Diffusion MRI of the Hippocampus.

The hippocampus is a brain structure that plays key roles in a variety of cognitive processes. Critically, a wide range of neurological disorders are associated with degeneration of the hippocampal microstructure, defined as neurons, dendrites, glial cells, and more. Thus, the hippocampus is a key target for methods that are sensitive to these microscale properties. Diffusion MRI is one such method, which can noninvasively probe neural architecture. Here we review the extensive use of diffusion MRI to capture hippocampal microstructure in both health and disease. The results of these studies indicate that (1) diffusion tensor imaging is sensitive but not specific to the hippocampal microstructure; (2) biophysical modeling of diffusion MRI signals is a promising avenue to capture more specific aspects of the hippocampal microstructure; (3) use of ultra-short diffusion times have shown unique laminar-specific microstructure and response to hippocampal injury; (4) dispersion of microstructure is likely abundant in the hippocampus; and (5) the angular richness of the diffusion MRI signal can be leveraged to improve delineation of the internal hippocampal circuitry. Overall, extant findings suggest that diffusion MRI offers a promising avenue for characterizing hippocampal microstructure.

Organization of pRF size along the AP axis of the hippocampus and adjacent medial temporal cortex is related to specialization for scenes versus faces.

The hippocampus is largely recognized for its integral contributions to memory processing. By contrast, its role in perceptual processing remains less clear. Hippocampal properties vary along the anterior-posterior (AP) axis. Based on past research suggesting a gradient in the scale of features processed along the AP extent of the hippocampus, the representations have been proposed to vary as a function of granularity along this axis. One way to quantify such granularity is with population receptive field (pRF) size measured during visual processing, which has so far received little attention. In this study, we compare the pRF sizes within the hippocampus to its activation for images of scenes versus faces. We also measure these functional properties in surrounding medial temporal lobe (MTL) structures. Consistent with past research, we find pRFs to be larger in the anterior than in the posterior hippocampus. Critically, our analysis of surrounding MTL regions, the perirhinal cortex, entorhinal cortex, and parahippocampal cortex shows a similar correlation between scene sensitivity and larger pRF size. These findings provide conclusive evidence for a tight relationship between the pRF size and the sensitivity to image content in the hippocampus and adjacent medial temporal cortex.

Trends in the availability and prices of quality-assured tuberculosis drugs: a systematic analysis of Global Drug Facility Product Catalogs from 2001 to 2024.

BACKGROUND: The Global Drug Facility (GDF) of the Stop TB Partnership was launched in 2001 with the goal of increasing access to quality-assured tuberculosis (TB) drugs and products. We aimed to describe the TB drugs and prices available from the GDF over time and to assess trends. METHODS: We searched the internet, including an internet archive, for past and recent GDF Product Catalogs and extracted the listed TB drugs and prices. We calculated the lowest price for the most common drug formulations assuming drugs with similar active pharmaceutical ingredients (APIs) are substitutes for each other. We assessed time trends in the TB drugs and prices offered by the GDF in univariable regressions over the longest possible period. RESULTS: We identified 43 different GDF Product Catalogs published between November 2001 and May 2024. These product catalogs included 122 single medicines (31 APIs), 28 fixed-dose combinations (9 API combinations), and 8 patient kits (8 API regimens and other materials). The number of TB drugs listed in the GDF Product Catalog increased from 9 (8 APIs) to 55 (32 APIs). The price decreased for 17, increased for 19, and showed no trend for 12 APIs. The price of 15 (53.6%) of 28 APIs used against drug-resistant TB decreased, including the price of drugs used in new treatment regimens. The decreasing price trend was strongest for linezolid (-16.60 [95% CI: -26.35 to -6.85] percentage points [pp] per year), bedaquiline (-12.61 [95% CI: -18.00 to -7.22] pp per year), cycloserine (-11.20 [95% CI: -17.40 to -4.99] pp per year), pretomanid (-10.47 [95% CI: -15.06 to -5.89] pp per year), and rifapentine (-10.46 [95% CI: -12.86 to -8.06] pp per year). The prices of 16 (61.5%) of 23 APIs for standard drug-susceptible TB treatment increased, including rifampicin (23.70 [95% CI: 18.48 to 28.92] pp per year), isoniazid (20.95 [95% CI: 18.96 to 22.95] pp per year), ethambutol (9.85 [95% CI: 8.83 to 10.88] pp per year), and fixed-dose combinations thereof. CONCLUSIONS: The number of TB drugs available from the GDF has substantially increased during its first 23 years of operation. The prices of most APIs for new TB treatments decreased or remained stable. The prices of most APIs for standard drug-sensitive TB treatment increased.

Lifetime familiarity cue effects for autobiographical memory.

Recollecting an autobiographical memory requires a cue to initiate processes related to accessing and then elaborating on a past personal experience. Prior work has shown that the familiarity of a cue can influence the autobiographical memory retrieval process. Extending this work, we tested how familiarity accrued from cumulative lifetime exposures associated with the cue-as well as associated semantic knowledge-can affect how we access and remember autobiographical memories. In Experiment 1, we measured reaction times to access and report memories in response to cue words. In Experiment 2 we examined the details with which participants described memories in response to cue words. For both experiments, participants provided estimates of lifetime exposure and semantic knowledge for each cue. In Experiment 1, we found a cue's lifetime exposure, independent of semantic knowledge, led to quicker memory access. In Experiment 2, we found the lifetime exposure and semantic knowledge of a cue interactively affected the specificity of a described autobiographical memory. These results provide new evidence that the amount of lifetime exposure associated with a cue, both independently and interactively with semantic knowledge, influences how autobiographical memories are accessed and described.Clinical trial This was not a clinical trial.Trial Registration Number (TRN) N/A.

Dentate Gyrus Integrity Is Necessary for Behavioral Pattern Separation But Not Statistical Learning.

Pattern separation, the creation of distinct representations of similar inputs, and statistical learning, the rapid extraction of regularities across multiple inputs, have both been linked to hippocampal processing. It has been proposed that there may be functional differentiation within the hippocampus, such that the trisynaptic pathway (entorhinal cortex > dentate gyrus > CA3 > CA1) supports pattern separation, whereas the monosynaptic pathway (entorhinal cortex > CA1) supports statistical learning. To test this hypothesis, we investigated the behavioral expression of these two processes in B. L., an individual with highly selective bilateral lesions in the dentate gyrus that presumably disrupt the trisynaptic pathway. We tested pattern separation with two novel auditory versions of the continuous mnemonic similarity task, requiring the discrimination of similar environmental sounds and trisyllabic words. For statistical learning, participants were exposed to a continuous speech stream made up of repeating trisyllabic words. They were then tested implicitly through a RT-based task and explicitly through a rating task and a forced-choice recognition task. B. L. showed significant deficits in pattern separation on the mnemonic similarity tasks and on the explicit rating measure of statistical learning. In contrast, B. L. showed intact statistical learning on the implicit measure and the familiarity-based forced-choice recognition measure. Together, these results suggest that dentate gyrus integrity is critical for high-precision discrimination of similar inputs, but not the implicit expression of statistical regularities in behavior. Our findings offer unique new support for the view that pattern separation and statistical learning rely on distinct neural mechanisms.

Mapping the macrostructure and microstructure of the in vivo human hippocampus using diffusion MRI.

The hippocampus is classically divided into mesoscopic subfields which contain varying microstructure that contribute to their unique functional roles. It has been challenging to characterize this microstructure with current magnetic resonance based neuroimaging techniques. In this work, we used diffusion magnetic resonance imaging (dMRI) and a novel surface-based approach in the hippocampus which revealed distinct microstructural distributions of neurite density and dispersion, T1w/T2w ratio as a proxy for myelin content, fractional anisotropy, and mean diffusivity. We used the neurite orientation dispersion and density imaging (NODDI) model optimized for grey matter diffusivity to characterize neurite density and dispersion. We found that neurite dispersion was highest in the cornu ammonis (CA) 1 and subiculum subfields which likely captures the large heterogeneity of tangential and radial fibres, such as the Schaffer collaterals, perforant path, and pyramidal neurons. Neurite density and T1w/T2w were highest in the subiculum and CA3 and lowest in CA1, which may reflect known myeloarchitectonic differences between these subfields. Using a simple logistic regression model, we showed that neurite density, dispersion, and T1w/T2w measures were separable across the subfields, suggesting that they may be sensitive to the known variability in subfield cyto- and myeloarchitecture. We report macrostructural measures of gyrification, thickness, and curvature that were in line with ex vivo descriptions of hippocampal anatomy. We employed a multivariate orthogonal projective non-negative matrix factorization (OPNNMF) approach to capture co-varying regions of macro- and microstructure across the hippocampus. The clusters were highly variable along the medial-lateral (proximal-distal) direction, likely reflecting known differences in morphology, cytoarchitectonic profiles, and connectivity. Finally, we show that by examining the main direction of diffusion relative to canonical hippocampal axes, we could identify regions with stereotyped microstructural orientations that may map onto specific fibre pathways, such as the Schaffer collaterals, perforant path, fimbria, and alveus. These results highlight the value of combining in vivo dMRI with computational approaches for capturing hippocampal microstructure, which may provide useful features for understanding cognition and for diagnosis of disease states.

Out-of-pocket Expenses and Time Spent on Clinic Visits Among HIV Pre-exposure Prophylaxis Users and Other Clinic Attendees in Eswatini.

User costs constitute a barrier to the uptake of HIV pre-exposure prophylaxis (PrEP), but their magnitude appears rarely assessed. In this prospective observational study, we assessed self-reported out-of-pocket expenses (OOPE) and time spent on clinic visits during a PrEP demonstration project in Eswatini. At six public primary care clinics, 240 PrEP users and other clinic attendees were interviewed after a clinic visit. Among the 79.2% of clinic attendees reporting any medical OOPE (e.g., expenses for consultations or drugs) and/or non-medical OOPE (e.g., expenses for transport, food, or phone use), the median total OOPE was $1.36 (IQR 0.91-1.96). Non-medical OOPE occurred mostly due to transport expenses. The median travel time for a clinic visit was 1.0 h (IQR 0.67-2.0). The median time spent in the clinic was 2.0 h (IQR 1.15-3.0). The median opportunity cost of a clinic visit was $7.54 (IQR 5.42-11) when valuing time spent on a clinic visit with Eswatini's per-capita gross domestic product. Our findings can guide measures to reduce the user costs of PrEP in Eswatini and other contexts in which oral PrEP is provided through health care facilities.

RESUMEN: Los costes de los usuarios constituyen un obstáculo para la adopción de la profilaxis previa a la exposición al VIH (PrEP), pero su magnitud rara vez se evalúa. En este estudio observacional prospectivo, evaluamos los gastos de bolsillo (OOPE) declarados por los propios usuarios y el tiempo dedicado a las visitas clínicas durante un proyecto de demostración de la PrEP en Eswatini. En seis clínicas públicas de atención primaria, se entrevistó a 240 usuarios de la PrEP y a otros asistentes a la clínica después de una visita a la misma. Entre el 79,2% de los asistentes a las clínicas que declararon algún OOPE médico (por ejemplo, gastos por consultas o medicamentos) y/o OOPE no médico (por ejemplo, gastos de transporte, comida o uso del teléfono), la mediana del OOPE total fue de 1,36 dólares (IQR: 0,91­1,96). Los gastos no médicos se debieron principalmente a los gastos de transporte. La mediana del tiempo de viaje para una visita a la clínica fue de 1,0 horas (IQR 0,67­2,0). La mediana del tiempo empleado en la clínica fue de 2 horas (IQR 1,15­3,0). La mediana del coste de oportunidad de una visita a la clínica fue de 7,65 dólares (IQR 5,55­11) al valorar el tiempo dedicado a una visita a la clínica con el producto interior bruto per cápita de Eswatini. Nuestros resultados pueden orientar las medidas para reducir los costes de uso de la PrEP en Eswatini y en otros contextos en los que se suministra la PrEP oral a través de los centros de salud.

Costs and import costs of past, present, and future TB drug regimens: a case study for Karakalpakstan, Uzbekistan.

BACKGROUND: Tuberculosis (TB) drugs and their import are costly. We assessed how shorter TB drug regimens, which were non-inferior or superior in recent TB trials, can affect the costs for purchasing and importing TB drugs. METHODS: We estimated the drug costs and import costs of 39 longer and shorter TB drug regimens using TB drug prices from the Global Drug Facility and import cost estimates for a TB program in Karakalpakstan, Uzbekistan. Drug regimens from recent TB trials were compared with TB drug regimens following present or past World Health Organization recommendations. RESULTS: We estimated an import cost of $4.19 and a drug cost of $43 per standard 6-month drug-sensitive (DS)-TB regimen. A new 17-week DS-TB regimen from the TBTC Study 31 currently requires more tablets and is more expensive to import ($6.08) and purchase ($233). The TB program can substantially decrease import costs ($2.26-14) and drug costs ($391-2308) per multidrug-resistant (MDR)-TB regimen when using new 6-month or shorter drug regimens from the Nix-TB, NExT, TB PRACTECAL, ZeNix, or BEAT TB trials instead of 9-20-month regimens with import costs of $9.96-507 and drug costs of $354-15 028. For a commonly used 20-month all-oral, bedaquiline-containing MDR-TB regimen, we estimated costs of $41 for drug import and $1773 for drug purchase. CONCLUSIONS: The implementation of a new and shorter DS-TB regimen may increase the costs for drug purchase and import. The implementation of new and shorter MDR-TB regimens may decrease the costs for drug purchase and/or drug import.

[Health and Professional Satisfaction of Freelance and Employed Midwives: Results of a Survey of Midwives in Baden-Wuerttemberg]. / Gesundheit und berufliche Zufriedenheit von freiberuflichen und angestellten Hebammen: Ergebnisse einer Hebammenbefragung in Baden-Württemberg.

BACKGROUND: A shortage of midwives has been the subject of discussion in Germany in recent years. In this study, we asked midwives in Baden-Wuerttemberg about their health and professional satisfaction. METHOD: In collaboration with the Baden-Wuerttemberg Midwives Association, an online midwives survey was conducted from October 16 to December 10, 2017. Using a visual analog scale (0-100 points), the WHO-5 questionnaire (0-100 points) and the Copenhagen Burnout Inventory (0-100 points), data on health, well-being and burnout were collected. Job satisfaction was assessed on a 7-point Likert scale. Seven hundred and twenty-two midwives participated in the survey. For this study, 545 to 608 data sets were analyzed. RESULTS: Of the studied midwives, 78.1% rated their health as good or very good (≥60 points). No statistically significant difference was observed between freelance midwives, employed midwives, and midwives who worked in both occupation forms (P=0.12). Midwives who were exclusively (15.0%) or partially (12.6%) employed were more likely to have very low well-being (≤25 points) than freelance midwives (7.3%; P=0.023). In addition, midwives who were exclusively (41.5%) or partially (39.4%) employed were more likely to have a moderate or high risk of burnout (≥50 points) than freelance midwives (20.6%; P<0.001). A lower health rating, lower well-being or higher burnout risk were associated with higher professional dissatisfaction in one or more domains. In multivariable analyses, higher burnout risk in particular was associated with higher job dissatisfaction in various domains. CONCLUSIONS: A large proportion of midwives in our study showed symptoms of depression and/or burnout. On average, the health status of midwives seems to be above the health status of women from the general population in Germany, but the well-being of midwives below. We recommend further investigation of how the stress of midwives can be reduced in the course of advancing midwifery and obstetric care structures.

Involuntary memory signals in the medial temporal lobe.

We highlight recent progress in neuroimaging and neuropsychological research on memory mechanisms in the medial temporal lobe that speaks to the involuntary nature of memory retrieval processes. We suggest that evidence form these studies supports Barzykowski and Moulin's proposal that memory signals involved in experiences of familiarity and déjà vu can be generated in the absence of retrieval intentionality.

Accuracy of pedicle screw placement using neuronavigation based on intraoperative 3D rotational fluoroscopy in the thoracic and lumbar spine.

INTRODUCTION: In spinal surgery, precise instrumentation is essential. This study aims to evaluate the accuracy of navigated, O-arm-controlled screw positioning in thoracic and lumbar spine instabilities. MATERIALS AND METHODS: Posterior instrumentation procedures between 2010 and 2015 were retrospectively analyzed. Pedicle screws were placed using 3D rotational fluoroscopy and neuronavigation. Accuracy of screw placement was assessed using a 6-grade scoring system. In addition, screw length was analyzed in relation to the vertebral body diameter. Intra- and postoperative revision rates were recorded. RESULTS: Thoracic and lumbar spine surgery was performed in 285 patients. Of 1704 pedicle screws, 1621 (95.1%) showed excellent positioning in 3D rotational fluoroscopy imaging. The lateral rim of either pedicle or vertebral body was protruded in 25 (1.5%) and 28 screws (1.6%), while the midline of the vertebral body was crossed in 8 screws (0.5%). Furthermore, 11 screws each (0.6%) fulfilled the criteria of full lateral and medial displacement. The median relative screw length was 92.6%. Intraoperative revision resulted in excellent positioning in 58 of 71 screws. Follow-up surgery due to missed primary malposition had to be performed for two screws in the same patient. Postsurgical symptom relief was reported in 82.1% of patients, whereas neurological deterioration occurred in 8.9% of cases with neurological follow-up. CONCLUSIONS: Combination of neuronavigation and 3D rotational fluoroscopy control ensures excellent accuracy in pedicle screw positioning. As misplaced screws can be detected reliably and revised intraoperatively, repeated surgery for screw malposition is rarely required.

The Costs of Creatinine Testing in the Context of a HIV Pre-Exposure Prophylaxis Demonstration Project in Eswatini.

HIV treatment and prevention as well as other chronic disease care can require regular kidney function assessment based on a creatinine test. To assess the costs of creatinine testing in a public health care system, we conducted activity-based costing during a HIV pre-exposure prophylaxis (PrEP) demonstration project in the Hhohho region of Eswatini. Resource use was assessed by a laboratory technician and valued with government procurement prices, public sector salaries, and own cost estimates. Obtaining a blood sample in a clinic and performing a creatinine test in a high-throughput referral laboratory (> 660,000 blood tests, including > 120,000 creatinine tests, in 2018) were estimated to have cost, on average, $1.98 in 2018. Per test, $1.95 were variable costs ($1.38 personnel, ¢39 consumables, and ¢18 other costs) and ¢2.6 were allocated semi-fixed costs (¢1.1 laboratory equipment, ¢0.85 other, ¢0.45 consumables, and ¢1.3 personnel costs). Simulating different utilization of the laboratory indicated that semi-fixed costs of the laboratory (e.g., equipment purchase or daily calibration of the chemistry analyzer) contributed less than variable costs (e.g., per-test personnel time and test reagents) to the average creatinine test cost when certain minimum test numbers can be maintained. Our findings suggest, first, lower creatinine testing costs than previously used in cost and cost-effectiveness analyses of HIV services and, second, that investment in laboratory equipment imposed a relatively small additional cost on each performed test in the high-throughput referral laboratory.

RESUMEN: El tratamiento y la prevención del VIH, así como el cuidado de otras enfermedades crónicas, pueden requerir una evaluación periódica de la función renal basada en una prueba de creatinina. Para evaluar los costes de las pruebas de creatinina en un sistema de atención sanitaria público, realizamos un cálculo de costes basado en actividades durante un proyecto de demostración de profilaxis preexposición al VIH (PrEP) en la región de Hhohho de Eswatini. El uso de los recursos fue evaluado por un técnico de laboratorio y valorado con los precios de adquisición del gobierno, los salarios del sector público y las estimaciones de costes propias. La obtención de una muestra de sangre en una clínica y la realización de una prueba de creatinina en un laboratorio de referencia de alto rendimiento (> 660.000 pruebas de sangre, incluidas > 120.000 pruebas de creatinina, en 2018) se estimó que habían costado, en promedio, $1,98 en 2018. Por prueba, $1,95 eran costes variables ($1,38 de personal, ¢39 de consumibles y ¢18 de otros costes) y ¢2,6 eran costes semifijos asignados (¢1,1 de equipamiento de laboratorio, ¢0,85 de otros, ¢0,45 de consumibles y ¢1,3 de personal). La simulación de utilización diferente del laboratorio indicó que los costes semifijos del laboratorio (por ejemplo, la compra de equipos o la calibración diaria del analizador químico) contribuyeron menos que los costes variables (por ejemplo, el tiempo del personal por prueba y los reactivos de la prueba) al coste medio de la prueba de creatinina cuando se pueden mantener ciertos números mínimos de pruebas. Nuestros resultados sugieren, en primer lugar, que los costes de las pruebas de creatinina son inferiores a los utilizados anteriormente en los análisis de coste y costo-efectividad de los servicios de VIH y, en segundo lugar, que la inversión en equipos de laboratorio supuso un coste adicional relativamente pequeño en cada prueba realizada en el laboratorio de referencia de alto rendimiento.

PrEP uptake and delivery setting preferences among clients visiting six healthcare facilities in Eswatini.

Due to the high HIV incidence among the general population of Eswatini, pre-exposure prophylaxis (PrEP) for HIV-exposed individuals is recommended. However, little is known about PrEP uptake and preferences in PrEP delivery healthcare setting among the general population. We conducted a secondary analysis of a randomized trial that aimed to increase PrEP uptake. All clients eligible for PrEP in one of six public-sector healthcare facilities in Eswatini were included. PrEP uptake was stratified by initial reason for visit (e.g. outpatient). Preferences in PrEP delivery setting were collected among those clients who initiated PrEP. A total of 1782 clients had their HIV acquisition risk assessed. Of these, 72% (1277/1782) were considered at risk by healthcare providers and, among them, 40% (517/1277) initiated PrEP. Uptake was higher among clients visiting specifically to initiate PrEP (93%), followed by HIV testing visits (45.8%) and outpatient visits (40%). Among those who initiated PrEP, preferred delivery settings were outpatient services (31%), HIV testing services (26%), family planning (21%) and antenatal services (14%). Men or those at high risk of HIV acquisition were more likely to prefer HIV testing and outpatient services, while young women were more likely to visit and express a preference for antenatal and family planning services. Outpatient services and HIV testing services could be preferable choices for PrEP delivery integration, due to the high PrEP uptake and delivery setting preferences of the populations who use these services. Antenatal and family planning could also be considered with a view to targeting the youngest women.

RESUMEN: Debido a la alta incidencia del VIH entre la población general de Eswatini, se recomienda la profilaxis previa a la exposición (PrEP) para las personas expuestas al VIH. Sin embargo, se sabe poco sobre la aceptación de la PrEP y las preferencias en el ámbito de la atención sanitaria de la PrEP entre la población general. Se realizó un análisis secundario de un ensayo clínico que pretendía aumentar la aceptación de la PrEP. Se incluyó a todos los clientes elegibles para la PrEP en uno de los seis centros sanitarios del sector público de Eswatini. La aceptación de la PrEP se estratificó según el motivo inicial de la visita (por ejemplo, paciente externo). Se recogieron las preferencias en el entorno de administración de la PrEP entre aquellos clientes que iniciaron la PrEP. Se evaluó el riesgo de adquisición del VIH de un total de 1.782 clientes (de 2.238 contactados, el 80%). De ellos, el 72% (1277/1782) fueron considerados de riesgo por los profesionales sanitarios y, entre ellos, el 40% (517/1277) iniciaron la PrEP. El consumo fue mayor entre los clientes que acudieron específicamente para iniciar la PrEP (93%), seguido de las visitas para realizar la prueba del VIH (45,8%) y las visitas ambulatorias (40%). Entre los que iniciaron la PrEP, los entornos de prestación preferidos fueron los servicios ambulatorios (31%), los servicios de pruebas del VIH (26%), la planificación familiar (21%) y los servicios prenatales (14%). Los hombres o las personas con alto riesgo de contraer el VIH tenían más probabilidades de preferir las pruebas del VIH y los servicios ambulatorios, mientras que las mujeres jóvenes tenían más probabilidades de acudir a los servicios prenatales y de planificación familiar y expresar su preferencia por ellos. Los servicios ambulatorios y los servicios de pruebas del VIH podrían ser opciones preferibles para la integración de la entrega de la PrEP, debido a la alta aceptación de la PrEP y a las preferencias del entorno de entrega de las poblaciones que utilizan estos servicios. Los servicios prenatales y de planificación familiar también podrían considerarse con vistas a dirigirse a las mujeres más jóvenes.

Human resource needs and costs for HIV pre-exposure prophylaxis provision in nurse-led primary care in Eswatini and opportunities for task sharing.

BACKGROUND: The global expansion of HIV pre-exposure prophylaxis (PrEP) includes health systems that face a shortage of skilled health care workers (HCWs). We estimated the human resource needs and costs for providing PrEP in nurse-led primary care clinics in Eswatini. Furthermore, we assessed potential cost savings from task sharing between nurses and other HCW cadres. METHODS: We conducted a time-and-motion and costing study in a PrEP demonstration project between August 2017 and January 2019. A form for recording time and performed activities ("motion") was filled by HCWs of six primary care clinics. To estimate the human resource needs for specific PrEP activities, we allocated recorded times to performed PrEP activities using linear regression with and without adjusting for a workflow interruption, that is, if a client was seen by different HCWs or by the same HCW at different times. We assessed a base case in which a nurse provides all PrEP activities and five task shifting scenarios, of which four include workflow interruptions due to task sharing between different HCW cadres. RESULTS: On average, PrEP initiation required 29 min (95% CI 25-32) of HCW time and PrEP follow-up 16 min (95% CI 14-18). The HCW time cost $4.55 (uncertainty interval [UI] 1.52-9.69) for PrEP initiation and $2.54 (UI 1.07-4.64) for PrEP follow-up when all activities were performed by a nurse. Time costs were $2.30-4.25 (UI 0.62-9.19) for PrEP initiation and $1.06-2.60 (UI 0.30-5.44) for PrEP follow-up when nurses shared tasks with HCWs from lower cadres. Interruptions of the workflow added, on average, 3.4 min (95% CI 0.69-6.0) to the time HCWs needed for a given number of PrEP activities. The cost of an interrupted workflow was estimated at $0.048-0.87 (UI 0.0098-1.63) depending on whose time need increased. CONCLUSIONS: A global shortage of skilled HCWs could slow the expansion of PrEP. Task shifting to lower-cadre HCW in nurse-led PrEP provision can free up nurse time and reduce the cost of PrEP provision even if interruptions associated with task sharing increase the overall human resource need.

Feeling-of-knowing experiences breed curiosity.

A central tenet in theoretical work on metacognition is that retrieval experiences during memory search can exert control over behaviour. States of curiosity, which reflect motivational tendencies to seek out information, may play a critical role in this control function. We conducted two experiments to address this idea, focusing on links between feeling-of knowing (FOK) experiences, memory-search duration, and subsequent information-seeking behaviour. We administered an episodic FOK paradigm that probed memory for previously studied face-name pairs, and subsequently provided an opportunity to select limited pairs for restudy. This set-up allowed us to test whether current search duration and subsequent restudy choices are biased towards items with high FOK ratings. Results revealed a positive relationship between FOK ratings and the response times of these judgements. We observed a similar positive relationship between FOK ratings and subsequent item selection for restudy. Moreover, experimental manipulations of FOK ratings based on familiarity of the face cues also had parallel effects. Our findings suggest that metacognitive experiences during unsuccessful retrieval from episodic memory can induce states of curiosity that shape behaviour beyond the immediate retrieval context. Curiosity may act as a bond to ensure that memory gaps identified through unsuccessful retrieval adaptively guide future learning.

Relationship between déjà vu experiences and recognition-memory impairments in temporal-lobe epilepsy.

Déjà vu is characterised by feelings of familiarity and concurrent awareness that this familiarity is wrong. Previous neuropsychological research has linked déjà vu during seizures in individuals with unilateral temporal-lobe epilepsy (uTLE) to rhinal-cortex abnormalities, and to recognition-memory deficits that selectively affect familiarity assessment. Here, we examined whether bilateral TLE patients with déjà vu (bTLE) show a similar pattern of performance. Using two experimental tasks, we found that bTLE patients exhibit deficits not only for familiarity but also for recollection. Relative to uTLE, this broader impairment also involved hippocampal abnormalities. Our findings confirm rhinal-cortex contributions to the generation of false familiarity in déjà vu that parallel its contributions to familiarity on recognition-memory tasks. While they do not rule out a role for recollection in identifying this familiarity as wrong, the deficits observed in bTLE patients weigh against the notion that any such role is necessary for déjà vu to occur.

Finding the engram.

Many attempts have been made to localize the physical trace of a memory, or engram, in the brain. However, until recently, engrams have remained largely elusive. In this Review, we develop four defining criteria that enable us to critically assess the recent progress that has been made towards finding the engram. Recent 'capture' studies use novel approaches to tag populations of neurons that are active during memory encoding, thereby allowing these engram-associated neurons to be manipulated at later times. We propose that findings from these capture studies represent considerable progress in allowing us to observe, erase and express the engram.

Global matching and fluency attribution in familiarity assessment.

In the integrative memory model proposed by Bastin et al., familiarity is thought to arise from attribution of fluency signals. We suggest that, from a computational and anatomical perspective, this conceptualization converges with a global-matching account of familiarity assessment. We also argue that consideration of global matching and evidence accumulation in decision making could help further our understanding of the proposed attribution system.

Heroes of the Engram.

In 1904, Richard Semon introduced the term "engram" to describe the neural substrate responsible for (or at least important in) storing and recalling memories (i.e., a memory trace). The recent introduction of a vast array of powerful new tools to probe and manipulate memory function at the cell and neuronal circuit level has spurred an explosion of interest in studying the engram. However, the present "engram renaissance" was not borne in isolation but rather builds on a long tradition of memory research. We believe it is important to acknowledge the debts our current generation of scientists owes to those scientists who have offered key ideas, persevered through failed experiments and made important discoveries before us. Examining the past can also offer a fresh perspective on the present state and future promise of the field. Given the large amount of empirical advances made in recent years, it seems particularly timely to look back and review the scientists who introduced the seminal terminology, concepts, methodological approaches, and initial data pertaining to engrams. Rather than simply list their many accomplishments, here we color in some details of the lives and milestone contributions of our seven personal heroes of the engram (Richard Semon, Karl Lashley, Donald Hebb, Wilder Penfield, Brenda Milner, James McConnell, and Richard Thompson). In reviewing their historic role, we also illustrate how their work remains relevant to today's studies.

How landmark suitability shapes recognition memory signals for objects in the medial temporal lobes.

A role of perirhinal cortex (PrC) in recognition memory for objects has been well established. Contributions of parahippocampal cortex (PhC) to this function, while documented, remain less well understood. Here, we used fMRI to examine whether the organization of item-based recognition memory signals across these two structures is shaped by object category, independent of any difference in representing episodic context. Guided by research suggesting that PhC plays a critical role in processing landmarks, we focused on three categories of objects that differ from each other in their landmark suitability as confirmed with behavioral ratings (buildings > trees > aircraft). Participants made item-based recognition-memory decisions for novel and previously studied objects from these categories, which were matched in accuracy. Multi-voxel pattern classification revealed category-specific item-recognition memory signals along the long axis of PrC and PhC, with no sharp functional boundaries between these structures. Memory signals for buildings were observed in the mid to posterior extent of PhC, signals for trees in anterior to posterior segments of PhC, and signals for aircraft in mid to posterior aspects of PrC and the anterior extent of PhC. Notably, item-based memory signals for the category with highest landmark suitability ratings were observed only in those posterior segments of PhC that also allowed for classification of landmark suitability of objects when memory status was held constant. These findings provide new evidence in support of the notion that item-based memory signals for objects are not limited to PrC, and that the organization of these signals along the longitudinal axis that crosses PrC and PhC can be captured with reference to landmark suitability.