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Stimulation of the mesencephalic locomotor region elicits exaggerated sympathetic nerve and pressor responses in spontaneously hypertensive rats (SHR) as compared with normotensive Wistar-Kyoto rats (WKY). This suggests that central command or its influence on vasomotor centers is augmented in hypertension. The decerebrate animal model possesses an ability to evoke intermittent bouts of spontaneously occurring motor activity (SpMA) and generates cardiovascular responses associated with the SpMA. It remains unknown whether the changes in sympathetic nerve activity and hemodynamics during SpMA are altered by hypertension. To test the hypothesis that the responses in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) during SpMA are exaggerated with hypertension, this study aimed to compare the responses in decerebrate, paralyzed SHR, WKY, and normotensive Sprague-Dawley (SD) rats. In all strains, an abrupt increase in RSNA occurred in synchronization with tibial motor discharge (an index of motor activity) and was followed by rises in MAP and heart rate. The centrally evoked increase in RSNA and MAP during SpMA was much greater (306 ± 110%) in SHR than WKY (187 ± 146%) and SD (165 ± 44%). Although resting baroreflex-mediated changes in RSNA were not different across strains, mechanically or pharmacologically induced elevations in MAP attenuated or abolished the RSNA increase during SpMA in WKY and SD but had no effect in SHR. It is likely that the exaggerated sympathetic nerve and pressor responses during SpMA in SHR are induced along a central command pathway independent of the arterial baroreflex and/or result from central command-induced inhibition of the baroreflex.

This paper introduces a protocol for the verification of multi-physics wildfire evacuation models, including a set of tests used to ensure that the conceptual modelling representation of each modelling layer is accurately implemented, as well as the interactions between different modelling layers and sub-models (wildfire spread, pedestrian movement, traffic evacuation, and trigger buffers). This work presents a total of 24 verification tests, including (1) 4 tests related to pedestrians, (2) 15 tests for traffic evacuation, (3) 5 tests concerning the interaction between different modelling layers, along with 5 tests for wildfire spread and trigger buffers. The evacuation tests are organized in accordance with different core components related to evacuation modelling, namely Population, Pre-evacuation, Movement, Route/destination selection, Flow constraints, Events, Wildfire spread and Trigger buffers. A reporting template has also been developed to facilitate the application of the verification testing protocol. An example application of the testing protocol has been performed using an open wildfire evacuation modelling platform called WUI-NITY and its associated trigger buffer model k-PERIL. The verification testing protocol is deemed to improve the credibility of wildfire evacuation model results and stimulate future modelling efforts in this domain.

Nigeria has an estimated TB prevalence of 219 per 100,000 population. In 2019, Nigeria diagnosed and notified 27% of the WHO-estimated cases of all forms of TB and contributed 11% of the missing TB cases globally.To assess TB underreporting by type and level of health facility (HF), and associated factors in Lagos State, Nigeria.Quantitative secondary data analysis of TB cases was conducted in 2015. χOverall, 2,064 persons with bacteriologically confirmed TB (15.5%) were not matched to patients in sampled TB registers. Treatment status was unknown for 86 cases (IQR 55-97) per LGA. LGAs with higher case-loads had higher proportions of cases with unknown TB status. Discrepant reporting of treated TB was also common (60% HFs). Primary-level TB treatment facilities and unengaged private facilities were less likely to notify.There was TB under-reporting across all types and levels of HFs and LGAs. There is a need to revise or strengthen the process of supervision and data quality assurance system at all levels.Le Nigeria a une prévalence de la TB estimée à 219 pour 100 000 habitants. En 2019, le Nigéria a diagnostiqué et notifié 27% des cas estimés par l’OMS de toutes les formes de TB et a contribué à 11% des cas de TB manquants dans le monde.Évaluer la sous-déclaration de la TB par type et niveau d’établissement de santé (HF), et les facteurs associés dans l’État de Lagos, au Nigeria.Une analyse quantitative des données secondaires des cas de TB a été réalisée en 2015. Le test χDans l’ensemble, 2 064 personnes ayant une TB confirmée par épreuve bactériologique (15,5%) n’ont pas été appariées à des patients dans les registres de TB échantillonnés. Le statut de traitement était inconnu pour 86 cas (IQR 55–97) par LGA. Les LGA ayant un plus grand nombre de cas avaient une plus grande proportion de cas dont le statut de traitement était inconnu. La déclaration discrète de la TB traitée était également fréquente (60% des HF). Les établissements de traitement de la TB de premier niveau et les établissements privés non engagés étaient moins susceptibles de faire des déclarations.Il y avait une sous-déclaration de la TB dans tous les types et niveaux d’HF et de LGA. Il est nécessaire de réviser ou de renforcer le processus de supervision et le système d’assurance qualité des données à tous les niveaux.

Mosonik, a 3.25 Ma extensively dissected stratovolcano located in the North Tanzanian Divergence of the East African Rift, consists predominantly of phonolite and three types of phonolitic nephelinite distinguished by the presence or absence of amphibole or garnet antecrysts and differing populations of complexly zoned antecrystal and phenocrystal pyroxenes. The antecryst–phenocryst assemblage is typical of hybrid lavas derived by magma mixing. Compositional data are given for all major minerals. Owing to the high modal proportions (30–60 vol. %) of antecrysts and phenocrysts of pyroxene and nepheline plus the hybrid character of the lavas, bulk-rock compositions do not represent those of the parental liquids. Thus, assimilation–fractional crystallization modelling of the bulk-rock major- and trace-element abundances is inappropriate and an unevolved parental magma cannot as yet be defined. Sr–Nd isotopic data for Mosonik and other Older Extrusive Series rocks suggest derivation by partial melting of ancient metasomatized lithospheric mantle with mixing of Sr and Nd from two sources coupled with minor lower crustal contamination, melting being induced by the plume currently impinging on the Tanzanian craton, and representing the initial interaction of the plume with the cratonic lithosphere. In contrast, the Younger Extrusives, as exemplified by Oldoinyo Lengai nephelinite–carbonatite volcanism, could be derived from this ancient metasomatized lithospheric mantle plus a recent plume-derived asthenospheric component and no contamination by crustal material. The isotopically and genetically distinct Natron–Engaruka melilitites are considered to represent direct adiabatic melting of the Tanzanian plume without lithospheric contributions. Carbonatites and melilite-bearing nephelinites also occur at Mosonik but are not considered in this study as they are only a very minor volumetric component of the volcano.

Introduction: Post-surgical pain following dental implant placement surgery is typically managed with non-opioid analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. However, the comparative analgesic efficacy of over-the-counter doses of non-steroidal anti-inflammatory drugs and acetaminophen in implant patients is unknown. Therefore, we compared the analgesic and anti-inflammatory effects of naproxen sodium and acetaminophen after surgical placement of one or two dental implants.Methods: Adult patients were treated with naproxen sodium (440 mg loading dose +220 mg q8h, n = 15) or acetaminophen (1,000 mg q6h—max daily dose 3,000 mg, n = 15) for 3 days after implant placement in a randomized, double-blind design. Pain was assessed on a 0–10 scale every 20 min for 6 h after study medication treatment. Tramadol (50 mg) was available as a rescue medication. Plasma and gingival crevicular fluid (GCF) were collected prior to the surgery and 0, 1, 2, 4, 6, 24, and 72 h after surgery for quantification of interleukin (IL)-6, IL-8, and IL-1β levels.Results: Pain scores were significantly lower in patients treated with naproxen sodium compared to those treated with acetaminophen. Inflammatory mediator levels in plasma and gingival crevicular fluid increased after surgery and returned to near baseline levels by 72 h. Plasma IL-6 levels were significantly lower 6 h after surgery in patients treated with naproxen sodium compared to acetaminophen. No differences in inflammatory mediator concentrations in gingival crevicular fluid were observed between the treatment groups. The number of implants placed and body mass index (BMI) influenced inflammatory mediator concentrations in plasma and gingival crevicular fluid, respectively.Discussion: Naproxen sodium was more effective than acetaminophen in reducing post-operative pain and systemic inflammation following surgical placement of one or two dental implants. Further studies are needed to determine whether these findings are applicable to more complex implant cases and how they affect clinical outcomes following implant placement.Clinical Trial Registration:ClinicalTrials.gov, identifier NCT04694300

Choice behavior requires animals to evaluate both short- and long-term advantages and disadvantages of all potential alternatives. Impulsive choice is traditionally measured in laboratory tasks by utilizing delay discounting (DD), a paradigm that offers a choice between a smaller immediate reward, or a larger more delayed reward. This study tested a large sample of Heterogeneous Stock (HS) male (n = 896) and female (n = 898) rats, part of a larger genetic study, to investigate whether measures of reward maximization overlapped with traditional models of delay discounting via the patch depletion model using a Sequential Patch Depletion procedure. In this task, rats were offered a concurrent choice between two water “patches” and could elect to “stay” in the current patch or “leave” for an alternative patch. Staying in the current patch resulted in decreasing subsequent reward magnitudes, whereas the choice to leave a patch was followed by a delay and a resetting to the maximum reward magnitude. Based on the delay in a given session, different visit durations were necessary to obtain the maximum number of rewards. Visit duration may be analogous to an indifference point in traditional DD tasks. While differences in traditional DD measures (e.g., delay gradient) have been detected between males and females, these effects were small and inconsistent. However, when examining measures of reward maximization, females made fewer patch changes at all delays and spent more time in the patch before leaving for the alternative patch compared to males. This pattern of choice resulted in males having a higher rate of reinforcement than females. Consistent with this, there was some evidence that females deviated from the optimal more, leading to less reward. Measures of reward maximization were only weakly associated with traditional DD measures and may represent distinctive underlying processes. Taken together, females performance differed from males with regard to reward maximization that were not observed utilizing traditional measures of DD, suggesting that the patch depletion model was more sensitive to modest sex differences when compared to traditional DD measures in a large sample of HS rats.

Polymeric foams, embedded with nano-scale conductive particles, have previously been shown to display quasi-piezoelectric (QPE) properties; i.e., they produce a voltage in response to rapid deformation. This behavior has been utilized to sense impact and vibration in foam components, such as in sports padding and vibration-isolating pads. However, a detailed characterization of the sensing behavior has not been undertaken. Furthermore, the potential for sensing quasi-static deformation in the same material has not been explored. This paper provides new insights into these self-sensing foams by characterizing voltage response vs frequency of deformation. The correlation between temperature and voltage response is also quantified. Furthermore, a new sensing functionality is observed, in the form of a piezoresistive response to quasi-static deformation. The piezoresistive characteristics are quantified for both in-plane and through-thickness resistance configurations. The new functionality greatly enhances the potential applications for the foam, for example, as insoles that can characterize ground reaction force and pressure during dynamic and/or quasi-static circumstances, or as seat cushioning that can sense pressure and impact.

The development and evaluation of an interprofessional education (IPE) pre-professional geriatrics experience involving learners from 10 different health discipline programs is described. The experience provided learners with opportunities to use small-group collaborative approaches in two 3-hour interprofessional sessions. Learners gained exposure to geriatric principles and awareness of the needs of older adults and their families using case studies developed by experienced interprofessional faculty. Learners completed pre- and post-experience surveys and worksheets on their confidence to function in interprofessional teams, knowledge of other disciplines, perceptions of importance of each discipline in providing older adult care, and the qualities considered for a successful team. Data were collected over three offerings of the experience (2016, 2017, 2018) and analyzed using paired sample t-tests and ANOVA. A total of 562 learners participated with outcome measures indicating increased knowledge of older adult services different health professionals provide and increased confidence in knowing when to complete care referrals. Mean increase in learners' confidence to function in interprofessional teams was significant, suggesting the experience was effective in facilitating confidence in functioning and improving views of other disciplines' roles. This experience demonstrated that learners gained exposure to apply geriatric principle skills and critical thinking as interprofessional team members.

The time and processes of hydrothermal mineralization are long-standing problems in geology. This work addresses these questions with reference to the Maoniuping giant rare earth elements (REE) deposit (southwest China), which has rare earth oxides (REO) reserves of 3.17 million tons with an average grade of 2.95 wt%. Bastnäsite is the dominant economic mineral, occurring as four distinct paragenetic types in the Maoniuping syenite–carbonatite complex: (1) primary euhedral bastnäsite (type-A) in syenite, with isolated melt inclusions; (2) macro-crystalline tabular euhedral bastnäsite (type-B) in pegmatitic dikes, with a diverse variety of fluid inclusions; (3) fine-grained, anhedral veinlet-disseminated bastnäsite (type-C) in syenite; and (4) coarse-grained anhedral bastnäsite (type-D) in carbonatite dikes, occurring as veinlets or interstitial to calcite, fluorite, and barite. From the paragenetic and compositional variations, it is inferred that type-A bastnäsite is of primary magmatic origin, whereas the other three types have characteristics of hydrothermal origins. In situ LA-ICP-MS U-Pb geochronology of the four types of bastnäsite results in lower intercept ages of 28.2 ± 0.5 Ma (n = 95, MSWD = 5.10), 27.8 ± 0.4 Ma (n = 43, MSWD = 0.73), 26.8 ± 0.7 Ma (n = 50, MSWD = 0.83), and 25.8 ± 0.7 Ma (n = 55, MSWD = 1.70), respectively, which are consistent with the weighted average 206Pb/238U and 208Pb/232Th ages by 207Pb-correction method. Compositional variations of clinopyroxene and apatite from the associated syenite, pegmatitic and carbonatitic dikes indicate a genetic relationship of the Maoniuping alkaline complex. The compositions of clinopyroxene range from Ae44–67Di14–18Hd17–41 in pegmatitic dikes, Ae43–66Di6–20Hd21–38 in carbonatitic dikes to Ae68–90Di0–3Hd10–30 in syenite. Apatites in the pegmatitic and carbonatitic dikes have similar compositions with higher F, total REE, and Sr, and lower CaO contents than those in the syenite, which suggests a cogenetic origin for the associated pegmatite and carbonatite. Clinopyroxene and apatite compositions suggest that the pegmatitic melt might differentiate directly from the initial carbonatitic melt rather than the syenitic magma. The bastnäsite U-Pb geochronology and minerals data indicate continuous magmatic-hydrothermal evolution for the REE mineralization in the Maoniuping alkaline complex.

Objectives: Tuberculosis (TB) stigma contributes to diagnostic delay, disease concealment, and reduced wellbeing for affected individuals. Despite the availability of several TB stigma scales, most high-TB burden countries do not have a culturally validated version available. This study evaluated the Van Rie TB stigma scale (VTSS) among people with TB in Vietnam. Methods: This study consisted of two phases. In phase 1, the VTSS was culturally and linguistically adapted to the Vietnamese context. In phase 2, people with TB were invited to complete a survey containing the VTSS, a depression scale, and a quality of life scale. The data analysis included confirmatory factor analysis (CFA), exploratory factor analysis (EFA), construct validity, and floor or ceiling effects. Results: In phase 1, items were reworded from the third person to the first person. The TB/HIV co-infection items (items 7 and 11) were the least relevant for people with TB (62% and 73% relevance, respectively). In phase 2, the CFA demonstrated adequate goodness-of-fit indices (GFI = 0.88, CFI = 0.96, RMSEA = 0.058); however several of the item factor loadings were low. The EFA demonstrated good internal consistency (α = 0.85) and revealed one dominant factor. Construct validity was low. Conclusions: The VTSS demonstrated good psychometric properties in Vietnam. Depending on the purpose of the scale, the HIV co-infection items and item 10 could be considered for removal.

Chronic low back pain (cLBP) is a prevalent and multifactorial ailment. No single treatment has been shown to dramatically improve outcomes for all cLBP patients, and current techniques of linking a patient with their most effective treatment lack validation. It has long been recognized that spinal pathology alters motion. Therefore, one potential method to identify optimal treatments is to evaluate patient movement patterns (i.e., motion-based phenotypes). Biomechanists, physical therapists, and surgeons each utilize a variety of tools and techniques to qualitatively assess movement as a critical element in their treatment paradigms. However, objectively characterizing and communicating this information is challenging due to the lack of economical, objective, and accurate clinical tools. In response to that need, we have developed a wearable array of nanocomposite stretch sensors which accurately capture the lumbar spinal kinematics, the SPINE Sense System. Data collected from this device are used to identify movement-based phenotypes and analyze correlations between spinal kinematics and patient-reported outcomes. The purpose of this paper is twofold: first, to describe the design and validity of the SPINE Sense System; and second, to describe the protocol and data analysis towards the application of this equipment to enhance understanding of the relationship between spinal movement patterns and patient metrics, which will facilitate the identification of optimal treatment paradigms for cLBP.

The stability of delay discounting across time has been well-established. However, limited research has examined the stability of probability discounting, and no studies of the stability of effort discounting are available. The present study assessed the steady-state characteristics of delay, probability, and effort discounting tasks across time with hypothetical rewards in humans, as well as whether response characteristics suggested a common discounting equation. Participants completed delay, probability, and effort discounting tasks on three occasions. We found moderate relative stability of delay and probability tasks, and similar evidence for absolute stability across time for all tasks. The interclass correlations coefficient showed some correspondence across time points and tasks, and higher levels of between subject variability, especially for the effort discounting task, suggesting trait level variables has a stronger influence on performance than state level variables. Performance on the delay and probability tasks were moderately correlated and similar mathematical functions fit choice patterns on both tasks (hyperbolic), suggesting that delay and probability discounting processes shared some common elements. Lower correlations and different function fits suggested that effort discounting involves more unique features.

In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the NIH initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program‘s goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science.

The association between ferritin and transferrin saturation (TS), respectively, and all-cause mortality is unclear. Furthermore, the influence of concurrent inflammation has not been sufficiently elucidated. We investigated these associations and the effect of concurrently elevated C-reactive protein (CRP), and accordingly report the levels associated with lowest all-cause mortality for females and males with and without inflammation. Blood test results from 161,921 individuals were included. Statistical analyses were performed in sex-stratified subpopulations, with ferritin or TS level as continuous exposure variables, and were adjusted for age, co-morbidity and inflammation status using CRP. An interaction was used to investigate whether the effect of ferritin or TS on all-cause mortality was modified by inflammation status (CRP ≥ 10 mg/L or CRP < 10 mg/L). Low and high ferritin and TS levels were respectively associated with increased all-cause mortality in females and in males. These associations persisted with concurrent CRP ≥ 10 mg/L. The ferritin level associated with lowest mortality was 60 µg/L for females and 125 µg/L for males with CRP < 10 mg/L. It was 52 µg/L for females and 118 µg/L for males with CRP ≥ 10 mg/L. The TS level associated with lowest mortality was 33.9% for females and 32.3% for males with CRP < 10 mg/L. It was 28.7% for females and 30.6% for males with CRP ≥ 10 mg/L. Our findings can nuance clinical interpretation and further aid in defining recommended ranges for ferritin and TS.

The discovery of compounds and proteins from plants has greatly contributed to modern medicine. Vernonia amygdalina Del. (Compositae) is used by humans and primates for a variety of conditions including parasitic infection. This paper describes the serendipitous discovery that V. amygdalina extract was able to bind to, and functionally inhibit, active TGFβ1. The binding agent was isolated and identified as chlorophyll a-b binding protein AB96. Given that active TGFβ1 contributes to the pathology of many infectious diseases, inhibiting these processes may explain some of the benefits associated with the ingestion of this species. This is the first plant-derived cytokine-neutralizing protein to be described and paves the way for further such discoveries.

The blood pressure response to exercise is exaggerated in type 2 diabetes mellitus (T2DM). However, the underlying mechanisms remain unclear. It is hypothesized that one mechanism mediating the potentiated cardiovascular response in T2DM is the sensitization of chemically sensitive afferent neurons by activation of metaboreceptors. To test this hypothesis, we examined transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced cardiovascular responses in vivo and muscle afferent discharge ex vivo in T2DM rats. Additionally, TRPV1 and protein kinase C (PKC) protein levels in dorsal root ganglia (DRG) subserving skeletal muscle were assessed. For 14-16 weeks, Sprague-Dawley rats were given either a normal diet (control) or high fat diet in combination with a low dose (35 and 25 mg/kg) of streptozotocin (T2DM). Administration of capsaicin, TRPV1 agonist, in hindlimb evoked significantly greater increases in mean arterial pressure and renal sympathetic neve activity in decerebrated T2DM than control. In a muscle-nerve preparation, the discharge to capsaicin exposure in group IV afferents isolated from T2DM was likewise significantly augmented at a magnitude that was proportional to glucose concentration. Moreover, the discharge to capsaicin was potentiated by acute exposure of group IV afferents to a high glucose environment. T2DM showed significantly increased phospholyrated-TRPV1 and −PKCα levels in DRG neurons as compared with control. These findings suggest that group IV muscle afferents are sensitized by PKC-induced TRPV1 overactivity in early-stage T2DM with hyperglycemia and, thereby, may contribute to the potentiated circulatory response to TRPV1 activation in the disease.

Background The strength and size of core muscles, including the abdominal muscles, are crucial to proper function in most activities. Therefore, it is important to reliably assess these characteristics. Our primary objective was to determine if the length, thickness and cross-sectional area of the transversus abdominis (TrA) can be visualized independently from the internal and external abdominal oblique muscles using extended field of view ultrasound imaging at rest and with contraction and to establish its intra- and inter-tester reliability. Methods Twenty-six individuals were recruited to participate in the study (20 F, 6 M), average age 24.0 years (SD 9.4), height 170.7 cm (SD 8.6) and weight 63.9 kg (SD 9.0). From this total number of participants, two groups of 16 randomly selected participants were assessed to determine intra- and inter-tester reliability respectively. Extended field of view ultrasound images were obtained at three vertebral levels during rest and contraction in the side lying position for both the right and left sides of the trunk. Results Excellent intra-tester and inter-tester reliability was seen (ICC range of 0.972 to 0.984). The overall average percent standard error of the measurement for all measurements and locations was approximately 4%. The overall average minimal difference for the thickness measurement for the resting and contraction conditions combined were as follows: intratester 0.056 (0.014) cm and intertester 0.054 (0.017) cm, for area intratester 0.287 (0.086) cm2 and intertester 0.289 (0.101) cm2 and for length intratester 0.519 (0.097) cm and intertester 0.507 (0.085) cm. Conclusions Extended field of view ultrasound imaging is an effective method of reliably capturing clear images of the TrA during rest and contraction. It provides an efficient mechanism for the analysis of muscle morphology by being able to measure the cross-sectional area, thickness, and length on one image. This methodology is recommended for studies investigating TrA function and training.

Purpose Acyclovir is most commonly used for treating ocular Herpes Keratitis, a leading cause of infectious blindness. However, emerging resistance to Acyclovir resulting from mutations in the thymidine kinase gene of Herpes Simplex Virus −1 (HSV-1), has prompted the need for new therapeutics directed against a different viral protein. One novel target is the HSV-1 Processivity Factor which is essential for tethering HSV-1 Polymerase to the viral genome to enable long-chain DNA synthesis. Methods A series of peptides, based on the crystal structure of the C-terminus of HSV-1 Polymerase, were constructed with hydrocarbon staples to retain their alpha-helical conformation. The stapled peptides were tested for blocking both HSV-1 DNA synthesis and infection. The most effective peptide was further optimized by replacing its negative N-terminus with two hydrophobic valine residues. This di-valine stapled peptide was tested for inhibiting HSV-1 infection of human primary corneal epithelial cells. Results The stapled peptides blocked HSV-1 DNA synthesis and HSV-1 infection. The unstapled control peptide had no inhibitory effects. Specificity of the stapled peptides was confirmed by their inabilities to block infection by an unrelated virus. Significantly, the optimized di-valine stapled peptide effectively blocked HSV-1 infection in human primary corneal epithelial cells with selectivity index of 11.6. Conclusions Hydrocarbon stapled peptides that simulate the α-helix from the C-terminus of HSV-1 DNA polymerase can specifically block DNA synthesis and infection of HSV-1 in human primary corneal epithelial cells. These stapled peptides provide a foundation for developing a topical therapeutic for treating human ocular Herpes Keratitis.

Background and objectives: documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia. Methods: following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as >= 75% agreement and weak consensus as 50%-74% agreement. Results: seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29. Conclusion: by means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia., European Society of Regional Anaesthesia and Pain Therapy (ESRA); ASRA Pain Medicine

Lamproite is a rare ultrapotassic alkaline rock of petrological importance as it is considered to be derived from metasomatized lithospheric mantle, and of economic significance, being the host of major diamond deposits. A review of the nomenclature of lamproite results in the recommendation that members of the lamproite petrological clan be named using mineralogical-genetic classifications to distinguish them from other genetically unrelated potassic alkaline rocks, kimberlite, and diverse lamprophyres. The names “Group 2 kimberlite” and “orangeite” must be abandoned as these rock types are varieties of bona fide lamproite restricted to the Kaapvaal Craton. Lamproites exhibit extreme diversity in their mineralogy which ranges from olivine phlogopite lamproite, through phlogopite leucite lamproite and potassic titanian richterite-diopside lamproite, to leucite sanidine lamproite. Diamondiferous olivine lamproites are hybrid rocks extensively contaminated by mantle-derived xenocrystic olivine. Currently, lamproites are divided into cratonic (e.g. Leucite Hills, USA; Baifen, China) and orogenic (Mediterranean) varieties (e.g. Murcia-Almeria, Spain; Afyon, Turkey; Xungba, Tibet). Each cratonic and orogenic lamproite province differs significantly in tectonic setting and Sr–Nd–Pb–Hf isotopic compositions. Isotopic compositions indicate derivation from enriched mantle sources, having long-term low Sm/Nd and high Rb/Sr ratios, relative to bulk earth and depleted asthenospheric mantle. All lamproites are considered, on the basis of their geochemistry, to be derived from ancient mineralogically complex K–Ti–Ba–REE-rich veins, or metasomes, in the lithospheric mantle with, or without, subsequent contributions from recent asthenospheric or subducted components at the time of genesis. Lamproite primary magmas are considered to be relatively silica-rich (~50–60 wt.% SiO2), MgO-poor (3–12 wt.%), and ultrapotassic (~8–12 wt.% K2O) as exemplified by hyalo-phlogopite lamproites from the Leucite Hills (Wyoming) or Smoky Butte (Montana). Brief descriptions are given of the most important phreatomagmatic diamondiferous lamproite vents. The tectonic processes which lead to partial melting of metasomes, and/or initiation of magmatism, are described for examples of cratonic and orogenic lamproites. As each lamproite province differs with respect to its mineralogy, geochemical evolution, and tectonic setting there is no simple or common petrogenetic model for their genesis. Each province must be considered as the unique expression of the times and vagaries of ancient mantle metasomatism, coupled with diverse and complex partial melting processes, together with mixing of younger asthenospheric and lithospheric material, and, in the case of many orogenic lamproites, with Paleogene to Recent subducted material., La lamproïte est une roche alcaline ultrapotassique rare d'importance pétrologique car elle est considérée comme dérivée du manteau lithosphérique métasomatisé, et d'importance économique, étant l'hôte de gisements de diamants majeurs. Un examen de la nomenclature des lamproïtes conduit à la recommandation que les membres du clan pétrologique des lamproïtes soient nommés en utilisant des classifications minéralogiques génétiques pour les distinguer des autres roches alcalines potassiques génétiquement non liées, de la kimberlite et de divers lamprophyres. Les noms « kimberlite du groupe 2 » et « orangéite » doivent être abandonnés car ces types de roches sont des variétés de véritables lamproïtes restreintes au craton de Kaapvaal. Les lamproïtes présentent une extrême diversité dans leur minéralogie qui va de la lamproïte à phlogopite et olivine, à la lamproïte à leucite et phlogopite et de la lamproïte à richtérite-diopside potassique titanifère, à la lamproïte à sanidine et leucite. Les lamproïtes à olivine diamantifères sont des roches hybrides largement contaminées par l'olivine xénocristique dérivée du manteau. Actuellement, les lamproïtes sont divisées en variétés cratoniques (par exemple Leucite Hills, États-Unis; Baifen, Chine) et orogéniques (méditerranéennes) (par exemple Murcie-Almeria, Espagne; Afyon, Turquie; Xungba, Tibet). Chaque province de lamproïte cratonique et orogénique diffère significativement par le contexte tectonique et les compositions isotopiques en Sr, Nd, Pb et Hf. Les compositions isotopiques indiquent que leur source est un manteau enrichi, ayant à long terme des rapports Sm/Nd bas et Rb/Sr élevés, par rapport à la Terre globale et au manteau asthénosphérique appauvri. Toutes les lamproïtes sont considérées, sur la base de leur géochimie, comme étant dérivées d'anciennes veines minéralogiquement complexes riches en K, Ti, Ba et ETR, ou métasomes, dans le manteau lithosphérique avec ou sans contributions ultérieures de composants asthénosphériques ou subductés récents au moment de la genèse. Les magmas primaires de lamproïte sont considérés comme relativement riches en silice (~ 50–60% en poids de SiO2), pauvres en MgO (3–12% en poids) et ultrapotassiques (~ 8–12% en poids de K2O) comme le montrent les lamproïtes hyalo à phlogopite de Leucite Hills (Wyoming) ou de Smoky Butte (Montana). De brèves descriptions sont données des cheminées de lamproïtes diamantifères phréatomagmatiques les plus importantes. Les processus tectoniques qui conduisent à la fusion partielle des métasomes et / ou à l'initiation du magmatisme sont décrits comme des exemples de lamproïtes cratoniques et orogéniques. Comme chaque province de lamproïte diffère en ce qui concerne sa minéralogie, son évolution géochimique et son cadre tectonique, il n'y a pas de modèle pétrogénétique simple ou commun pour leur genèse. Chaque province doit être considérée comme l'expression unique de l'époque et des caprices du métasomatisme du manteau ancien, associée à des processus de fusion partielle divers et complexes, ainsi qu'à un mélange de matériaux asthénosphériques et lithosphériques plus jeunes et, dans le cas de nombreuses lamproïtes orogéniques, à du matériel paléogène à récent subducté.

We find the Colin de Verdiere number μ for all complete multipartite graphs and show that for any graph G there exists a reduction process that results in a complete multipartite graph H with μ ( G ) ≤ μ ( H ) . We give examples of the upper bounds that can be obtained via this process.

Patients with type 2 diabetes display an exaggerated pressor response to exercise. However, evidence supporting the association between the magnitude of the pressor response to exercise and insulin resistance-related factors including hemoglobin A1c (HbA1c) or homeostatic model assessment of insulin resistance (HOMA-IR) in nondiabetic subjects has remained sparse and inconclusive. Thus we investigated the relationship between cardiovascular responses to exercise and insulin resistance-related factors in nondiabetic healthy men (n = 23) and women (n = 22) above 60 yr old. We measured heart rate (HR) and blood pressure (BP) responses during: isometric handgrip (IHG) exercise of 30% maximal voluntary contraction, a period of skeletal muscle ischemia (SMI) induced by tourniqueting the arm after IHG, and rhythmic dynamic handgrip (DHG) exercise during SMI. Greater diastolic BP (DBP) responses to DHG with SMI was associated with male sex (r = 0.44, P = 0.02) and higher HbA1c (r = 0.33, P = 0.03), heart-ankle pulse wave velocity (haPWV) (r = 0.45, P < 0.01), and resting systolic BP (SBP) (r = 0.36, P = 0.02). HbA1c persisted as a significant determinant explaining the variance in the DBP response to DHG with SMI in multivariate models despite adjustment for sex, haPWV, and resting SBP. It was also determined that the DBP response to DHG with SMI in a group in which HOMA-IR was abnormal (Δ33 ± 3 mmHg) was significantly higher than that of groups in which HOMA-IR was at intermediate (Δ20 ± 4 mmHg) and normal (Δ23 ± 2 mmHg) levels. These data suggest that even in nondiabetic older adults, insulin resistance is related to an exaggerated pressor response to exercise especially when performed under ischemic conditions. NEW & NOTEWORTHY The diastolic blood pressure response to rhythmic dynamic handgrip exercise under ischemic conditions was demonstrated to be correlated with insulin resistance-related factors in nondiabetic older adults. This finding provides important insight to the prescription of exercise in this particular patient population as the blood pressure response to exercise, especially under ischemic conditions, could be exaggerated to nonsafe levels.

An acute bout of distance running decreases Achilles tendon CSA. The purpose of this study was to examine if three-week stretch training of the Achilles tendon alters the Achilles tendon thinning response to running. Thirty-three recreational runners were divided into a control group (n = 17) and an intervention group (n = 16). The intervention included a three-week soleus stretch (knee flexed) and gastrocnemius stretch (knee extended). Three gastrocnemius stretches and three soleus stretches were performed each day, six days per week. Stretches were held for 30 s per repetition for a total duration of 180 s per leg per day. Achilles tendon CSA and range of motion measures were completed pre and post-run before and after the three-week stretching intervention. The runs prior to and following the three-week stretch training intervention both resulted in a 6% decrease in Achilles tendon CSA (p < 0.0001). There was no interaction across time between control and intervention groups in CSA (p = 0.446). Only the intervention group experienced a significant increase in dorsiflexion range of motion following the stretch training (p = 0.009). We therefore conclude that even when an increased dorsiflexion range of motion occurs, three weeks of triceps surae stretching does not alter the response of the Achilles tendon CSA.

Background Transition to clerkship courses bridge the curricular gap between preclinical and clinical medical education. However, despite the use of simulation-based teaching techniques in other aspects of medical training, these techniques have not been adequately described in transition courses. We describe the development, structure and evaluation of a simulation-based transition to clerkship course. Approach Beginning in 2012, our institution embarked upon an extensive curricular transformation geared toward competency-based education. As part of this effort, a group of 12 educators designed, developed and implemented a simulation-based transition course. The course curriculum involved seven goals, centered around the 13 Association of American Medical Colleges Core Entrustable Professional Activities for entering residency. Instructional techniques included high-fidelity simulation, and small and large group didactics. Student competency was determined through a simulation-based inpatient-outpatient objective structured clinical examination, with real-time feedback and remediation. The effectiveness of the course was assessed through a mixed methods approach involving pre- and post-course surveys and a focus group. Evaluation Of 166 students, 152 (91.6%) completed both pre- and post-course surveys, and nine students participated in the focus group. Students reported significant improvements in 21 out of 22 course objectives. Qualitative analysis revealed three key themes: learning environment, faculty engagement and collegiality. The main challenge to executing the course was procuring adequate faculty, material and facility resources. Reflection This simulation-based, resource-heavy transition course achieved its educational objectives and provided a safe, supportive learning environment for practicing and refining clinical skills. Electronic supplementary material The online version of this article (10.1007/s40037-020-00590-4) contains supplementary material, which is available to authorized users.

PURPOSE This study aimed to investigate if the Functional Movement Screen (FMS) total score, individual component test scores, or number of asymmetries can predict noncontact injury risk over three consecutive seasons of National Collegiate Athletic Association Division I football. METHODS Because football teams comprise individuals with vastly different physical characteristics and playing responsibilities, we divided the subjects into three homogeneous groups based on position (big, combo, and skill). Each FMS score was assessed with regard to the total team score and by individual position groups. For our injury analysis, we also controlled for exposure. Two hundred and eight National Collegiate Athletic Association Division I athletes participated over three consecutive seasons, yielding a total of 343 observations. RESULTS There was no significant relationship between total FMS score and likelihood of injury when analyzed by the total team or by position group. These findings were the same for all groups, for both the total number of injuries and injuries weighted by injury exposure. The only significant findings occurred when we considered individual test item scores to injury by position group. We only found a significant relationship in the expected direction with push-up stability in the combo group. CONCLUSIONS FMS was not a good predictor of noncontact injury.

Injury of the tooth pulp is excruciatingly painful and yet the receptors and neural circuit mechanisms that transmit this form of pain remain poorly defined in both the clinic and preclinical rodent models. Easily quantifiable behavioral assessment in the mouse orofacial area remains a major bottleneck in uncovering molecular mechanisms that govern inflammatory pain in the tooth. In this study we sought to address this problem using the Mouse Grimace Scale and a novel approach to the application of mechanical Von Frey hair stimuli. We use a dental pulp injury model that exposes the pulp to the outside environment, a procedure we have previously shown produces inflammation. Using RNAscope technology, we demonstrate an upregulation of genes that contribute to the pain state in the trigeminal ganglia of injured mice. We found that mice with dental pulp injury have greater Mouse Grimace Scores than sham within 24 hours of injury, suggestive of spontaneous pain. We developed a scoring system of mouse refusal to determine thresholds for mechanical stimulation of the face with Von Frey filaments. This method revealed that mice with a unilateral dental injury develop bilateral mechanical allodynia that is delayed relative to the onset of spontaneous pain. This work demonstrates that tooth pain can be quantified in freely behaving mice using approaches common for other types of pain assessment. Harnessing these assays in the orofacial area during gene manipulation should assist in uncovering mechanisms for tooth pulp inflammatory pain and other forms of trigeminal pain.

Some food and ferment manufacturing steps such as spray-drying result in the application of viscous stresses to bacteria. This study explores how a viscous flow impacts both bacterial adhesion functionality and bacterial cell organization using a combined experimental and modeling approach. As a model organism we study Lactobacillus rhamnosus GG (LGG) "wild type" (WT), known to feature strong adhesive affinities towards beta-lactoglobulin thanks to pili produced by the bacteria on cell surfaces, along with three cell-surface mutant strains. Applying repeated flows with high shear-rates reduces bacterial adhesive abilities up to 20% for LGG WT. Bacterial chains are also broken by this process, into 2-cell chains at low industrial shear rates, and into single cells at very high shear rates. To rationalize the experimental observations we study numerically and analytically the Stokes equations describing viscous fluid flow around a chain of elastically connected spheroidal cell bodies. In this model setting we examine qualitatively the relationship between surface traction (force per unit area), a proxy for pili removal rate, and bacterial chain length (number of cells). Longer chains result in higher maximal surface tractions, particularly at the chain extremities, while inner cells enjoy a small protection from surface tractions due to hydrodynamic interactions with their neighbors. Chain rupture therefore may act as a mechanism to preserve surface adhesive functionality in bacteria.

Systemic insulin administration evokes sympathoexcitatory actions, but the mechanisms underlying these observations are unknown. We reported that insulin sensitizes the response of thin-fibre primary afferents, as well as the dorsal root ganglion (DRG) that subserves them, to mechanical stimuli. However, little is known about the effects of insulin on primary neuronal responses to chemical stimuli. TRPV1, whose agonist is capsaicin (CAP), is widely expressed on chemically sensitive metaboreceptors and/or nociceptors. The aim of this investigation was to determine the effects of insulin on CAP-activated currents in small DRG neurons and CAP-induced action potentials in thin-fibre muscle afferents of normal healthy rodents. Additionally, we investigated whether insulin potentiates sympathetic nerve activity (SNA) responses to CAP. In whole-cell patch-clamp recordings from cultured mice DRG neurons in vitro, the fold change in CAP-activated current from pre- to post-application of insulin (n = 13) was significantly (P 0.05) higher than with a vehicle control (n = 14). Similar results were observed in single-fibre recording experiments ex vivo as insulin potentiated CAP-induced action potentials compared to vehicle controls (n = 9 per group, P 0.05). Furthermore, insulin receptor blockade with GSK1838705 significantly suppressed the insulin-induced augmentation in CAP-activated currents (n = 13) as well as the response magnitude of CAP-induced action potentials (n = 9). Likewise, the renal SNA response to CAP after intramuscular injection of insulin (n = 8) was significantly (P 0.05) greater compared to vehicle (n = 9). The findings suggest that insulin potentiates TRPV1 responsiveness to CAP at the DRG and muscle tissue levels, possibly contributing to the augmentation in sympathoexcitation during activities such as physical exercise. KEY POINTS: Evidence suggests insulin centrally activates the sympathetic nervous system, and a chemical stimulus to tissues activates the sympathetic nervous system via thin fibre muscle afferents. Insulin is reported to modulate putative chemical-sensitive channels in the dorsal root ganglion neurons of these afferents. In the present study, it is demonstrated that insulin potentiates the responsiveness of thin fibre afferents to capsaicin at muscle tissue levels as well as at the level of dorsal root ganglion neurons. In addition, it is demonstrated that insulin augments the sympathetic nerve activity response to capsaicin in vivo. These data suggest that sympathoexcitation is peripherally mediated via insulin-induced chemical sensitization. The present study proposes a possible physiological role of insulin in the regulation of chemical sensitivity in somatosensory thin fibre muscle afferents.

A detailed petrographic and mineralogical investigation of olivine-phlogopite micro-ijolite xenoliths from Oldoinyo Lengai, Tanzania indicates a complex evolutional history. These xenoliths consist of diverse textural subdomains characterized by minerals ranging from early-formed olivine, through diopside-hosted perovskite and phlogopite, to evolved aegirine-augite and titanite. Thermometry and mineral compositions in the subdomains suggest crystallization temperatures from 1070–970 °C to 850–700 °C at plutonic pressures and SiO2-activities controlled by perovskite-titanite equilibria. Double coronas are a characteristic textural feature of the olivine-phlogopite micro-ijolite, consisting of olivine cores surrounded by an inner clinopyroxene corona and an outer phlogopite corona. These double coronas might have formed during early magma chamber processes, including magma movement to a subsequent chamber resulting in dissolution of olivine with subsequent crystallization and accumulation of diopside and phlogopite. Diopside−aegirine-augite compositional zonation indicates several magma injections followed by cooling periods, during the formation of micro-ijolite groundmass. Mg# (80–83) and Ca (0.1–0.3 in wt%) contents of olivine together with the presence of primary melt inclusions in clinopyroxene, phlogopite, and nepheline indicate a magmatic origin from a possible parental olivine-nephelinite melt. There is evidence for subsolidus, or near-solidus, re-equilibration processes as indicated by the reaction of olivine with titanite forming symplectitic textures of ilmenite and diopside with minor zirconolite. Ti-exchange between phlogopite phenocrysts and other Ti-bearing minerals (perovskite, titanite, magnetite) resulted in ∼750 °C equilibrium temperatures for phlogopite, which are much lower than mafic magmatic (>900 °C) conditions. Calculated subsolidus temperatures suggest crystallization of olivine-phlogopite micro-ijolites over a 10–20 km depth interval.

Poor intervertebral disc (IVD) health is associated with low back pain (LBP). This 12-week parallel randomised controlled trial will evaluate the efficacy of a progressive interval running programme on IVD health and other clinical outcomes in adults with chronic LBP. Participants will be randomised to either a digitally delivered progressive interval running programme or waitlist control. Participants randomised to the running programme will receive three individually tailored 30 min community-based sessions per week over 12 weeks. The waitlist control will undergo no formal intervention. All participants will be assessed at baseline, 6 and 12 weeks. Primary outcomes are IVD health (lumbar IVD T2 via MRI), average LBP intensity over the prior week (100-point visual analogue scale) and disability (Oswestry Disability Index). Secondary outcomes include a range of clinical measures. All outcomes will be analysed using linear mixed models. This study has received ethical approval from the Deakin University Human Research Ethics Committee (ID: 2022-162). All participants will provide informed written consent before participation. Regardless of the results, the findings of this study will be disseminated, and anonymised data will be shared via an online repository. This will be the first study to evaluate whether a progressive interval running programme can improve IVD health in adults with chronic LBP. Identifying conservative options to improve IVD health in this susceptible population group has the potential to markedly reduce the burden of disease. This study was registered via the Australian New Zealand Clinical Trials Registry on 29 September 2022 (ACTRN12622001276741).

IMPORTANCE: For critically ill adults undergoing emergency tracheal intubation, failure to intubate the trachea on the first attempt occurs in up to 20% of cases and is associated with severe hypoxemia and cardiac arrest. Whether using a tracheal tube introducer (“bougie”) increases the likelihood of successful intubation compared with using an endotracheal tube with stylet remains uncertain. OBJECTIVE: To determine the effect of use of a bougie vs an endotracheal tube with stylet on successful intubation on the first attempt. DESIGN, SETTING, AND PARTICIPANTS: The Bougie or Stylet in Patients Undergoing Intubation Emergently (BOUGIE) trial was a multicenter, randomized clinical trial among 1102 critically ill adults undergoing tracheal intubation in 7 emergency departments and 8 intensive care units in the US between April 29, 2019, and February 14, 2021; the date of final follow-up was March 14, 2021. INTERVENTIONS: Patients were randomly assigned to use of a bougie (n = 556) or use of an endotracheal tube with stylet (n = 546). MAIN OUTCOMES AND MEASURES: The primary outcome was successful intubation on the first attempt. The secondary outcome was the incidence of severe hypoxemia, defined as a peripheral oxygen saturation less than 80%. RESULTS: Among 1106 patients randomized, 1102 (99.6%) completed the trial and were included in the primary analysis (median age, 58 years; 41.0% women). Successful intubation on the first attempt occurred in 447 patients (80.4%) in the bougie group and 453 patients (83.0%) in the stylet group (absolute risk difference, −2.6 percentage points [95% CI, −7.3 to 2.2]; P = .27). A total of 58 patients (11.0%) in the bougie group experienced severe hypoxemia, compared with 46 patients (8.8%) in the stylet group (absolute risk difference, 2.2 percentage points [95% CI, −1.6 to 6.0]). Esophageal intubation occurred in 4 patients (0.7%) in the bougie group and 5 patients (0.9%) in the stylet group, pneumothorax was present after intubation in 14 patients (2.5%) in the bougie group and 15 patients (2.7%) in the stylet group, and injury to oral, glottic, or thoracic structures occurred in 0 patients in the bougie group and 3 patients (0.5%) in the stylet group. CONCLUSIONS AND RELEVANCE: Among critically ill adults undergoing tracheal intubation, use of a bougie did not significantly increase the incidence of successful intubation on the first attempt compared with use of an endotracheal tube with stylet. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03928925

Introduction The most common cancers in the UK are keratinocyte cancers (KCs): the combined term for basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (cSCCs). Registration of KC is challenging due to high numbers and multiplicity of tumours per person. Methods We provide an updated report on the descriptive epidemiology of trends in KC incidence for the resident populations of UK countries (England, Northern Ireland, Scotland and Wales) using population‐based cancer registry and pathology report data, 2013–18. Results Substantial increases in cSCC incidence in England, Scotland and Northern Ireland can be detected for the period of 2013–18, and the incidence of cSCC also increased in Wales from 2016 to 2018. In contrast, however, the pattern of annual change in the incidence of BCC across the nations differs. In England, the incidence of BCC declined slightly from 2016 to 2018, however, the overall trend across 2013–18 is not statistically significant. In Scotland, the incidence of BCC shows some variability, declining in 2017 before increasing in 2018, and the overall trend across 2013–18 was also not statistically significant. In Northern Ireland, the incidence of BCC increased significantly over the study period, and in Wales, the incidence of BCC increased from 2016 to 2018. One in five people will develop non‐melanoma skin cancers (NMSC) in their lifetime in England. This estimate is much higher than the lifetime risk of melanoma (1 in 36 males and 1 in 47 females born after 1960 in the UK), which further highlights the burden of the disease and importance of early prevention strategies. Conclusions We highlight how common these tumours are by publishing the first ever lifetime incidence of NMSC. Additionally, the first time reporting of the age standardised incidence of KC in Wales further confirms the scale of the disease burden posed by these cancers in the UK. With approximately one in five people developing NMSC in their lifetime, optimisation of skin cancer prevention, management and research are essential.