Hair cell maturation is differentially regulated along the tonotopic axis of the mammalian cochlea

Sound amplification within the mammalian cochlea depends upon specialized hair cells, the outer hair cells (OHCs), which possess both sensory and motile capabilities. In various altricial rodents, OHCs become functionally competent from around postnatal day 7 (P7), before the primary sensory inner hair cells (IHCs), which become competent at about the onset of hearing (P12). The mechanisms responsible for the maturation of OHCs and their synaptic specialization remain poorly understood. We report that spontaneous Ca2+ activity in the immature cochlea, which is generated by CaV1.3 Ca2+ channels, differentially regulates the maturation of hair cells along the cochlea. Under near‐physiological recording conditions we found that, similar to IHCs, immature OHCs elicited spontaneous Ca2+ action potentials (APs), but only during the first few postnatal days. Genetic ablation of these APs in vivo, using CaV1.3−/− mice, prevented the normal developmental acquisition of mature‐like basolateral membrane currents in low‐frequency (apical) hair cells, such as IK,n (carried by KCNQ4 channels), ISK2 and IACh (α9α10nAChRs) in OHCs and IK,n and IK,f (BK channels) in IHCs. Electromotility and prestin expression in OHCs were normal in CaV1.3−/− mice. The maturation of high‐frequency (basal) hair cells was also affected in CaV1.3−/− mice, but to a much lesser extent than apical cells. However, a characteristic feature in CaV1.3−/− mice was the reduced hair cell size irrespective of their cochlear location. We conclude that the development of low‐ and high‐frequency hair cells is differentially regulated during development, with apical cells being more strongly dependent on experience‐independent Ca2+ APs

Spontaneous symmetry breaking and trapping of temporal Kerr cavity solitons by pulsed or amplitude-modulated driving fields

We report on a systematic study of temporal Kerr cavity soliton dynamics in the presence of pulsed or amplitude-modulated driving fields. In stark contrast to the more extensively studied case of phase modulations, we find that Kerr cavity solitons are not always attracted to maxima or minima of driving field amplitude inhomogeneities. Instead, we find that the solitons are attracted to temporal positions associated with specific driving field values that depend only on the cavity detuning. We describe our findings in light of a spontaneous symmetry breaking instability that physically ensues from a competition between coherent driving and nonlinear propagation effects. In addition to identifying a previously unfamiliar type of Kerr cavity soliton behavior, our results provide valuable insights into practical cavity configurations employing pulsed or amplitude-modulated driving fields

Patient-reported measurement of time to diagnosis in cancer: development of the Cancer Symptom Interval Measure (C-SIM) and randomised controlled trial of method of delivery

Background: The duration between first symptom and a cancer diagnosis is important because, if shortened, may lead to earlier stage diagnosis and improved cancer outcomes. We have previously developed a tool to measure this duration in newly-diagnosed patients. In this two-phase study, we aimed further improve our tool and to conduct a trial comparing levels of anxiety between two modes of delivery: self-completed versus researcher-administered. Methods: In phase 1, ten patients completed the modified tool and participated in cognitive debrief interviews. In phase 2, we undertook a Randomised Controlled Trial (RCT) of the revised tool (Cancer Symptom Interval Measure (C-SIM)) in three hospitals for 11 different cancers. Respondents were invited to provide either exact or estimated dates of first noticing symptoms and presenting them to primary care. The primary outcome was anxiety related to delivery mode, with completeness of recording as a secondary outcome. Dates from a subset of patients were compared with GP records. Results: After analysis of phase 1 interviews, the wording and format were improved. In phase 2, 201 patients were randomised (93 self-complete and 108 researcher-complete). Anxiety scores were significantly lower in the researcher-completed group, with a mean rank of 83.5; compared with the self-completed group, with a mean rank of 104.0 (Mann-Whitney U = 3152, p = 0.007). Completeness of data was significantly better in the researcher-completed group, with no statistically significant difference in time taken to complete the tool between the two groups. When comparing the dates in the patient questionnaires with those in the GP records, there was evidence in the records of a consultation on the same date or within a proscribed time window for 32/37 (86%) consultations; for estimated dates there was evidence for 23/37 consultations (62%). Conclusions: We have developed and tested a tool for collecting patient-reported data relating to appraisal intervals, help-seeking intervals, and diagnostic intervals in the cancer diagnostic pathway for 11 separate cancers, and provided evidence of its acceptability, feasibility and validity. This is a useful tool to use in descriptive and epidemiological studies of cancer diagnostic journeys, and causes less anxiety if administered by a researcher

Learning by building: A visual modelling language for psychology students

Cognitive modelling involves building computational models of psychological theories in order to learn more about them, and is a major research area allied to psychology and artificial intelligence. The main problem is that few psychology students have previous programming experience. The course lecturer can avoid the problem by presenting the area only in general terms. This leaves the process of building and testing models, which is central to the methodology, an unknown. Alternatively, students can be introduced to one of the existing cognitive modelling languages, though this can easily be overwhelming, hindering rather than helping their understanding. Our solution was to design and build a programming language for the intended population. The result is Hank, a visual cognitive modelling language for the psychologist. Our informal analyses have investigated the effectiveness of Hank in its intended context of use, both as a paper and pencil exercise for individuals, and as a computer based project to be carried out in groups. The findings largely support the Hank design decisions, and illuminate many of the challenges inherent in designing a programming language for an educational purpose

Coordinated calcium signalling in cochlear sensory and non‐sensory cells refines afferent innervation of outer hair cells

Outer hair cells (OHCs) are highly specialized sensory cells conferring the fine‐tuning and high sensitivity of the mammalian cochlea to acoustic stimuli. Here, by genetically manipulating spontaneous Ca2+ signalling in mice in vivo, through a period of early postnatal development, we find that the refinement of OHC afferent innervation is regulated by complementary spontaneous Ca2+ signals originating in OHCs and non‐sensory cells. OHCs fire spontaneous Ca2+ action potentials during a narrow period of neonatal development. Simultaneously, waves of Ca2+ activity in the non‐sensory cells of the greater epithelial ridge cause, via ATP‐induced activation of P2X3 receptors, the increase and synchronization of the Ca2+ activity in nearby OHCs. This synchronization is required for the refinement of their immature afferent innervation. In the absence of connexin channels, Ca2+ waves are impaired, leading to a reduction in the number of ribbon synapses and afferent fibres on OHCs. We propose that the correct maturation of the afferent connectivity of OHCs requires experience‐independent Ca2+ signals from sensory and non‐sensory cells

Follow-up of cancer in primary care versus secondary care: systematic review

Background Cancer follow-up has traditionally been undertaken in secondary care, but there are increasing calls to deliver it in primary care. Aim To compare the effectiveness and cost-effectiveness of primary versus secondary care follow-up of cancer patients, determine the effectiveness of the integration of primary care in routine hospital follow-up, and evaluate the impact of patient-initiated follow-up on primary care. Design of study Systematic review. Setting Primary and secondary care settings. Method A search was carried out of 19 electronic databases, online trial registries, conference proceedings, and bibliographies of included studies. The review included comparative studies or economic evaluations of primary versus secondary care follow-up, hospital follow-up with formal primary care involvement versus conventional hospital follow-up, and hospital follow-up versus patient-initiated or minimal follow-up if the study reported the impact on primary care. Results There was no statistically significant difference for patient wellbeing, recurrence rate, survival, recurrence-related serious clinical events, diagnostic delay, or patient satisfaction. GP-led breast cancer follow-up was cheaper than hospital follow-up. Intensified primary health care resulted in increased home-care nurse contact, and improved discharge summary led to increased GP contact. Evaluation of patient-initiated or minimal follow-up found no statistically significant impact on the number of GP consultations or cancer-related referrals. Conclusion Weak evidence suggests that breast cancer follow-up in primary care is effective. Interventions improving communication between primary and secondary care could lead to greater GP involvement. Discontinuation of formal follow-up may not increase GP workload. However, the quality of the data in general was poor, and no firm conclusions can be reached

Silicon isotopes highlight the role of glaciated fjords in modifying coastal waters

Glaciers and ice sheets are experiencing rapid warming under current climatic change and there is increasing evidence that glacial meltwaters provide key dissolved and dissolvable amorphous nutrients to downstream ecosystems. However, large debate exists around the fate of these nutrients within complex and heterogenous fjord environments, where biogeochemical cycling is still often poorly understood. We combine silicon (Si) concentration data with isotopic compositions to better understand silicon cycling and export in two contrasting fjordic environments in south-west Greenland. We show that both fjords have isotopically light dissolved silicon (DSi) within surface waters, despite an apparently rapid biological drawdown of DSi with increasing salinity. We hypothesise that such observations cannot be explained by simple water mass mixing processes, and postulate that an isotopically light source of Si, most likely glacially-derived amorphous silica (ASi), is responsible for further modifying these coastal waters within the fjords and beyond. Fjord to coastal exchange is likely a relatively slow process (several months), and thus is less impacted by short-term (< seasonal) changes of glacial meltwater input into the fjord, which has implications when considering the role of glacial meltwaters on nutrient export beyond the shelf break. We highlight the need for isotopic studies combined with dissolved and particulate nutrient concentration analysis to provide a more detailed analysis into the biogeochemical cycles within these highly dynamic fjord environments