Optogenetics Reveals Roles for Supporting Cells in Force Transmission to and From Outer Hair Cells in the Mouse Cochlea.

Outer hair cells (OHCs) of the organ of Corti (OoC), acting as bidirectional cellular mechanoelectrical transducers, generate, receive, and exchange forces with other major elements of the cochlear partition, including the sensory inner hair cells (IHCs). Force exchange is mediated via a supporting cell scaffold, including Deiters' (DC) and outer pillar cells (OPC), to enable the sensitivity and exquisite frequency selectivity of the mammalian cochlea and to transmit its responses to the auditory nerve. To selectively activate DCs and OPCs in male and female mice, we conditionally expressed in them a hyperpolarizing halorhodopsin (HOP), a light-gated inward chloride ion pump, and measured extracellular receptor potentials (ERPs) and their DC component (ERPDCs) from the cortilymph, which fills the OoC fluid spaces, and compared the responses with similar potentials from HOP-/- littermates. The compound action potentials (CAP) of the auditory nerve were measured as an indication of IHC activity and transmission of cochlear responses to the CNS. HOP light-activated hyperpolarization of DCs and OPCs suppressed cochlear amplification through changing the timing of its feedback, altered basilar membrane (BM) responses to tones at all measured levels and frequencies, and reduced IHC excitation. HOP activation findings reported here complement recent studies that revealed channelrhodopsin activation depolarized DCs and OPCs and effectively bypassed, rather than blocked, the control of OHC mechanical and electrical responses to sound and their contribution to timed and directed electromechanical feedback to the mammalian cochlea. Moreover, our findings identify DCs and OPCs as potential targets for the treatment of noise-induced hearing loss.

Local cochlear mechanical responses revealed through outer hair cell receptor potential measurements.

Sensory hair cells, including the sensorimotor outer hair cells, which enable the sensitive, sharply tuned responses of the mammalian cochlea, are excited by radial shear between the organ of Corti and the overlying tectorial membrane. It is not currently possible to measure directly in vivo mechanical responses in the narrow cleft between the tectorial membrane and organ of Corti over a wide range of stimulus frequencies and intensities. The mechanical responses can, however, be derived by measuring hair cell receptor potentials. We demonstrate that the seemingly complex frequency and intensity dependent behaviour of outer hair cell receptor potentials could be qualitatively explained by a two-degrees of freedom system with local cochlear partition and tectorial membrane resonances strongly coupled by the outer hair cell stereocilia. A local minimum in the receptor potential below the characteristic frequency should always be observed at a frequency where the tectorial membrane mechanical impedance is minimal, i.e., at the presumed tectorial membrane resonance frequency. The tectorial membrane resonance frequency might, however, shift with stimulus intensity in accordance with a shift in the maximum of the tectorial membrane radial mechanical responses to lower frequencies, as observed in experiments.

Debate: More, not less social media content moderation? How to better protect youth mental health online.

BACKGROUND: This article challenges Zhang et al.'s claims that social media content moderation is proving detrimental to youth mental health and asserts that greater emphasis on the systemic risks posed by social media platforms is required. METHOD: This commentary draws on my lived experience as a bereaved parent, empiricial evidence and ongoing public policy and regulatory debates. CONCLUSIONS: Greater attention should be paid to the effects of algorithmic recommendation systems, which can result in teenagers becoming rapidly exposed to large amounts of harmful content on social media sites such as Instagram, Pinterest and TikTok.

A Gap-Junction Mutation Reveals That Outer Hair Cell Extracellular Receptor Potentials Drive High-Frequency Cochlear Amplification.

Cochlear amplification enables the enormous dynamic range of hearing through amplifying cochlear responses to low- to moderate-level sounds and compressing them to loud sounds. Amplification is attributed to voltage-dependent electromotility of mechanosensory outer hair cells (OHCs) driven by changing voltages developed across their cell membranes. At low frequencies, these voltage changes are dominated by intracellular receptor potentials (RPs). However, OHC membranes have electrical low-pass filter properties that attenuate high-frequency RPs, which should potentially attenuate amplification of high-frequency cochlear responses and impede high-frequency hearing. We made in vivo intracellular and extracellular electrophysiological measurements from the organ of Corti of male and female mice of the CBA/J strain, with excellent high-frequency hearing, and from the CD-1 mouse strain, which has sensitive hearing below 12 kHz but loses high-frequency hearing within a few weeks postpartum. The CD-1 mouse strain was transfected with an A88V mutation of the connexin 30 gap-junction protein. By blocking the action of the GJ protein to reduce input resistance, the mutation increased the OHC extracellular RP (ERP) magnitude and rescued high-frequency hearing. However, by increasing the organ of Corti resistance, the mutation rescued high-frequency hearing through preserving the OHC extracellular RP (ERP) magnitude. We measured the voltage developed across the basolateral membranes of OHCs, which controls their electromotility, for low- to high-frequency sounds in male and female mice of the CD-1 strain that expressed the A88V mutation. We demonstrate that ERPs, not RPs, drive OHC motility and cochlear amplification at high frequencies because at high frequencies, ERPs are not frequency attenuated, exceed RPs in magnitude, and are appropriately timed to provide cochlear amplification.SIGNIFICANCE STATEMENT Cochlear amplification, which enables the enormous dynamic range of hearing, is attributed to voltage-dependent electromotility of the mechanosensory outer hair cells (OHCs) driven by sound-induced voltage changes across their membranes. OHC intracellular receptor potentials are electrically low-pass filtered, which should hinder high-frequency hearing. We measured the intracellular and extracellular voltages that control OHC electromotility in vivo in a mouse strain with impaired high-frequency hearing. A gap-junction mutation of the strain rescued high-frequency hearing, increased organ of Corti resistance, and preserved large OHC extracellular receptor potentials but reduced OHC intracellular receptor potentials and impaired low-frequency hearing. We concluded intracellular potentials drive OHC motility at low frequencies and extracellular receptor potentials drive OHC motility and cochlear amplification at high frequencies.

In vivo optogenetics reveals control of cochlear electromechanical responses by supporting cells.

Cochlear sensitivity, essential for communication and exploiting the acoustic environment, results from sensory-motor outer hair cells (OHCs) operating in a structural scaffold of supporting cells and extracellular cortilymph (CL) within the organ of Corti (OoC). Cochlear sensitivity control is hypothesized to involve interaction between the OHCs and OoC supporting cells (e.g., Deiters' cells (DCs) and outer pillar cells (OPCs)), but this has never been established in vivo Here, we conditionally expressed channelrhodopsins (ChR2) specifically in male and female mouse DCs and OPCs. illumination of the OoC activated the nonselective ChR2 cation conductance and depolarized DCs when measured in vivo and in isolated OoC. Measurements of sound-induced cochlear mechanical and electrical responses revealed OoC illumination suppressed the normal functions of OoC supporting cells transiently and reversibly. OoC illumination blocked normally occurring continuous minor adjustments of tone-evoked basilar membrane (BM) displacements over their entire dynamic range and OHC voltage responses to tones at levels and frequencies subject to cochlear amplification. OoC illumination altered the OHC MET conductance operating point, which reversed the asymmetry of OHC voltage responses to high level tones. OoC illumination accelerated recovery from temporary loud sound-induced acoustic desensitization. We concluded that DCs and OPCs are involved in both the control of cochlear responses that are essential for normal hearing, and the recovery from temporary acoustic desensitization. This is the first direct in vivo evidence for the interdependency of the structural, mechanical, and electrochemical arrangements of OHCs and OoC supporting cells that together provide fine control of cochlear responses.Significance statement:A striking feature of the mammalian cochlear sensory epithelium, the organ of Corti, is the cellular architecture and supporting cell arrangement that provides a structural scaffold for the sensory-motor outer hair cells. The role of the supporting cell scaffold, however, has never been elucidated in vivo, although in vitro and modelling studies indicate the scaffold is involved in exchange of forces between the outer hair cells and the organ of Corti. We used in vivo techniques, including optogenetics, that do not disrupt arrangements between the outer hair cells and supporting cells, but selectively, transiently, and reversibly interfere with supporting cell normal function. We revealed the supporting cells provide continuous adjustment of cochlear sensitivity, which is instrumental in normal hearing.

Co-Producing Narratives and Indicators as Catalysts for Adaptive Governance of a Common-Pool Resource within a Protected Area.

The theory and practice of adaptive management and adaptive governance have been widely studied in the complex social contexts that mediate how humans interact with ecosystems. Adaptive governance is thought to enable adaptive management in such contexts. In this study, we examine four often-used principles of adaptive governance (polycentric institutions, collaboration, social learning and complexity thinking) to develop a framework for reflecting on adaptive governance of a social-ecological system-the Knysna Estuary in South Africa. This estuary is a priority for biodiversity conservation, as well as a common-pool resource central to livelihoods. We used the framework to structure dialogue on the extent to which the four principles of adaptive governance were being applied in the management of the Knysna Estuary. The dialogue included diverse stakeholders, from those who have the power to influence adaptive management to those most dependent on the resource for their livelihoods. Based on a combination of theory and current reality we then identified eight indicators that could be used to guide a transition towards improved adaptive governance of the estuary. These indicators were assessed and supported by most stakeholders. The main contributions of our research are (a) a process for combining theory and stakeholder dialogue to reflect on adaptive governance of a social-ecological system; (b) a set of indicators or conditions that emerged from our participatory process that can be used for reflexive monitoring and adaptation of adaptive governance of Knysna Estuary; and (c) a real-world example of seeking complementary links between adaptive governance and adaptive management to promote effective management of complex social-ecological systems.

Dementia Early-Stage Cognitive Aids New Trial (DESCANT) of memory aids and guidance for people with dementia: randomised controlled trial.

BACKGROUND: Common memory aids for people with dementia at home are recommended. However, rigorous evaluation is lacking, particularly what guidance or support is valued. OBJECTIVE: To investigate effects of memory aids and guidance by dementia support practitioners (DSPs) for people in early-stage dementia through a pragmatic, randomised controlled trial. METHODS: Of 469 people with mild-to-moderate dementia and their informal carers, 468 were randomised to a DSP with memory aids or to usual care plus existing dementia guide. Allocation was stratified by Trust/Health Board; time since first attendance at memory service; gender; age; and living with primary carer or not. Primary outcome was Bristol Activities of Daily Living Scale (BADLS) Score at 3 and 6 months (primary end-point). Secondary outcomes for people with dementia: quality of life (CASP-19; DEMQOL); cognition and functioning (Clinical Dementia Rating Scale; S-MMSE); capability (ICECAP-O); social networks (LSNS-R); and instrumental daily living activities (R-IDDD). Secondary outcomes for carers: psychological health (GHQ-12); sense of competence (SSCQ). RESULTS: DSPs were successfully trained, compliance was good and welcomed by participants. Mean 6 months BADLS Score increased to 14.6 (SD: 10.4) in intervention and 12.6 (SD: 8.1) in comparator, indicative of greater dependence in the activities of daily living. Adjusted between-group difference was 0.38 (95% CI: -0.89 to 1.65, p=0.56). Though this suggests greater dependency in the intervention group the difference was not significant. No differences were found in secondary outcomes. CONCLUSIONS: This intervention did not maintain independence in the activities of daily living with no improvement in other outcomes for people with dementia or carers. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN12591717.

Implementing the Dementia Early Stage Cognitive Aids New Trial (DESCANT) intervention: mixed-method process evaluation alongside a pragmatic randomised trial.

OBJECTIVES: The DESCANT (Dementia Early Stage Cognitive Aids New Trial) intervention provided a personalised care package designed to improve the cognitive abilities, function and well-being of people with early-stage dementia and their carers, by providing a range of memory aids, together with appropriate training and support. This sub-study aimed to assess implementation and identify contextual factors potentially associated with participant outcomes. METHOD: A mixed-methods approach was adopted alongside the pragmatic randomised trial. Data were obtained from intervention records and interviews with five dementia support practitioners across seven National Health Service Trusts in England and Wales. A reporting framework was constructed from available literature and data assessed by descriptive statistics and thematic analysis. RESULTS: Participation and engagement was high with 126 out of 128 participants completing the intervention with packages tailored to individual participants. Misplacing items and poor orientation to date and time were common areas of need. Memory aids frequently supplied included orientation clocks (91%), whiteboards (60%), calendars (43%) and notebooks (32%), plus bespoke items. Intervention duration and timing were broadly consistent with expectations. Variation reflected participants' needs, circumstances and preferences. Qualitative findings suggested a potentially positive impact on the well-being of people with dementia and their carers. Issues associated with successful roll-out of the intervention are explored in the discussion. CONCLUSION: Successful implementation increased confidence in future findings of the randomised trial. Depending on these, DESCANT may prove a scalable intervention with potential to improve the function and quality of life of people with dementia and their carers.

Community Occupational Therapy for people with dementia and family carers (COTiD-UK) versus treatment as usual (Valuing Active Life in Dementia [VALID]) study: A single-blind, randomised controlled trial.

BACKGROUND: We aimed to estimate the clinical effectiveness of Community Occupational Therapy for people with dementia and family carers-UK version (Community Occupational Therapy in Dementia-UK version [COTiD-UK]) relative to treatment as usual (TAU). We hypothesised that COTiD-UK would improve the ability of people with dementia to perform activities of daily living (ADL), and family carers' sense of competence, compared with TAU. METHODS AND FINDINGS: The study design was a multicentre, 2-arm, parallel-group, assessor-masked, individually randomised controlled trial (RCT) with internal pilot. It was conducted in 15 sites across England from September 2014 to January 2018. People with a diagnosis of mild to moderate dementia living in their own home were recruited in pairs with a family carer who provided domestic or personal support for at least 4 hours per week. Pairs were randomised to either receive COTiD-UK, which comprised 10 hours of occupational therapy delivered over 10 weeks in the person with dementia's home or TAU, which comprised the usual local service provision that may or may not include standard occupational therapy. The primary outcome was the Bristol Activities of Daily Living Scale (BADLS) score at 26 weeks. Secondary outcomes for the person with dementia included the following: the BADLS scores at 52 and 78 weeks, cognition, quality of life, and mood; and for the family carer: sense of competence and mood; plus the number of social contacts and leisure activities for both partners. Participants were analysed by treatment allocated. A total of 468 pairs were recruited: people with dementia ranged from 55 to 97 years with a mean age of 78.6 and family carers ranged from 29 to 94 with a mean of 69.1 years. Of the people with dementia, 74.8% were married and 19.2% lived alone. Of the family carers, 72.6% were spouses, and 22.2% were adult children. On randomisation, 249 pairs were assigned to COTiD-UK (62% people with dementia and 23% carers were male) and 219 to TAU (52% people with dementia and 32% carers were male). At the 26 weeks follow-up, data were available for 364 pairs (77.8%). The BADLS score at 26 weeks did not differ significantly between groups (adjusted mean difference estimate 0.35, 95% CI -0.81 to 1.51; p = 0.55). Secondary outcomes did not differ between the groups. In total, 91% of the activity-based goals set by the pairs taking part in the COTiD-UK intervention were fully or partially achieved by the final COTiD-UK session. Study limitations include the following: Intervention fidelity was moderate but varied across and within sites, and the reliance on primarily proxy data focused on measuring the level of functional or cognitive impairment which may not truly reflect the actual performance and views of the person living with dementia. CONCLUSIONS: Providing community occupational therapy as delivered in this study did not improve ADL performance, cognition, quality of life, or mood in people with dementia nor sense of competence or mood in family carers. Future research should consider measuring person-centred outcomes that are more meaningful and closely aligned to participants' priorities, such as goal achievement or the quantity and quality of activity engagement and participation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10748953.

Plasma Methylmalonic Acid Concentration in Folic Acid-Supplemented Depressed Patients with Low or Marginal Vitamin B-12: A Randomized Trial.

BACKGROUND: Individuals with low serum vitamin B-12 and high serum folate have higher plasma concentrations of methylmalonic acid (MMA). Whether folic acid (FA) causes an increase in MMA is not known. OBJECTIVES: We aimed to determine the impact of FA supplementation on plasma MMA concentration in people with low or marginal serum vitamin B-12. METHODS: We conducted a multicenter double-blind placebo-controlled randomized trial of oral FA (5 mg/d for 12 wk) in middle-aged patients treated with antidepressant medication participating in the FoLATED (Folate Augmentation of Treatment-Evaluation for Depression) trial. Participants defined as having "low" serum vitamin B-12 (vitamin B-12 ≥150 and <220 ng/L) or "marginal" serum vitamin B-12 (vitamin B-12 ≥ 220 and <280 ng/L) were included. The primary outcome of this substudy was MMA at week 12. A mixed-effects linear regression was fitted and reported using the adjusted mean difference (aMD). RESULTS: A total of 177 participants were included (85 randomly assigned to placebo and 92 to FA); the mean ± SD age was 46.2 ± 11.8 y, and 112 (63.3%) were female. The MMA analysis included 135 participants and the aMD was -0.01 (95% CI: -0.06, 0.04; P = 0.71). Serum folate was measured on 166 participants and increased in the supplementation group; the aMD was 21.6 µg/L (95% CI: 8.13, 25.02 µg/L; P < 0.001). A total of 117 participants were assessed for RBC folate, which also increased in the supplementation group; the aMD was 461 µg/L (95% CI: 387, 535 µg/L; P < 0.001). CONCLUSIONS: Supplementation of FA leads to an increase of serum and RBC folate, but does not change plasma MMA concentration in individuals with serum vitamin B-12 between 150 and 280 ng/L. We cannot exclude effects in older people or those with serum vitamin B-12 <150 ng/L. Previously reported associations may arise from effects of impaired vitamin B-12 status on folate metabolism.This trial was registered at www.isrctn.com as ISRCTN37558856.

The Dementia Early Stage Cognitive Aids New Trial (DESCANT) intervention: A goal attainment scaling approach to promote self-management.

OBJECTIVES: This study investigated goals identified by people with dementia and their carers to promote the self-management of symptoms and abilities; measured achievement using goal attainment scaling (GAS); and explored the reflections of Dementia Support Practitioners (DSPs) facilitating it. METHODS AND DESIGN: Within this pragmatic randomised trial, DSPs gave memory aids, training and support to people with mild to moderate dementia and their carers at home. Data were collected across seven NHS Trusts in England and Wales (2016-2018) and abstracted from intervention records and semi-structured interviews with DSPs delivering the intervention, supplemented by a subset of the trial dataset. Measures were created to permit quantification and descriptive analysis and interview data thematically analysed. A GAS measure for this intervention in this client group was derived. RESULTS: Engagement was high across the 117 participants and 293 goals were identified. These reflected individual circumstances and needs and enabled classification and assessment of their attainment. Seventeen goal types were identified across six domains: self-care, household tasks, daily occupation, orientation, communication, and well-being and safety. On average participants achieved nominally significant improvement regarding the specified goals of 1.4 with standard deviation of 0.6. Five interviews suggested that DSPs' experiences of goal setting were also positive. CONCLUSIONS: GAS is useful for assessing psychosocial interventions for people with early-stage dementia. It has a utility in identifying goals, promoting self-management and providing a personalised outcome measure. There is a strong case for exploring whether these clear benefits translate to other interventions in other populations in other places.

Refractory depression - mechanisms and efficacy of radically open dialectical behaviour therapy (RefraMED): findings of a randomised trial on benefits and harms.

BACKGROUND: Individuals with depression often do not respond to medication or psychotherapy. Radically open dialectical behaviour therapy (RO DBT) is a new treatment targeting overcontrolled personality, common in refractory depression. AIMS: To compare RO DBT plus treatment as usual (TAU) for refractory depression with TAU alone (trial registration: ISRCTN 85784627). METHOD: RO DBT comprised 29 therapy sessions and 27 skills classes over 6 months. Our completed randomised trial evaluated RO DBT for refractory depression over 18 months in three British secondary care centres. Of 250 adult participants, we randomised 162 (65%) to RO DBT. The primary outcome was the Hamilton Rating Scale for Depression (HRSD), assessed masked and analysed by treatment allocated. RESULTS: After 7 months, immediately following therapy, RO DBT had significantly reduced depressive symptoms by 5.40 points on the HRSD relative to TAU (95% CI 0.94-9.85). After 12 months (primary end-point), the difference of 2.15 points on the HRSD in favour of RO DBT was not significant (95% CI -2.28 to 6.59); nor was that of 1.69 points on the HRSD at 18 months (95% CI -2.84 to 6.22). Throughout RO DBT participants reported significantly better psychological flexibility and emotional coping than controls. However, they reported eight possible serious adverse reactions compared with none in the control group. CONCLUSIONS: The RO DBT group reported significantly lower HRSD scores than the control group after 7 months, but not thereafter. The imbalance in serious adverse reactions was probably because of the controls' limited opportunities to report these.

Opportunistic screening for alcohol use problems in adolescents attending emergency departments: an evaluation of screening tools.

OBJECTIVE: To estimate and compare the optimal cut-off score of Alcohol Use Disorders Identification Test (AUDIT) and AUDIT-C in identifying at-risk alcohol consumption, heavy episodic alcohol use, ICD-10 alcohol abuse and alcohol dependence in adolescents attending ED in England. DESIGN: Opportunistic cross-sectional survey. SETTING: 10 emergency departments across England. PARTICIPANTS: Adolescents (n = 5377) aged between their 10th and 18th birthday who attended emergency departments between December 2012 and May 2013. MEASURES: Scores on the AUDIT and AUDIT-C. At-risk alcohol consumption and monthly episodic alcohol consumption in the past 3 months were derived using the time-line follow back method. Alcohol abuse and alcohol dependence was assessed in accordance with ICD-10 criteria using the MINI-KID. FINDINGS: AUDIT-C with a score of 3 was more effective for at-risk alcohol use (AUC 0.81; sensitivity 87%, specificity 97%), heavy episodic use (0.84; 76%, 98%) and alcohol abuse (0.98; 91%, 90%). AUDIT with a score of 7 was more effective in identifying alcohol dependence (0.92; 96%, 94%). CONCLUSIONS: The 3-item AUDIT-C is more effective than AUDIT in screening adolescents for at-risk alcohol use, heavy episodic alcohol use and alcohol abuse. AUDIT is more effective than AUDIT-C for the identification of alcohol dependence.

Reaction Force Generation and Mechanical Demand Imposed on the Shoulder When Initiating Manual Wheelchair Propulsion and at Self-Selected Fast Speeds.

Manual wheelchair (WC) users with spinal cord injury (SCI) experience shoulder pain and fatigue associated with their increased reliance on the upper extremity during activities of daily living (Bayley et al. 1987, "The Weight-Bearing Shoulder. The Impingement Syndrome in Paraplegics," J. Bone Jt. Surg. Am., 69(5), pp. 676-678). We hypothesized that the mechanical demand imposed on the shoulder, represented as resultant shoulder net joint moment (NJM) impulse, would be greater when initiating manual WC propulsion from a stationary position without momentum than when manually propelling at speed on a level sidewalk. Thirty manual WC users with paraplegia participated. Each individual initiated manual WC propulsion from a stationary position and propelled on a level sidewalk at their self-selected fast speed. Upper extremity kinematics and pushrim reaction forces (RFs) were measured and upper extremity joint kinetics were calculated and compared (α = 0.05) between cycle 1, initiated without momentum, and cycle 3 with momentum. Results indicate that multiple factors contributing to the mechanical demand imposed on the shoulder were significantly greater when manual WC propulsion was initiated without momentum than with momentum. Significant differences in resultant shoulder NJM impulse, push duration, orientation of RF relative to forearm, and resultant average shoulder NJMs during push were observed between momentum conditions. No significant differences in average resultant RF during push were found. These results indicate that mechanical loading of the shoulder during manual WC propulsion differs between momentum conditions; these differences in resultant shoulder NJM impulse during push need to be considered when assessing shoulder load exposure in stop-and-start activities.

Evolution of Endolymph Secretion and Endolymphatic Potential Generation in the Vertebrate Inner Ear.

The ear of extant vertebrates reflects multiple independent evolutionary trajectories. Examples include the middle ear or the unique specializations of the mammalian cochlea. Another striking difference between vertebrate inner ears concerns the differences in the magnitude of the endolymphatic potential. This differs both between the vestibular and auditory part of the inner ear as well as between the auditory periphery in different vertebrates. Here we provide a comparison of the cellular and molecular mechanisms in different endorgans across vertebrates. We begin with the lateral line and vestibular systems, as they likely represent plesiomorphic conditions, then review the situation in different vertebrate auditory endorgans. All three systems harbor hair cells bathed in a high (K+) environment. Superficial lateral line neuromasts are bathed in an electrogenically maintained high (K+) microenvironment provided by the complex gelatinous cupula. This is associated with a positive endocupular potential. Whether this is a special or a universal feature of lateral line and possibly vestibular cupulae remains to be discovered. The vestibular system represents a closed system with an endolymph that is characterized by an enhanced (K+) relative to the perilymph. Yet only in land vertebrates does (K+) exceed (Na+). The endolymphatic potential ranges from +1 to +11 mV, albeit we note intriguing reports of substantially higher potentials of up to +70 mV in the cupula of ampullae of the semicircular canals. Similarly, in the auditory system, a high (K+) is observed. However, in contrast to the vestibular system, the positive endolymphatic potential varies more substantially between vertebrates, ranging from near zero mV to approximately +100 mV. The tissues generating endolymph in the inner ear show considerable differences in cell types and location. So-called dark cells and the possibly homologous ionocytes in fish appear to be the common elements, but there is always at least one additional cell type present. To inspire research in this field, we propose a classification for these cell types and discuss potential evolutionary relationships. Their molecular repertoire is largely unknown and provides further fertile ground for future investigation. Finally, we propose that the ultimate selective pressure for an increased endolymphatic potential, as observed in mammals and to a lesser extent in birds, is specifically to maintain the AC component of the hair-cell receptor potential at high frequencies. In summary, we identify intriguing questions for future directions of research into the molecular and cellular basis of the endolymph in the different compartments of the inner ear. The answers will provide important insights into evolutionary and developmental processes in a sensory organ essential to many species, including humans.

Under what circumstances does the capture and tagging of wild Atlantic salmon Salmo salar smolts affect probability of return as adults?

Adult return rates for wild Atlantic salmon Salmo salar smolts captured in a rotary screw trap and tagged with coded wire (CW) tags were compared with a control group, using detections from passive integrated transponder (PIT) antennae systems over 7 years in a small chalk stream in southern England, U.K. Compared with control smolts, capture and CW-tagging of experimental smolts affected detected return rates only under certain conditions, with a decreased return probability for smolts caught and tagged following mild winter river temperature anomalies and during the night. Similarly, analysis of the experimental smolts revealed that capture and CW-tagging following mild winters decreased their probability of return as adults. There were also marginal positive effects of length at PIT-tagging as parr and length at CW-tagging as smolts, on individual probability of return as adult. The results support the hypothesis that the effect of procedures involving the capture and tagging of migrating wild S. salar smolts will vary with the circumstances under which they are performed. The implications of the findings are considered in the context of ongoing investigations to derive and report marine return rates for S. salar in support of national and international stock assessments and in developing best practice.

The impact of individual Cognitive Stimulation Therapy (iCST) on cognition, quality of life, caregiver health, and family relationships in dementia: A randomised controlled trial.

BACKGROUND: Cognitive stimulation therapy (CST) is a well-established group psychosocial intervention for people with dementia. There is evidence that home-based programmes of cognitive stimulation delivered by family caregivers may benefit both the person and the caregiver. However, no previous studies have evaluated caregiver-delivered CST. This study aimed to evaluate the effectiveness of a home-based, caregiver-led individual cognitive stimulation therapy (iCST) program in (i) improving cognition and quality of life (QoL) for the person with dementia and (ii) mental and physical health (well-being) for the caregiver. METHODS AND FINDINGS: A single-blind, pragmatic randomised controlled trial (RCT) was conducted at eight study sites across the United Kingdom. The intervention and blinded assessment of outcomes were conducted in participants' homes. Three hundred fifty-six people with mild to moderate dementia and their caregivers were recruited from memory services and community mental health teams (CMHTs). Participants were randomly assigned to iCST (75, 30-min sessions) or treatment as usual (TAU) control over 25 wk. iCST sessions consisted of themed activities designed to be mentally stimulating and enjoyable. Caregivers delivering iCST received training and support from an unblind researcher. Primary outcomes were cognition (Alzheimer's Disease Assessment Scale-cognitive [ADAS-Cog]) and self-reported QoL (Quality of Life Alzheimer's Disease [QoL-AD]) for the person with dementia and general health status (Short Form-12 health survey [SF-12]) for the caregiver. Secondary outcomes included quality of the caregiving relationship from the perspectives of the person and of the caregiver (Quality of the Carer Patient Relationship Scale) and health-related QoL (European Quality of Life-5 Dimensions [EQ-5D]) for the caregiver. Intention to treat (ITT) analyses were conducted. At the post-test (26 wk), there were no differences between the iCST and TAU groups in the outcomes of cognition (mean difference [MD] = -0.55, 95% CI -2.00-0.90; p = 0.45) and self-reported QoL (MD = -0.02, 95% CI -1.22-0.82; p = 0.97) for people with dementia, or caregivers' general health status (MD = 0.13, 95% CI -1.65-1.91; p = 0.89). However, people with dementia receiving iCST rated the relationship with their caregiver more positively (MD = 1.77, 95% CI 0.26-3.28; p = 0.02), and iCST improved QoL for caregivers (EQ-5D, MD = 0.06, 95% CI 0.02-0.10; p = 0.01). Forty percent (72/180) of dyads allocated to iCST completed at least two sessions per week, with 22% (39/180) completing no sessions at all. Study limitations include low adherence to the intervention. CONCLUSIONS: There was no evidence that iCST has an effect on cognition or QoL for people with dementia. However, participating in iCST appeared to enhance the quality of the caregiving relationship and caregivers' QoL. TRIAL REGISTRATION: The iCST trial is registered with the ISRCTN registry (identified ISRCTN 65945963, URL: DOI 10.1186/ISRCTN65945963).

Pre-copula acoustic behaviour of males in the malarial mosquitoes Anopheles coluzzii and Anopheles gambiae s.s. does not contribute to reproductive isolation.

We reveal that males of two members of the Anopheles gambiae s.l. species complex, Anopheles coluzzii and Anopheles gambiae s.s. (hereafter A. gambiae), which are both malaria vectors, perform a stereotypical acoustic behaviour in response to pure tones at frequencies that encompass the frequency range of the female's flight-tones. This behaviour resembles that described for Culex quinquefasciatus and consists of phonotactic flight initiated by a steep increase in wing-beat frequency (WBF) followed by rapid frequency modulation (RFM) of WBF when in close proximity to the sound source. RFM was elicited without acoustic feedback or the presence of a live female, but it appears to be a stereotypic behaviour in the immediate lead up to copula formation. RFM is an independent and different behavioural process from harmonic convergence interactions used by male-female pairs for mate recognition at earlier stages of mating. Acoustic threshold for RFM was used to plot behavioural audiograms from free-flying A coluzzii and A gambiae males. These audiograms were almost identical (minima ∼400 Hz) and encompassed the WBF ranges of A coluzzii (378-601 Hz) and A gambiae (373-590 Hz) females, indicating that males of the two species share similar frequency tuning and range. Furthermore, no differences were found between the two species in their WBFs, RFM behaviour or harmonic convergence ratios. These results indicate that assortative mating between A coluzzii and A gambiae is unlikely to be based on male-specific acoustic behaviours during RFM. The significance of these findings in relation to possible mechanisms for assortative mating is discussed.

Paramedic Assessment of Older Adults After Falls, Including Community Care Referral Pathway: Cluster Randomized Trial.

STUDY OBJECTIVE: We aim to determine clinical and cost-effectiveness of a paramedic protocol for the care of older people who fall. METHODS: We undertook a cluster randomized trial in 3 UK ambulance services between March 2011 and June 2012. We included patients aged 65 years or older after an emergency call for a fall, attended by paramedics based at trial stations. Intervention paramedics could refer the patient to a community-based falls service instead of transporting the patient to the emergency department. Control paramedics provided care as usual. The primary outcome was subsequent emergency contacts or death. RESULTS: One hundred five paramedics based at 14 intervention stations attended 3,073 eligible patients; 110 paramedics based at 11 control stations attended 2,841 eligible patients. We analyzed primary outcomes for 2,391 intervention and 2,264 control patients. One third of patients made further emergency contacts or died within 1 month, and two thirds within 6 months, with no difference between groups. Subsequent 999 call rates within 6 months were lower in the intervention arm (0.0125 versus 0.0172; adjusted difference -0.0045; 95% confidence interval -0.0073 to -0.0017). Intervention paramedics referred 8% of patients (204/2,420) to falls services and left fewer patients at the scene without any ongoing care. Intervention patients reported higher satisfaction with interpersonal aspects of care. There were no other differences between groups. Mean intervention cost was $23 per patient, with no difference in overall resource use between groups at 1 or 6 months. CONCLUSION: A clinical protocol for paramedics reduced emergency ambulance calls for patients attended for a fall safely and at modest cost.

The contribution of caregiver psychosocial factors to distress associated with behavioural and psychological symptoms in dementia.

OBJECTIVE: The objective of the study is to examine caregiver factors as predictors of BPSD-related distress and their potential mechanisms. METHOD: Informal caregivers of people with dementia (n = 157) recruited from 28 community mental health teams in six NHS Trusts across England completed questionnaires regarding psychosocial factors (relationship quality, competence, guilt, health-related quality of life in the caregiver and person with dementia, reactivity to behavioural and psychological symptoms in dementia [BPSD] and burden) and frequency of BPSD. Analyses of BPSD-related distress include hierarchical multiple regression, mediation, moderation and path analysis. RESULTS: Caregiver psychosocial factors explained 56% of the variance in BPSD-related distress. After controlling for these factors, frequency of BPSD was not a significant predictor of BPSD-related distress. Caregiver reactivity to BPSD, burden, competence and relationship quality directly influenced BPSD-related distress. Guilt influenced distress indirectly via competence, burden and reactivity to BPSD. The final model accounted for 41% of the variance in BPSD-related distress and achieved a good fit to the data (χ2 = 23.920, df = 19, p = 0.199). CONCLUSIONS: Caregiver psychosocial factors including sense of competence, guilt, burden and reactivity to BPSD contribute to BPSD-related distress. Tailored interventions for managing behaviour problems in family settings could focus on these factors associated with BPSD-related distress to minimise distress in families. Copyright © 2016 John Wiley & Sons, Ltd.