Adaptation to ex vivo culture reduces human hematopoietic stem cell activity independently of cell cycle.

Loss of long-term hematopoietic stem cell (LT-HSC) function ex vivo hampers the success of clinical protocols reliant on culture. However, the kinetics and mechanisms by which this occurs remain incompletely characterized. Here, through time-resolved scRNA-Seq, matched in vivo functional analysis and the use of a reversible in vitro system of early G1 arrest, we define the sequence of transcriptional and functional events occurring during the first ex vivo division of human LT-HSCs. We demonstrate that the sharpest loss of LT-HSC repopulation capacity happens early on, between 6 and 24 hours of culture, before LT-HSCs commit to cell cycle progression. During this time window, LT-HSCs adapt to the culture environment, limiting global variability in gene expression and transiently upregulating gene networks involved in signaling and stress responses. From 24 hours, LT-HSC progression past early G1 contributes to the establishment of differentiation programmes in culture. However, contrary to current assumptions, we demonstrate that loss of HSC function ex vivo is independent of cell cycle progression. Finally, we show that targeting LT-HSC adaptation to culture by inhibiting early activation of JAK/STAT signaling improves HSC long-term repopulating function ex vivo. Collectively, our study demonstrates that controlling early LT-HSC adaptation to ex vivo culture, for example via JAK inhibition, is of critical importance to improve HSC gene therapy and expansion protocols.

"This is real", "this is hard" and "I'm not making it up": Experience of diagnosis and living with non-epileptic attack disorder.

PURPOSE: To use a qualitative research approach to explore adults' experience of living with non-epileptic attack disorder. OBJECTIVE: The objective was to explore the experience of adults (18 years+) with a confirmed diagnosis of non-epileptic attack disorder (NEAD) across the trajectory of the disorder. The topics investigated included the onset of symptoms, the experience of non-epileptic attacks, the diagnostic process and living with NEAD. METHOD: Twelve people diagnosed with NEAD who attended a tertiary hospital neurology department took part in semi-structured interviews. The data generated were analysed using reflexive thematic analysis. RESULTS: Eleven women and one man with median age of 25 years took part. Three themes were developed: mind-body (dis)connect, a stigmatised diagnosis and a role for containment. Adults spoke about their experience of nonepileptic attacks, the diagnostic and management process and the impact of both nonepileptic attacks and the NEAD diagnosis on their lives. CONCLUSIONS: Adults' experience's within the healthcare system across the trajectory of NEAD influenced their own understanding and trust in their NEAD experience, how they shared this with others in their social and work lives and how they managed their NEAD symptoms on a daily basis. The research suggests the need for a consistent, timely implementation of a rule-in diagnostic approach and multi-disciplinary management of NEAD. It is recommended that lessons be taken from theoretical models including the common-sense model and a modified version of the reattribution model to support the de-stigmatisation of this diagnosis to inform psychoeducation and professionally facilitated peer-support groups.

'No one else understands', 'I wouldn't want to pity myself over something that's not really my problem': siblings' experiences of their adolescent brothers and sisters' inpatient treatment for mental health difficulties.

BACKGROUND: Family life is disrupted when a child experiences mental health difficulties. This can have long-standing effects on sibling relationships. This study explores the lived experiences of young people who have an adolescent sibling hospitalised for treatment of a mental health difficulty. METHOD: Semi-structured interviews of 45-60 min were conducted to explore the experiences of 10 siblings (6 sisters/4 brothers aged 13-22) of nine patients (5 sisters/4 brothers aged 15-17) receiving treatment for a mental health difficulty in a child and adolescent inpatient unit (IPU). Interpretative phenomenological analysis was used to analyse the data. RESULTS: Two superordinate themes were identified: 'Who am I if I'm not supporting them?' and 'On the fringes: actively involved but from the outside'. The interplay of these two super-ordinate themes was found to influence the five sub-ordinate themes: 'Confusion and disbelief', 'Don't worry about me, focus on them.', 'Powerless when I need to be powerful.', 'Helping or hindering- what is this place??' and 'Knowledge is power.' CONCLUSION: Siblings described experiencing conflicting and confusing emotions which may impact their attendance in IPU and engagement in siblings' treatment. Siblings of adolescents in inpatient treatment for mental health difficulties may be at increased risk of experiencing psychological distress. The mental well-being of siblings must be borne in mind by child and adolescent inpatient services supporting families in crisis.

Short- and long-term effects of season-long infestation of Lycorma delicatula (Hemiptera: Fulgoridae) on young apple (Malus domestica) and peach (Prunus persica) trees.

Lycorma delicatula White, commonly called spotted lanternfly, is an invasive fulgorid that was first detected in the United States in Pennsylvania in 2014 and has spread across Eastern states. Lycorma delicatula is a phloem feeder, and feeding of persistent populations can cause wilt and dieback in host plants. Vineyards in infested regions have experienced vine loss, where damage has been attributed to L. delicatula. Nymphal and adult lifestages have been observed on cultivated apple and peach trees, but the feeding effects of this pest on these crops have not been quantified. Here, we caged young potted apple and peach trees and infested them with 50 nymphal or 25 adult L. delicatula per plant for 3 months and tracked plant health. Horticultural measurements including trunk diameter, height, leaf drop, and photosynthesis rates were recorded before, during, and after the infestation. To evaluate the long-term effects of infestation, all apple and peach trees were removed from pots and planted in an orchard block where their phenology, growth, and physiology could be evaluated the following growing season. Short- and long-term measurements showed no significant differences in apple tree health between infested and noninfested trees. There was a significant reduction in the growth of trunk diameter in peach trees during exposure to early-instar nymphs; infested peach trees also had significantly increased frost damage to buds the following spring. However, there were no long-term impacts on peach growth and physiology. These results indicate that L. delicatula likely will not be a major threat to these deciduous fruit crops.

Mental health and resilience in the Irish defense forces during the COVID-19 global pandemic.

The Irish Defense Forces (DF) responded to the COVID-19 pandemic and national public health crisis by deploying personnel to aid domestic civil authorities in medical and care settings, contact tracing, logistics, and operations. Current research on COVID-19 reveals increased psychological distress among frontline workers and the general public. Resilience has previously been associated with lower levels of psychological distress. This study sets out to test these associations, and to examine mental health differences between DF personnel deployed in Ireland on pandemic-related duties (DIPD) and non-DIPD. Participants were 231 DF members who completed the: Connor-Davidson Resilience Scale-10, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Perceived Coronavirus Threat Questionnaire, Brief Trauma Questionnaire, Post-traumatic Stress Disorder Checklist-5, and Alcohol Use Disorder Identification Test. Independent t-tests revealed no differences between DIPD and non-DIPD on measures of psychological distress or on self-rated mental health prior to COVID-19 (PC19) and during COVID-19 (DC19). Results of multiple hierarchical regression analyses revealed that depression predicted lower levels of resilience, while multiple traumatic events predicted higher levels of resilience. The total adjusted variance explained by the model was 25%. Clinical and policy implications for improving access to psychological support within the DF and military populations are discussed.

The Changing Face of Lung Cancer: Oligometastatic Renal Metastasis Post Chemo-Immunotherapy Combination.

This report describes a rare case of oligometastatic renal disease in a 69 year-old Caucasian male with non-small cell lung cancer (NSCLC). Diagnosed with Stage IIIb, NSCLC he completed chemoradiotherapy followed by 1 year of immunotherapy. Surveillance CT scans after nearly three years showed an ill-defined lesion in the left kidney. Biopsy results were consistent with metastasis from the known lung carcinoma. Following neo-adjuvant Pembrolizumab (200mg, q3w), the patient underwent a left radical nephrectomy, without complications. One year post-operatively, CT of the thorax, abdomen and pelvis (TAP) did not identify any recurrence. Renal metastases were historically demonstrated predominantly by autopsy studies[1]. Any mass manifesting in the kidney in the context of previous NSCLC warrants comprehensive investigations. The combination of immunotherapy followed by definitive treatment appears to be a promising management strategy[2]. With regards to local curative options, the advantages and disadvantages of surgery and radiotherapy have been well described[3-4]. LEARNING POINTS: With improved treatment strategies for advanced malignancies, rare cases will continue to emerge and thus, maintaining a high index of suspicion is fundamentalThis case demonstrates that immunotherapy increases the efficacy of definitive treatment.

Hypergonadotropic hypogonadism and chromosomal aberrations: clinical heterogeneity and implications on the health of elderly men, case series.

BACKGROUND: Hypogonadism in older men is often considered as late onset hypogonadism. However, this clinical condition results from primary testicular failure which could be of genetic origin with Klinefelter syndrome being the most common chromosomal abnormality associated with it. CASE PRESENTATION: We report a heterogeneous group of cases who were diagnosed with hypergonadotropic hypogonadism in their adulthood and were found to have rare chromosomal aberrations. All were elderly men (in their 70 s and 80 s) for whom the diagnosis was made during the evaluation of incidental symptoms suggestive of endocrinopathy. The first had hyponatremia; the other two had gynaecomastia and features of hypogonadism noted during admission for various acute medical problems. With respect to their genetic results; the first had a male karyotype with balanced reciprocal translocation between the long arm of chromosome 4 and the short arm of chromosome 7. The second case had a male karotype with one normal X chromosome and an isochrome for the short arm of the Y chromosome. The third case was an XX male with unbalanced translocation between the X & Y chromosomes with retention of the SRY locus. CONCLUSION: Hypergonadotrophic hypogonadism in the elderly, may be due to chromosomal aberrations, resulting in heterogeneous and diverse clinical phenotypes. Vigilance must be exercised when seeing cases with subtle clinical findings. This report suggests that in selected cases of adult hypergonadotropic hypogonadism, chromosomal analysis may be indicated.

Parents Plus parenting programme for parents of adolescents with intellectual disabilities: A cluster randomised controlled trial.

OBJECTIVE: This study evaluated the effectiveness of the Parents Plus Special Needs (PPSN) programme, a seven-week parenting group intervention for parents of adolescents with intellectual disabilities. METHOD: In a cluster randomised controlled trial, 24 intellectual disability services supporting families of adolescents with an intellectual disability were assigned to PPSN (12 services; 141 parents) or waitlist control group (12 services; 136 parents). Primary outcomes were parent-reported parenting practices, family adjustment, problem behaviours, emotional problems, and prosocial behaviours. Secondary outcomes were parental satisfaction, parental self-efficacy, and goal attainment. RESULTS: Compared to the waitlist group, participants in the PPSN group reported improvements in parenting practices, problem behaviours, parental satisfaction, parental self-efficacy and goal attainment, which were retained at 3-month follow-up. There were additional gains for family adjustment at follow-up. CONCLUSION: The PPSN is effective in improving parenting behaviour, family relationships, and problem behaviours in adolescents, but not in improving emotional difficulties.

Parental anxiety and offspring development: A systematic review.

BACKGROUND: Parental anxiety has been associated with increased risk of emotional and behavioural problems for offspring, yet the differing impact of each parent is unclear. As emotional disorders continue to present a significant challenge to the health system and with the role of mothers and fathers changing over the past two decades, we sought to systematically review the available literature for an association between parental anxiety and offspring suboptimal outcomes. METHODS: A systematic review was conducted using the following databases: Ovid MEDLINE, Embase; PsycINFO and Google Scholar. Reference lists of the included papers were also searched. Data was analysed and grouped based on offspring age. RESULTS: Eighteen studies were included in this review. Results suggest that both parents' mental health can impact negatively on the functioning of offspring, during infancy, childhood, and adolescence. This association is weak in infancy, with equivocal results, however the association in childhood appears robust for both mothers and fathers. In adolescence, the findings suggest that maternal anxiety may be more influential than paternal anxiety. LIMITATIONS: As the methodology of the included studies was heterogenous, and the timing of assessment varied across the papers, drawing concrete conclusions from the existing research is somewhat impaired. CONCLUSIONS: Both mothers' and fathers' anxiety have the propensity to negatively impact on their child's development. Implementing preventative interventions, which include both parents, as well as systemic interventions, which include the whole family, are essential in stemming the intergenerational transmission of mental health problems within families.

Teachers' perceptions of the barriers to assessment of mental health in schools with implications for educational policy: A systematic review.

BACKGROUND: Assessment of mental health in schools has garnered increased interest in recent years. Children spend a large proportion of their waking hours in schools. Teachers can act as gatekeepers by playing a key role in identifying children with mental health difficulties in the classroom and making the necessary onward referrals to external services. The prevalence of mental health difficulties, their impact on schooling (and beyond) and the importance of early intervention means that it is incumbent on schools to identify and support potentially affected children. AIMS: Previous reviews focused on mental health interventions in schools; however, this review focuses on the assessment of mental health in schools and on teachers' perceptions of this, as such a review is still lacking. Therefore, the study fills a gap in the existing literature while also providing new, highly relevant evidence that may inform policy making in this area. COMPOSITION OF STUDIES INCLUDED IN THIS REVIEW: This review included 19 studies. Five studied teachers exclusively at primary/elementary level, and seven focused on secondary level, while six included both primary and secondary teachers. Three studies employed mixed methods, ten were primarily qualitative studies, and five were primarily quantitative. METHODS: Bronfenbrenner's (The ecology of human development: Experiments by nature and design, Harvard University Press, 1979) framework, adapted by Harvest (How can EPs best support secondary school staff to work effectively with children and young people who experience social, emotional and mental health difficulties? 2018), which includes the mature version of the theory (Tudge et al., 2009, J. Fam. Theory Rev., 1, 198), was used to analyse the literature. RESULTS: Results found that lack of training in assessment of mental health and 'role conflict' were key barriers; some teachers attributed this to their lack of knowledge, skills and confidence in the area. CONCLUSION: Implications for practice and research are discussed in relation to the importance of sustained training both pre-service and in-service.

A pilot study of local anesthesia training using a mixed-reality haptic fidelity model.

PURPOSE/OBJECTIVES: One of the most difficult local anesthetic blocks to master in dentistry is the inferior alveolar nerve block (IANB). Historically, dental students have practiced local anesthesia on one another. At the University of Colorado, these practice sessions have been limited to one required laboratory session. The predictability and confidence of student IANB success have not been high in the past. Therefore, the objective of this study was to investigate the impact of a novel IANB simulator, built on a three dimensional (3D)-printed mixed-reality haptic model, for second-year dental students to practice on prior to their laboratory session. METHODS: Thirty-nine student participants volunteered to practice with the IANB simulator. Participants were divided into two groups, Group A and Group B. Self-reported confidence and injection-specific accuracy were measured during IANB simulator practice and the laboratory session. During lab, partner numbness was assessed as a measure of IANB success. Groups A (n = 20) and B (n = 19) practiced with the simulator before and after laboratory, respectively. Injection domains were not assessed during Group B's practice with the IANB simulator. RESULTS: Self-reported confidence increased for both groups (p < 0.001). However, for anesthetic success, Group A exhibited significantly greater success (52.6%) than Group B (17.6%) (p = 0.029). CONCLUSION: Self-reported confidence in performing an IANB improved and higher anesthetic success was achieved for Group A. Further investigation is necessary to determine the long-term impact of using the IANB simulator in dental education.

Effect of Animal Stocking Density and Habitat Enrichment on Survival and Vitality of Wild Green Shore Crabs, Carcinus maenas, Maintained in the Laboratory.

The wide geographic distribution, large size and ease of capture has led to decapod crustaceans being used extensively in laboratory experiments. Recently in the United Kingdom decapod crustaceans were listed as sentient beings, resulting in their inclusion in animal care protocols. Ironically, little is known about how captive conditions affect the survival and general condition of wild decapod crustaceans. We used the green shore crab, Carcinus maenas, to investigate the effects of stocking density and shelter on survival and vitality indices during a 6 month period in the laboratory. Neither stocking density nor the presence of shelter affected survival. Stocking density also had no effect on the vitality indices (limb loss, claw strength, BRIX, righting time, leg flare and retraction). The presence of shelter did affect the number of limbs lost and the leg retraction response, but had no effect on the other vitality indices. All vitality indices changed, and mortality increased over time, independent of treatment: this became most apparent after 8 to 11 weeks storage in the laboratory. This decline in condition may have been due to repeated handling of the crabs, rather than the stocking conditions. In support of this, untracked, non-handled (control) individuals sustained a 4% mortality rate compared with 67% mortality in experimental crabs during the 6 month period. Although simple experimental monitoring of crabs with biweekly vitality tests only produced transient short-term stress events, the repeated handling over time apparently led to a cumulative stress and a deterioration in animal health. Bringing wild crustaceans into the laboratory and holding them, even with modest experimental manipulation, may result in high mortality rates. Researchers and animal care committees need to be aware that wild captive invertebrates will respond very differently to laboratory-bred vertebrates, and plan experiments accordingly.

A comparison of emotion-focused therapy and cognitive-behavioral therapy in the treatment of generalized anxiety disorder: Results of a feasibility randomized controlled trial.

Generalized anxiety disorder (GAD) is a chronic mental health difficulty typically present in primary care settings. Cognitive-behavioral therapy (CBT) is the psychological intervention with the best evidence for its efficacy for GAD. The development of other psychological interventions can increase client choice. This feasibility trial examined an initial assessment of the efficacy of EFT in comparison to CBT in the treatment of GAD in the context of an Irish public health service. The trial provided information on recruitment, therapist training/adherence, and client retention relevant for a potential noninferiority trial. A randomized controlled trial compared the efficacy of EFT versus CBT for GAD. Both therapies were offered in a 16-20 sessions format. Therapists (n = 8) were trained in both conditions and offered both therapies. Clients were randomly assigned to the two therapies EFT (n = 29) and CBT (n = 29). Outcomes were assessed using several measures, with the Generalized Anxiety Disorder-7 (GAD-7) being the primary outcome. Clients were assessed at baseline, week 16, end of therapy, and at 6-month follow-up. Therapists were able to learn the two models after a short training and showed moderate levels of adherence. Although not statistically significant, the drop out from treatment was 10% for EFT and 27% for CBT. The two therapies showed large pre-post change and similar outcomes across all measures, with these benefits retained at 6-month follow-up. Results suggest that EFT is a potentially promising treatment for GAD. Further investigation is indicated to establish its potential to expand the available psychological therapies for GAD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Beliefs About Worry and Pain Amongst Adolescents With and Without Chronic Pain.

OBJECTIVE: To explore beliefs about worries, beliefs about pain, and worries about pain held by adolescents with and without chronic pain. METHODS: Adolescents with and without chronic pain aged 14-19 completed an online survey with free text questions about pain and worry. We collected demographics and used the Penn State Worry Questionnaire and Pain Catastrophizing Scale for Children to contextualize the qualitative data, which was analyzed with reflexive thematic analysis. RESULTS: Eighty-one participants completed the survey, 36 with chronic pain and 45 without (mean age: 16.73). Compared to adolescents without chronic pain, adolescents living with chronic pain reported significantly higher general worry and pain catastrophizing. Thematic analysis generated two themes, "Worry changes perceptions of selfhood" and "Pain changes perceptions of selfhood." Each theme comprised two sub-themes showing how current and future identity trajectories were distorted by worry and pain. The theme "Pain changes perceptions of selfhood" also included a third sub-theme: "Pain impedes future working choices." Worry content as well as process was problematic in all adolescents. Adolescents experiencing chronic pain had specific, additional worries that pain reduces future career progression. These worries appeared highly salient and challenging. CONCLUSIONS: Adolescents may need greater support in recognizing worry as part of normative development. Adolescents in pain may benefit from specific support identifying and reducing how pain-related worries interact with their futures and careers, and from school-based and vocational interventions to reduce the realistic risks they face negotiating modern labor markets.

Parents' Experiences of Their Child's Solid-Organ Transplant: A Meta-Ethnography of Qualitative Studies.

OBJECTIVE: The aim of this paper was to conduct a systematic review and meta-ethnography of qualitative studies examining the experiences of parents adjusting to life after the solid organ transplant (SOT) of their child. METHODS: A systematic review of the literature was conducted to identify qualitative studies that examined this topic. The search retrieved 4,964 studies to review against inclusion criteria. A total of 21 studies were included in the meta-ethnography. A reciprocal translation was conducted to compare themes identified in each study. A line of argument synthesis was then conducted in order to integrate the similarities and differences between all of the studies into a new interpretative context. RESULTS: The synthesis identified four themes: (a) adjusting to life after transplant, (b) factors that facilitate adjustment, (c) factors that disrupt adjustment, and (d) changes caused by transplant. As a result of the synthesis, a new interpretation of parents' experiences of adjusting to life after the SOT of their child was constructed. A summary figure is presented. CONCLUSION: This review found that while parents may struggle to adapt to life post-transplant and the demands of caring for their child, the experience can also result in the development of new skills, a new appreciation for life, and viewing the self in a more positive manner. A better understanding of parental experiences will promote the development of more effective interventions for the adjustment of parents and families to post-transplant life.

Parental experiences of psychological interventions for recurrent abdominal pain in childhood.

Active components of psychological intervention for RAP remain unclear. This study involved completing interviews about parental experience of psychological intervention for RAP to ascertain how and why psychological intervention can be effective. Difficulty making sense of RAP and barriers to treatment were identified as struggles. Acceptance and containment were key overlapping mechanisms, which allowed families to develop a changed relationship with the pain and manage the impact of pain. To further develop interventions, the role of containment should be considered and acceptance-based interventions explored, given the growing evidence base in this area. Practical implications of this research are also discussed.

Transcriptional Regulation of Plant Biomass Degradation and Carbohydrate Utilization Genes in the Extreme Thermophile Caldicellulosiruptor bescii.

Extremely thermophilic bacteria from the genus Caldicellulosiruptor can degrade polysaccharide components of plant cell walls and subsequently utilize the constituting mono- and oligosaccharides. Through metabolic engineering, ethanol and other industrially important end products can be produced. Previous experimental studies identified a variety of carbohydrate-active enzymes in model species Caldicellulosiruptor saccharolyticus and Caldicellulosiruptor bescii, while prior transcriptomic experiments identified their putative carbohydrate uptake transporters. We investigated the mechanisms of transcriptional regulation of carbohydrate utilization genes using a comparative genomics approach applied to 14 Caldicellulosiruptor species. The reconstruction of carbohydrate utilization regulatory network includes the predicted binding sites for 34 mostly local regulators and point to the regulatory mechanisms controlling expression of genes involved in degradation of plant biomass. The Rex and CggR regulons control the central glycolytic and primary redox reactions. The identified transcription factor binding sites and regulons were validated with transcriptomic and transcription start site experimental data for C. bescii grown on cellulose, cellobiose, glucose, xylan, and xylose. The XylR and XynR regulons control xylan-induced transcriptional response of genes involved in degradation of xylan and xylose utilization. The reconstructed regulons informed the carbohydrate utilization reconstruction analysis and improved functional annotations of 51 transporters and 11 catabolic enzymes. Using gene deletion, we confirmed that the shared ATPase component MsmK is essential for growth on oligo- and polysaccharides but not for the utilization of monosaccharides. By elucidating the carbohydrate utilization framework in C. bescii, strategies for metabolic engineering can be pursued to optimize yields of bio-based fuels and chemicals from lignocellulose. IMPORTANCE To develop functional metabolic engineering platforms for nonmodel microorganisms, a comprehensive understanding of the physiological and metabolic characteristics is critical. Caldicellulosiruptor bescii and other species in this genus have untapped potential for conversion of unpretreated plant biomass into industrial fuels and chemicals. The highly interactive and complex machinery used by C. bescii to acquire and process complex carbohydrates contained in lignocellulose was elucidated here to complement related efforts to develop a metabolic engineering platform with this bacterium. Guided by the findings here, a clearer picture of how C. bescii natively drives carbohydrate utilization is provided and strategies to engineer this bacterium for optimal conversion of lignocellulose to commercial products emerge.

Identification of a series of hair-cell MET channel blockers that protect against aminoglycoside-induced ototoxicity.

To identify small molecules that shield mammalian sensory hair cells from the ototoxic side effects of aminoglycoside antibiotics, 10,240 compounds were initially screened in zebrafish larvae, selecting for those that protected lateral-line hair cells against neomycin and gentamicin. When the 64 hits from this screen were retested in mouse cochlear cultures, 8 protected outer hair cells (OHCs) from gentamicin in vitro without causing hair-bundle damage. These 8 hits shared structural features and blocked, to varying degrees, the OHC's mechano-electrical transducer (MET) channel, a route of aminoglycoside entry into hair cells. Further characterization of one of the strongest MET channel blockers, UoS-7692, revealed it additionally protected against kanamycin and tobramycin and did not abrogate the bactericidal activity of gentamicin. UoS-7692 behaved, like the aminoglycosides, as a permeant blocker of the MET channel; significantly reduced gentamicin-Texas red loading into OHCs; and preserved lateral-line function in neomycin-treated zebrafish. Transtympanic injection of UoS-7692 protected mouse OHCs from furosemide/kanamycin exposure in vivo and partially preserved hearing. The results confirmed the hair-cell MET channel as a viable target for the identification of compounds that protect the cochlea from aminoglycosides and provide a series of hit compounds that will inform the design of future otoprotectants.