Patient-reported measures of tinnitus for individuals with neurofibromatosis type 2-related schwannomatosis: Recommendations for clinical trials.

BACKGROUND: Neurofibromatosis type 2-related schwannomatosis is a genetic disease characterized by the development of bilateral vestibular schwannomas, ependymomas, meningiomas, and cataracts. Mild to profound hearing loss and tinnitus are common symptoms reported by individuals with neurofibromatosis type 2. While tinnitus is known to have a significant and negative impact on the quality of life of individuals from the general population, the impact on individuals with neurofibromatosis type 2 is unknown. Consensus regarding the selection of suitable patient-reported outcome measures for assessment could advance further research into tinnitus in neurofibromatosis type 2 patients. The purpose of this work is to achieve a consensus recommendation by the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration for patient-reported outcome measures used to evaluate quality of life in the domain of tinnitus for neurofibromatosis type 2 clinical trials. METHODS: The Response Evaluation in Neurofibromatosis and Schwannomatosis Patient-Reported Outcomes Communication Subgroup systematically evaluated patient-reported outcome measures of quality of life in the domain of tinnitus for individuals with neurofibromatosis type 2 using previously published Response Evaluation in Neurofibromatosis and Schwannomatosis rating procedures. Of the 19 identified patient-reported outcome measures, 3 measures were excluded because they were not validated as an outcome measure or could not have been used as a single outcome measure for a clinical trial. Sixteen published patient-reported outcome measures for the domain of tinnitus were scored and compared on their participant characteristics, item content, psychometric properties, and feasibility for use in clinical trials. RESULTS: The Tinnitus Functional Index was identified as the most highly rated measure for the assessment of tinnitus in populations with neurofibromatosis type 2, due to strengths in the areas of item content, psychometric properties, feasibility, and available scores. DISCUSSION: Response Evaluation in Neurofibromatosis and Schwannomatosis currently recommends the Tinnitus Functional Index for the assessment of tinnitus in neurofibromatosis type 2 clinical trials.

Recommendations for assessing appearance concerns related to plexiform and cutaneous neurofibromas in neurofibromatosis 1 clinical trials.

BACKGROUND/AIMS: Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance concerns related to these physical changes can lead to psychological distress and poorer quality of life. While many neurofibromatosis 1 clinical trials focus on assessing changes in tumor volume, evaluating patients' perspectives on corresponding changes in symptoms such as physical appearance can be key secondary outcomes. We aimed to determine whether any existing patient-reported outcome measures are appropriate for evaluating changes in appearance concerns within neurofibromatosis 1 clinical trials. METHODS: After updating our previously published systematic review process, we used it to identify and rate existing patient-reported outcome measures related to disfigurement and appearance. Using a systematic literature search and initial triage process, we focused on identifying patient-reported outcome measures that could be used to evaluate changes in appearance concerns in plexiform or cutaneous neurofibroma clinical trials in neurofibromatosis 1. Our revised Patient-Reported Outcome Rating and Acceptance Tool for Endpoints then was used to evaluate each published patient-reported outcome measures in five domains, including (1) respondent characteristics, (2) content validity, (3) scoring format and interpretability, (4) psychometric data, and (5) feasibility. The highest-rated patient-reported outcome measures were then re-reviewed in a side-by-side comparison to generate a final consensus recommendation. RESULTS: Eleven measures assessing appearance concerns were reviewed and rated; no measures were explicitly designed to assess appearance concerns related to neurofibromatosis 1. The FACE-Q Craniofacial Module-Appearance Distress scale was the top-rated measure for potential use in neurofibromatosis 1 clinical trials. Strengths of the measure included that it was rigorously developed, included individuals with neurofibromatosis 1 in the validation sample, was applicable to children and adults, covered item topics deemed important by neurofibromatosis 1 patient representatives, exhibited good psychometric properties, and was feasible for use in neurofibromatosis 1 trials. Limitations included a lack of validation in older adults, no published information regarding sensitivity to change in clinical trials, and limited availability in languages other than English. CONCLUSION: The Response Evaluation in Neurofibromatosis and Schwannomatosis patient-reported outcome working group currently recommends the FACE-Q Craniofacial Module Appearance Distress scale to evaluate patient-reported changes in appearance concerns in clinical trials for neurofibromatosis 1-related plexiform or cutaneous neurofibromas. Additional research is needed to validate this measure in people with neurofibromatosis 1, including older adults and those with tumors in various body locations, and explore the effects of nontumor manifestations on appearance concerns in people with neurofibromatosis 1 and schwannomatosis.

The preventable burden of mortality from unsafe abortion among female sex workers: a Community Knowledge Approach survey among peer networks in eight countries.

Previous studies have found high levels of unintended pregnancy among female sex workers (FSW), but less attention has been paid to their abortion practices and outcomes. This study is the first to investigate abortion-related mortality among FSW across eight countries: Angola, Brazil, Democratic Republic of Congo (DRC), India, Indonesia, Kenya, Nigeria, and South Africa. The Community Knowledge Approach (CKA) was used to survey a convenience sample of FSW (n = 1280). Participants reported on the deaths of peer FSW in their social networks during group meetings convened by non-governmental organisations (n = 165 groups, conducted across 24 cities in 2019). Details on any peer FSW deaths in the preceding five years were recorded. The circumstances of abortion-related deaths are reported here. Of the 1320 maternal deaths reported, 750 (56.8%) were due to unsafe abortion. The number of abortion-related deaths reported was highest in DRC (304 deaths reported by 270 participants), Kenya (188 deaths reported by 175 participants), and Nigeria (216 deaths reported by 312 participants). Among the abortion-related deaths, mean gestational age was 4.6 months and 75% occurred outside hospital. Unsafe abortion methods varied by country, but consumption of traditional or unknown medicines was most common (37.9% and 29.9%, respectively). The 750 abortion-related deaths led to 1207 children being left motherless. The CKA successfully recorded a stigmatised practice among a marginalised population, identifying very high levels of abortion-related mortality. Urgent action is now needed to deliver comprehensive sexual and reproductive healthcare to this vulnerable population, including contraption, safe abortion, and post-abortion care.

Drug Use and Human Milk: Legal and Child Welfare Considerations.

INTRODUCTION: Preventing new parents who use drugs from bonding with and bodyfeeding their babies undermines public health. Because U.S. culture treats substance use as a moral failing rather than a health concern, punitive responses to perinatal substance use continue to dominate. This is particularly true for families of color, who are more likely to be targeted by the family regulation system. These approaches fail to protect families, and cause their own, separate harm. This article will lay out existing evidence surrounding bodyfeeding. Then, it will debunk harmful mythologies about drug use and human milk, and compare the risks associated with using drugs while bodyfeeding to those inherent in family separation. Finally, it will make the case for harm-reduction approaches over criminal ones. OBJECTIVES: The health risks associated with family separation are only rarely weighed against those associated with drug exposure through human milk. Our objective for this paper is to contribute new ways of framing the importance of keeping families together at birth, even when perinatal substance use is detected. METHODS: This manuscript is not based upon clinical study or patient data, and exclusively references studies and research publications that have been approved by the appropriate ethics committee and which have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. RESULTS: Significant research data support the position that the risks associated with family separation are arguably greater than those associated with exposure to substance use in human milk. CONCLUSIONS FOR PRACTICE: Harm reduction approaches should be favored over criminal approaches when perinatal substance use is detected or confirmed.

The harms of family separation have already been well-documented by public health and social science researchers. The risks associated with substance use and human milk have also been the subject of significant academic research. However, the authors have not come across any articles that weigh the health risks associated with family separation against those associated with drug exposure through human milk. This paper contributes new ways of framing the importance of keeping families together at birth, even when perinatal substance use is detected.

Causes of mortality among female sex workers: Results of a multi-country study.

Background: The vast majority of studies on female sex workers (FSW) focus on causes of morbidity while data on causes of mortality are scarce. In low- and middle-income countries, where civil registry and vital statistics data are often incomplete and FSW may not be identified as such in official registries, identifying causes of mortality among FSW has proven challenging. Methods: As part of a larger investigation on the maternal health of FSW, the current study used the Community Knowledge Approach (CKA) to identify causes of mortality among FSW in LMIC across three global regions in 2019. The CKA, validated to identify maternal, neonatal, and jaundice-associated deaths among women living in a community, was employed to identify deaths of any cause among communities of FSW. Study participants, recruited by in-country partner non-governmental organizations (NGOs) working with local FSW, provided detailed information about FSW deaths in their communities. Findings: 1280 FSW participated in 165 group meetings through which 2112 FSW deaths were identified. Of these reported deaths, 57·9% occurred in 2019 and 57·2% were among women aged 20-29. Causes of death included abortion (35·5%), other maternal causes (16·6%), suicide (13·6%), murder (12·5%), unclassified causes (11·6%), HIV/AIDS (7·9%), and accidents (3·2%). A total of 3659 children lost their mothers. Interpretation: Maternal death comprised the leading cause of FSW mortality in our sample. This methodology can be used by local governments and NGOs to identify unrecognized patterns and clusters of FSW deaths in near-real time and urgently steer targeted preventative strategies. Funding: New Venture Fund.

Outcomes of Cannabis Use During Pregnancy Within the American Association of Birth Centers Perinatal Data Registry 2007-2020: Opportunities Within Midwifery-Led Care.

BACKGROUND: Healthcare providers require data on associations between perinatal cannabis use and birth outcomes. METHODS: This observational secondary analysis come from the largest perinatal data registry in the United States related to the midwifery-led birth center model care (American Association of Birth Centers Perinatal Data Registry; N = 19 286). Births are planned across all birth settings (home, birth center, hospital); care is provided by midwives and physicians. RESULTS: Population data show that both early and persistent self-reports of cannabis use were associated with higher rates of preterm birth, low-birth-weight, lower 1-minute Apgar score, gestational weight gain, and postpartum hemorrhage. Once controlled for medical and social risk factors using logistic regression, differences for childbearing people disappeared except that the persistent use group was less likely to experience "no intrapartum complications" (adjusted odds ratio [aOR] = 0.49; 95% confidence interval [CI], 0.32-0.76; P < .01), more likely to experience an indeterminate fetal heart rate in labor (aOR = 3.218; 95% CI, 2.23-4.65; P < .05), chorioamnionitis (aOR = 2.8; 95% CI, 1.58-5.0; P < .01), low-birth-weight (aOR = 1.8; 95% CI, 1.08-3.05; P < .01), and neonatal intensive care unit (NICU) admission (aOR = 2.4; 95% CI, 1.30-4.69; P < .05). CONCLUSIONS: Well-controlled data demonstrate that self-reports of persistent cannabis use through the third trimester are associated with an increased risk of low-birth-weight and NICU admission.

Current Recommendations for Patient-Reported Outcome Measures Assessing Domains of Quality of Life in Neurofibromatosis Clinical Trials.

OBJECTIVE: To review and recommend patient-reported outcome (PRO) measures assessing multidimensional domains of quality of life (QoL) to use as clinical endpoints in medical and psychosocial trials for children and adults with neurofibromatosis (NF) type 1, NF2, and schwannomatosis. METHODS: The PRO working group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration used systematic methods to review, rate, and recommend existing self-report and parent-report PRO measures of generic and disease-specific QoL for NF clinical trials. Recommendations were based on 4 main criteria: patient characteristics, item content, psychometric properties, and feasibility. RESULTS: The highest-rated generic measures were (1) the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales for NF clinical trials for children or for children through adults, (2) the Functional Assessment of Cancer Therapy-General for adult medical trials, and (3) the World Health Organization Quality of Life-BREF for adult psychosocial trials. The highest-rated disease-specific measures were (1) the PedsQL NF1 Module for NF1 trials, (2) the NF2 Impact on Quality of Life Scale for NF2 trials, and (3) the Penn Acoustic Neuroma Quality of Life Scale for NF2 trials targeting vestibular schwannomas. To date, there are no disease-specific tools assessing multidimensional domains of QoL for schwannomatosis. CONCLUSIONS: The REiNS Collaboration currently recommends these generic and disease-specific PRO measures to assess multidimensional domains of QoL for NF clinical trials. Additional research is needed to further evaluate the use of these measures in both medical and psychosocial trials.

Patient Report of Hearing in Neurofibromatosis Type 2: Recommendations for Clinical Trials.

OBJECTIVE: To systematically evaluate published patient-reported outcome measures for the assessment of hearing function and hearing-related quality of life (QoL) and recommend measures selected by the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration (REiNS) as endpoints for clinical trials in neurofibromatosis type 2 (NF2). METHODS: The REiNS Patient-Reported Outcomes Working Group systematically evaluated published patient-reported outcome measures of (1) hearing function and (2) hearing-related QoL for individuals with hearing loss of various etiologies using previously published REiNS rating procedures. Ten measures of hearing functioning and 11 measures of hearing-related QoL were reviewed. Measures were numerically scored and compared primarily on their participant characteristics (including participant age range and availability of normative data), item content, psychometric properties, and feasibility for use in clinical trials. RESULTS: The Self-Assessment of Communication and the Self-Assessment of Communication-Adolescent were identified as most useful for adult and pediatric populations with NF2, respectively, for the measurement of both hearing function and hearing-related QoL. Measures were selected for their strengths in participant characteristics, item content, psychometric properties, and feasibility for use in clinical trials. CONCLUSIONS: REiNS recommends the Self-Assessment of Communication adult and adolescent forms for the assessment of patient-reported hearing function and hearing-related QoL for NF2 clinical trials. Further work is needed to demonstrate the utility of these measures in evaluating pharmacologic or behavioral interventions.

Recommendations for Social Skills End Points for Clinical Trials in Neurofibromatosis Type 1.

OBJECTIVE: To review parent-report social skills measures to identify and recommend consensus outcomes for use in clinical trials of social deficit in children and adolescents (ages 6-18 years) with neurofibromatosis type 1 (NF1). METHODS: Searches were conducted via PubMed and ClinicalTrials.gov to identity social skills outcome measures with English language versions used in clinical trials in the past 5 years with populations with known social skills deficits, including attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD). Measures were rated by the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Neurocognitive Committee on patient characteristics, use in published studies, domains assessed, availability of standard scores, psychometric properties, and feasibility to determine their appropriateness for use in NF1 clinical trials. RESULTS: Two measures were ultimately recommended by the committee: the Social Responsiveness Scale-2 (SRS-2) and the Social Skills Improvement System-Rating Scale (SSIS-RS). CONCLUSIONS: Each of the 2 measures assesses different aspects of social functioning. The SSIS-RS is appropriate for studies focused on broader social functioning; the SRS-2 is best for studies targeting problematic social behaviors associated with ASD. Researchers will need to consider the goals of their study when choosing a measure, and specific recommendations for their use are provided.

Recommendations for Measurement of Attention Outcomes in Preschoolers With Neurofibromatosis.

Children with neurofibromatosis type 1 (NF1) are at increased risk for attention problems. While most research has been conducted with school-aged cohorts, preschool-aged children offer a novel developmental window for clinical studies, with the promise that treatments implemented earlier in the developmental trajectory may most effectively modify risk for later difficulties. Designing research studies around the youngest children with NF1 can result in intervention earlier in the developmental cascade associated with NF1 gene abnormalities. Furthermore, clinical trials for medications targeting physical and psychological aspects of NF1 often include individuals spanning a wide age range, including preschool-aged children. In a prior report, the REiNS Neurocognitive Subcommittee made recommendations regarding performance-based and observer-rated measures of attention for use in clinical trials and highlighted the need for separate consideration of assessment methods for young children. The observer-rated Attention-Deficit/Hyperactivity Disorder Rating Scale-Preschool version is recommended as a primary outcome measure. The NIH Toolbox Flanker, Dimensional Change Card Sort, and List Sort Working Memory tasks and Digits Forward from the Differential Ability Scales-2nd Edition (performance-based measures) are recommended as secondary outcome measures. Specific methodologic recommendations for inclusion of preschoolers in clinical trials research are also offered.

IL-6 can singlehandedly drive many features of frailty in mice.

Frailty is a geriatric syndrome characterized by age-related declines in function and reserve resulting in increased vulnerability to stressors. The most consistent laboratory finding in frail subjects is elevation of serum IL-6, but it is unclear whether IL-6 is a causal driver of frailty. Here, we characterize a new mouse model of inducible IL-6 expression (IL-6TET-ON/+ mice) following administration of doxycycline (Dox) in food. In this model, IL-6 induction was Dox dose-dependent. The Dox dose that increased IL-6 levels to those observed in frail old mice directly led to an increase in frailty index, decrease in grip strength, and disrupted muscle mitochondrial homeostasis. Littermate mice lacking the knock-in construct failed to exhibit frailty after Dox feeding. Both naturally old mice and young Dox-induced IL-6TET-ON/+ mice exhibited increased IL-6 levels in sera and spleen homogenates but not in other tissues. Moreover, Dox-induced IL-6TET-ON/+ mice exhibited selective elevation in IL-6 but not in other cytokines. Finally, bone marrow chimera and splenectomy experiments demonstrated that non-hematopoietic cells are the key source of IL-6 in our model. We conclude that elevated IL-6 serum levels directly drive age-related frailty, possibly via mitochondrial mechanisms.

Corrigendum: Defective Transcriptional Programming of Effector CD8 T Cells in Aged Mice Is Cell-Extrinsic and Can Be Corrected by Administration of IL-12 and IL-18.

[This corrects the article DOI: 10.3389/fimmu.2019.02206.].

Exploring the Experiences of Child Welfare-Focused Therapeutic Service Providers.

The importance of mental and behavioral health for child welfare clients is well-documented; yet, little is known about the challenges therapeutic service providers (TSPs) experience working in child welfare practice. To explore this topic, five focus groups were conducted with 40 TSPs in a contracted mental and behavioral health agency and data were analyzed following an inductive thematic process. Eleven primary challenges were identified, including the difficulty of navigating numerous involved parties, an overwhelmed work environment, legal intersections common to child welfare cases, unrealistic agency expectations, and heighten case complexity when working with child welfare populations. Findings are organized across system, agency, and client levels and add to the understanding of TSP perspectives working with child welfare. Targeted interventions are discussed, such as efforts to promote realistic expectations and training strategies, as well as directions for future research to improve the intersection between child welfare and mental and behavioral health.

Temporal Summation in Chronic Pelvic Pain.

OBJECTIVE: This study sought to characterize central sensitization further among women with chronic pelvic pain by identifying temporal summation using a cotton-tipped applicator test that can be used at the bedside. METHOD: A total of 36 women (18 with chronic pain and allodynia; 18 without pain) were recruited. Both groups were randomly assigned to receive 3 strokes of a benign stimulus on the abdomen at differing frequencies: 10, 30, or 100 seconds. Each group included 6 women. Pain was assessed using a rating scale of 1 to 10. Data were analyzed using the multivariate approach to repeated measures analysis of variance. RESULTS: The pattern of pain scores differed significantly between women with and without chronic pain (P = 0.002). Women with chronic pelvic pain and allodynia showed a statistically significant increase in pain with successive strokes of the cotton-tipped applicator (P = 0.012 for stroke 1 vs. 2, P = 0.026 for stroke 2 vs. 3, and P = 0.005 for stroke 1 vs. 3). CONCLUSION: Women with chronic pelvic pain and allodynia showed significant worsening of pain with successive strokes of a cotton-tipped applicator. This finding indicates that pain wind-up and central sensitization are present in women with chronic pelvic pain and allodynia. Identification of summation is further evidence of neuroplasticity, which is helpful in innovative therapies for chronic pelvic pain.

Defective Transcriptional Programming of Effector CD8 T Cells in Aged Mice Is Cell-Extrinsic and Can Be Corrected by Administration of IL-12 and IL-18.

In response to infection with intracellular microorganisms, old mice mobilize decreased numbers of antigen-specific CD8 T cells with reduced expression of effector molecules and impaired cytolytic activity. Molecular mechanisms behind these defects and the cell-intrinsic (affecting naïve CD8 T cells themselves) vs. extrinsic, microenvironmental origin of such defects remain unclear. Using reciprocal transfer experiments of highly purified naïve T cells from adult and old transgenic OT-1 mice, we decisively show that the dominant effect is cell-extrinsic. Naïve adult OT-1 T cells failed to expand and terminally differentiate in the old organism infected with Listeria-OVA. This defect was preceded by blunted expression of the master transcription factor T-bet and impaired glycolytic switch when T cells are primed in the old organism. However, both old and adult naïve CD8 T cells proliferated and produced effector molecules to a similar extent when stimulated in vitro with polyclonal stimuli, as well as when transferred into adult recipients. Multiple inflammatory cytokines with direct effects on T cell effector differentiation were decreased in spleens of old animals, particularly IL-12 and IL-18. Of note, in vivo treatment of mice with IL-12 and IL-18 on days 4-6 of Listeria infection reconstituted cytotoxic T cell response of aged mice to the level of adult. Therefore, critical cytokine signals which are underproduced in the old priming environment can restore proper transcriptional programming of old naïve CD8 T cells and improve immune defense against intracellular microorganisms.

Caring for children with neurofibromatosis type 1.

This article discusses the variable physical manifestations of neurofibromatosis type 1 among children in terms of presentation, disease severity, and prognosis, and addresses appropriate nursing interventions and patient teaching.

Lymph nodes as barriers to T-cell rejuvenation in aging mice and nonhuman primates.

In youth, thymic involution curtails production of new naïve T cells, placing the onus of T-cell maintenance upon secondary lymphoid organs (SLO). This peripheral maintenance preserves the size of the T-cell pool for much of the lifespan, but wanes in the last third of life, leading to a dearth of naïve T cells in blood and SLO, and contributing to suboptimal immune defense. Both keratinocyte growth factor (KGF) and sex steroid ablation (SSA) have been shown to transiently increase the size and cellularity of the old thymus. It is less clear whether this increase can improve protection of old animals from infectious challenge. Here, we directly measured the extent to which thymic rejuvenation benefits the peripheral T-cell compartment of old mice and nonhuman primates. Following treatment of old animals with either KGF or SSA, we observed robust rejuvenation of thymic size and cellularity, and, in a reporter mouse model, an increase in recent thymic emigrants (RTE) in the blood. However, few RTE were found in the spleen and even fewer in the lymph nodes, and SSA-treated mice showed no improvement in immune defense against West Nile virus. In parallel, we found increased disorganization and fibrosis in old LN of both mice and nonhuman primates. These results suggest that SLO defects with aging can negate the effects of successful thymic rejuvenation in immune defense.

Critical reflection: a general practice support group experience.

The problem of medical practitioner burnout and loss of morale remains an ongoing challenge in the Australian health workforce. Collegiate recommendations are individualistic or personalised, or worse, punitive. Critical reflection in supervision is a long-accepted and key aspect of social work theory and practice. The use of critical reflection within a general practitioner support group is examined and key learnings from our findings over 3years are discussed. All participants reported the group enhanced individual and team workplace satisfaction, and wellbeing. This Practice and Innovation paper offers an example that could help improve current best practice in the pastoral support of medical practitioners.

Health Outcomes of Medically and Economically Vulnerable Adults: A Comparison of Former Foster Youth and Nonfoster Youth.

Medically and economically vulnerable adults experience various challenges that can impact their health. Within this vulnerable population, there may be individuals who are even more vulnerable, those who have a history of involvement with the foster care system. The purpose of this study was to evaluate the difference of reported health-related problems between adults with previous foster care experience and other vulnerable adults. Physical, mental, and relational health was evaluated in this study. Practice and policy implications for mental health and medical professionals are discussed.