (in 33 children, including 25 boys [76%]; mean age, 4.3 years; median [range] age, 3.4 [1.0-14.3] years) were analyzed. The number of unclogged TTs was higher in the dornase alfa group (13 [59%]) compared with the ofloxacin group (8 [44%]), with a difference of 15% (odds ratio, 1.8; 95% CI, 0.54-6.72). Conclusions and Relevance: The chinchilla model suggests that dornase alfa is likely nonototoxic. The pilot clinical trial failed to show efficacy of dornase alfa to unclog TTs. With the difference seen between the treatment groups, a sample size estimate could be calculated for a future large-scale trial. Trial Registration: ClinicalTrials.gov identifier: NCT00419380.

Complications and parent satisfaction in pediatric osseointegrated bone-conduction hearing implants.

OBJECTIVE: To assess long-term complication rate and parental satisfaction of osseointegrated bone conduction hearing implants (OBCHIs). STUDY DESIGN: Retrospective chart review of children undergoing OBCHIs. METHODS: A retrospective chart review of children undergoing OBCHIs for the treatment of conductive, mixed, and single-sided sensorineural hearing loss in children. RESULTS: Forty-five subjects were identified with 0.3 to 10.4 years of follow-up. The mean/median age and age range at implant were 9.0/7.8 and 1.7 to 19.1 years. The underlying hearing loss for the cohort included conductive (N = 30), sensorineural (N = 7), and mixed (N = 8) hearing loss. Conductive hearing loss, caused by aural atresia (62.9), was the most common indication for implantation. Fifty-eight complications occurred in 29 subjects, most related to skin infection or overgrowth. Seventeen events required revision surgery, and 18 required oral antibiotics and/or office-based cauterization. Children under the age of 5 years were more likely to have failure of osseointegration or require revision surgery. Parents of 33 subjects underwent a phone interview; 76% rated the overall satisfaction as satisfied or very satisfied. CONCLUSION: A large percentage of children undergoing OBCHI develop postoperative complications, and up to 44% require revision surgery-a figure higher than generally reported and higher than in adults. No factors were found to adequately explain the higher complication rates in children compared to adults. Despite the occurrence of complications, parents viewed this device as satisfactory from many perspectives. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2165-2170, 2017.

Prognostic Factors in the Outcome of Invasive Fungal Sinusitis in a Pediatric Population.

BACKGROUND: Pediatric invasive fungal sinusitis (IFS) is rare, and its prognosticators are poorly understood. The aim of this study was to determine important factors affecting outcome. METHODS: A 10-year retrospective review at a tertiary academic children's hospital was performed using an International Classification of Diseases, 9th revision, and a procedure-based search after institutional review board approval. All relevant demographic and clinical information was collected. RESULTS: Fourteen immune-compromised patients (male:female = 7:7, mean age = 10 years, range 2-16 years) were identified who had hematologic malignancies (11), diabetes mellitus (2) and unknown predisposing factors (1). Fungal species included Aspergillus (5), Mucor (5), Alternaria (2), Rhizopus (1) and Scopulariopsis (1). The cohort underwent an average of 6.1 (median = 5) endoscopic sinus surgeries and were treated with aggressive antifungal therapy. Four deaths occurred in the study population: 2 were attributable to IFS and 2 attributable to their underlying malignancies. There was a significant difference in the median absolute neutrophil count (ANC) at follow-up after treatment of IFS between the survival and the mortality subgroups, with ANC being 4290.5 and 169, respectively (P < 0.001). CONCLUSIONS: Despite the small sample size, this study represents the largest case series in the medical literature on pediatric IFS. Age, gender, underlying cause for immunodeficiency and mycologic agent were not important prognosticators. ANC appears to be the only factor responsible for survival. The role of endoscopic sinus surgeries in survival is indeterminate.

Dacryocystitis As the Initial Presentation of Invasive Fungal Sinusitis in Immunocompromised Children.

Sino-orbital fungal infection is a rare, but life-threatening disease seen mainly in immunocompromised patients. While initial clinical impression may vary, dacryocystitis has rarely been described as the initial presenting sign. The authors present 2 pediatric cases of dacryocystitis as the initial sign of invasive fungal sinusitis. To their knowledge, this presenting sign has not been previously reported in the pediatric population. Management strategies and outcomes are discussed.

Parent, dentist, and orthodontist satisfaction following alveolar cleft repair using recombinant human bone morphogenic protein.

OBJECTIVE: Our aim was to evaluate dental/orthodontic outcomes for patients who underwent recombinant human bone morphogenic protein (rhBMP-2) alveolar cleft repair and to examine parental satisfaction following the procedure. Design Retrospective review. Setting Tertiary children's hospital. Participants Parents, dentists, and orthodontists completed satisfaction questionnaires. Main Outcome Measures Parent, dentist, and orthodontist satisfaction with the use of rhBMP-2 in alveolar cleft repair. Results Parent response rate was 71.4% (30/42). The dentist response rate was 60% (18/30). The orthodontist response rate was 53.3% (16/30). Parent and patient satisfaction was 93.3% and 83.3%, respectively. Of dentist respondents, 55.6% reported that the bone quality and alveolar ridge mucosal repair allowed for dental treatment. Of orthodontist respondents, 87.5% reported the graft enabled treatment, and 73.3% felt the graft prevented tooth root exposure and resorption. Conclusions Parents, dentists, and orthodontists are satisfied with outcomes when rhBMP-2 is used for alveolar cleft repair. The bone formed was reported as adequate to support dental and orthodontic treatment in most cases with few complications. Because of safety concerns over the use of this product in an off-label manner, further controlled studies are warranted.

Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the North American malignant hyperthermia registry of the malignant hyperthermia association of the United States.

BACKGROUND: AMRA (adverse metabolic or muscular reaction to anesthesia) reports submitted to The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States from 1987 to 2006 revealed a 2.7% cardiac arrest and a 1.4% death rate for 291 malignant hyperthermia (MH) events. We analyzed 6 years of recent data to update MH cardiac arrest and death rates, summarized characteristics associated with cardiac arrest and death, and documented differences between early and recent cohorts of patients in the MH Registry. We also tested whether the available data supported the hypothesis that risk of dying from an episode of MH is increased in patients with inadequate temperature monitoring. METHODS: We included U.S. or Canadian reports of adverse events after administration of at least 1 anesthetic drug, received between January 1, 2007, and December 31, 2012, with an MH clinical grading scale rank of "very likely MH" or "almost certain MH." We excluded reports that, after review, were judged to be due to pathologic conditions other than MH. We analyzed patient demographics, family and patient anesthetic history, anesthetic management including temperature monitoring, initial dantrolene dose, use of cardiopulmonary resuscitation, MH complications, survival, and reported molecular genetic DNA analysis of RYR1 and CACNA1S. A one-sided Cochran-Armitage test for proportions evaluated associations between mode of monitoring and mortality. We used Miettinen and Nurminen's method for assessing the relative risk of dying according to monitoring method. We used the P value of the slope to evaluate the relationship between duration of anesthetic exposure before dantrolene administration and peak temperature. We calculated the relative risk of death in this cohort compared with our previous cohort by using the Miettinen and Nurminen method adjusted for 4 comparisons. RESULTS: Of 189 AMRA reports, 84 met our inclusion criteria. These included 7 (8.3%) cardiac arrests, no successful resuscitations, and 8 (9.5%) deaths. Of the 8 patients who died, 7 underwent elective surgeries considered low to intermediate risk. The average age of patients who died was 31.4 ± 16.9 years. Five were healthy preoperatively. Three of the 8 patients had unrevealed MH family history. Four of 8 anesthetics were performed in freestanding facilities. In those who died, 3 MH-causative RYR1 mutations and 3 RYR1 variants likely to have been pathogenic were found in the 6 patients in whom RYR1 was examined. Compared to core temperature monitoring, the relative risk of dying with no temperature monitoring was 13.8 (lower limit 2.1). Compared to core temperature monitoring, the relative risk of dying with skin temperature monitoring was 9.7 (1.5). Temperature monitoring mode best distinguished patients who lived from those who died. End-tidal CO2 was the worst physiologic measure to distinguish patients who lived from those who died. Longer anesthetic exposures before dantrolene were associated with higher peak temperatures (P = 0.00056). Compared with the early cohort, the recent cohort had a higher percentage of MH deaths (4/291 vs 8/84; relative risk = 6.9; 95% confidence interval, 1.7-28; P = 0.0043 after adjustment for 4 comparisons). CONCLUSIONS: Despite a thorough understanding of the management of MH and the availability of a specific antidote, the risk of dying from an MH episode remains unacceptably high. To increase the chance of successful MH treatment, the American Society of Anesthesiologists and Malignant Hyperthermia Association of the U.S. monitoring standards should be altered to require core temperature monitoring for all general anesthetics lasting 30 minutes or longer.

Long-term safety and efficacy data on botulinum toxin type A: an injection for sialorrhea.

OBJECTIVE: To evaluate the safety and efficacy data on salivary gland injection botulinum toxin type A for the treatment of sialorrhea. DESIGN AND SETTING: Retrospective cohort study in a tertiary academic children's hospital. PATIENTS: A 10-year review (January 1, 2001, through December 31, 2010) of 69 children with sialorrhea who had undergone salivary gland injection of botulinum toxin type A. INTERVENTIONS: Injection of botulinum toxin type A to the submandibular and parotid glands. MAIN OUTCOME MEASURES: Postinjection complications, supplemental treatments, and caregiver satisfaction. RESULTS: A total of 69 children were included in the study (42 boys and 27 girls). The first injection was given at a mean age of 9.9 years with a mean follow-up of 3.1 years. Children underwent ultrasonography-guided 4-gland injection at a constant dosage range. The telephone survey response rate was 51%. Postinjection complications occurred in 19 patients (23 events)-14 (15 events) with minor and 5 (8 events) with major complications. Major complications included aspiration pneumonia (n = 3), severe dysphagia (n = 2), and loss of motor control of the head (n = 3), resulting in 5 hospitalizations and 2 nasogastric tube insertions. Complications were not associated with demographic or clinical factors except for a male preponderance (P = .05). Satisfaction scores were evenly distributed among respondents. Thirty-one children (45%) required supplemental treatments: medical treatment alone (n = 21), surgical treatment alone (n = 2), and combined medical and surgical treatment (n = 8). CONCLUSIONS: Although our complication rate is within the published range, some of the major complications had significant morbidity. A subsequent surgical rate of 15% suggests the efficacy is less than universal. Thus, botulinum toxin type A injection for sialorrhea in children is a useful tool but has safety and efficacy limitations.

Early intervention: distraction osteogenesis of the mandible for severe airway obstruction.

OBJECTIVE: To determine benefits of early intervention in neonates with symptomatic micrognathia who underwent bilateral mandibular distraction osteogenesis within the first 90 days of life as relates to growth, need for supportive care, and further invasive procedures. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care, academic children's hospital. SUBJECTS AND METHODS: Review of neonates with symptomatic micrognathia who underwent bilateral mandibular distraction osteogenesis in the past 5 years. Inclusion criteria included mandibular distraction osteogenesis performed within the first 90 days of life. Outcome measures included hospital course, growth curves, supportive home care needs, and airway at cleft repair. RESULTS: Twenty-four patients met inclusion criteria. The mean age at distraction was 30 days, and the average discharge was postoperative day 14. One patient required home oxygen, 50% were able to feed exclusively by oral diet, and no patients required tracheotomy. In addition, airway results were substantial, with 90% of patients showing objective improvement in airway grade from time of mandibular distraction to time of cleft repair. CONCLUSION: We present our initial outcomes on mandibular distraction osteogenesis in neonates with symptomatic micrognathia. Early intervention allows discharge to home with minimal supportive care needs by avoiding tracheostomy and facilitating transition to oral feeds. The airway improvement is significant and is sustained and allows for easier intubation at time of cleft repair.

The architecture of CopA from Archeaoglobus fulgidus studied by cryo-electron microscopy and computational docking.

CopA uses ATP to pump Cu(+) across cell membranes. X-ray crystallography has defined atomic structures of several related P-type ATPases. We have determined a structure of CopA at 10 Å resolution by cryo-electron microscopy of a new crystal form and used computational molecular docking to study the interactions between the N-terminal metal-binding domain (NMBD) and other elements of the molecule. We found that the shorter-chain lipids used to produce these crystals are associated with movements of the cytoplasmic domains, with a novel dimer interface and with disordering of the NMBD, thus offering evidence for the transience of its interaction with the other cytoplasmic domains. Docking identified a binding site that matched the location of the NMBD in our previous structure by cryo-electron microscopy, allowing a more detailed view of its binding configuration and further support for its role in autoinhibition.

Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006.

BACKGROUND: We analyzed cases of malignant hyperthermia (MH) reported to the North American MH Registry for clinical characteristics, treatment, and complications. METHODS: Our inclusion criteria were as follows: AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports between January 1, 1987 and December 31, 2006; "very likely" or "almost certain" MH as ranked by the clinical grading scale; United States or Canadian location; and more than one anesthetic drug given. An exclusion criterion was pathology other than MH; for complication analysis, patients with unknown status or minor complications attributable to dantrolene were excluded. Wilcoxon rank sum and Pearson exact chi(2) tests were applied. A multivariable model of the risk of complications from MH was created through stepwise selection with fit judged by the Hosmer-Lemeshow statistic. RESULTS: Young males (74.8%) dominated in 286 episodes. A total of 6.5% had an MH family history; 77 of 152 patients with MH reported >or=2 prior unremarkable general anesthetics. In 10 cases, skin liquid crystal temperature did not trend. Frequent initial MH signs were hypercarbia, sinus tachycardia, or masseter spasm. In 63.5%, temperature abnormality (median maximum, 39.1 degrees C) was the first to third sign. Whereas 78.6% presented with both muscular abnormalities and respiratory acidosis, only 26.0% had metabolic acidosis. The median total dantrolene dose was 5.9 mg/kg (first quartile, 3.0 mg/kg; third quartile, 10.0 mg/kg), although 22 patients received no dantrolene and survived. A total of 53.9% received bicarbonate therapy. Complications not including recrudescence, cardiac arrest, or death occurred in 63 of 181 patients (34.8%) with MH. Twenty-one experienced hematologic and/or neurologic complications with a temperature <41.6 degrees C (human critical thermal maximum). The likelihood of any complication increased 2.9 times per 2 degrees C increase in maximum temperature and 1.6 times per 30-minute delay in dantrolene use. CONCLUSION: Elevated temperature may be an early MH sign. Although increased temperature occurs frequently, metabolic acidosis occurs one-third as often. Accurate temperature monitoring during general anesthetics and early dantrolene administration may decrease the 35% MH morbidity rate.

Plexiform fibrohistiocytic tumor: ultrastructural studies may aid in discrimination from cellular neurothekeoma.

Plexiform fibrohistiocytic tumor is a low-grade soft tissue malignancy that can at times be difficult to differentiate from the less biologically aggressive cellular neurothekeoma. The two entities, which may display identical clinical and histological features, cannot be distinguished by immunohistochemical or molecular diagnostic means. Electron microscopy may enable the accurate identification of problematic examples and thus aid in resolving these occasionally occurring diagnostic dilemmas. To illustrate typical variations in the ultrastructural appearance of plexiform fibrohistiocytic tumor, the authors present two diagnostically noncontroversial examples, and to demonstrate the potential diagnostic utility of electron microscopy in this setting, they present an example of plexiform fibrohistiocytic tumor that could not otherwise have been distinguished from cellular neurothekeoma.