The role of cultural, community and natural assets in addressing societal and structural health inequalities in the UK: future research priorities.

BACKGROUND: Reducing health inequalities in the UK has been a policy priority for over 20 years, yet, despite efforts to create a more equal society, progress has been limited. Furthermore, some inequalities have widened and become more apparent, particularly during the Covid-19 pandemic. With growing recognition of the uneven distribution of life expectancy and of mental and physical health, the current research was commissioned to identify future research priorities to address UK societal and structural health inequalities. METHODS: An expert opinion consultancy process comprising an anonymous online survey and a consultation workshop were conducted to investigate priority areas for future research into UK inequalities. The seven-question survey asked respondents (n = 170) to indicate their current role, identify and prioritise areas of inequality, approaches and evaluation methods, and comment on future research priorities. The workshop was held to determine areas of research priority and attended by a closed list of delegates (n = 30) representing a range of academic disciplines and end-users of research from policy and practice. Delegates self-selected one of four breakout groups to determine research priority areas in four categories of inequality (health, social, economic, and other) and to allocate hypothetical sums of funding (half, one, five, and ten million pounds) to chosen priorities. Responses were analysed using mixed methods. RESULTS: Survey respondents were mainly 'academics' (33%), 'voluntary/third sector professionals' (17%), and 'creative/cultural professionals'(16%). Survey questions identified the main areas of inequality as 'health' (58%), 'social care' (54%), and 'living standards' (47%). The first research priority was 'access to creative and cultural opportunities' (37%), second, 'sense of place' (23%), and third, 'community' (17%). Approaches seen to benefit from more research in relation to addressing inequalities were 'health/social care' (55%), 'advice services' (34%), and 'adult education/training' (26%). Preferred evaluation methods were 'community/participatory' (76%), 'action research' (62%), and 'questionnaires/focus groups' (53%). Survey respondents (25%) commented on interactions between inequalities and issues such as political and economic decisions, and climate. The key workshop finding from determining research priorities in areas of inequality was that health equity could only be achieved by tackling societal and structural inequalities, environmental conditions and housing, and having an active prevention programme. CONCLUSIONS: Research demonstrates a clear need to assess the impact of cultural and natural assets in reducing inequality. Collaborations between community groups, service providers, local authorities, health commissioners, GPs, and researchers using longitudinal methods are needed within a multi-disciplinary approach to address societal and structural health inequalities.

Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole-exome sequencing on five families in which second- and third-degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes. Among these, a novel private missense C1143F variant in the second intracellular loop of the voltage-gated sodium channel NaV1.7, encoded by the SCN9A gene, was identified in one family. Through electrophysiological analysis, we show that NaV1.7C1143F exhibits partial loss-of-function effects, resulting in slower recovery from inactivation and decreased excitability in cultured cortical neurons. Furthermore, for the same intracellular loop of NaV1.7, we found an excess of rare variants in a case-control variant-burden study. Functional analysis of one of these variants, M932L/V991L, also demonstrated reduced firing in cortical neurons. However, although this variant is rare in Caucasians, it is frequent in Latino population, suggesting that genetic background can alter its effects on phenotype. Although the involvement of the SCN1A and SCN2A genes encoding NaV1.1 and NaV1.2 channels in de novo ASD has previously been demonstrated, our study indicates the involvement of inherited SCN9A variants and partial loss-of-function of NaV1.7 channels in the etiology of rare familial ASD.

Predictors of referral uptake in children with disabilities in Bangladesh--exploring barriers as a first step to improving referral provision.

PURPOSE: Making services available to children with disabilities in low- and middle-income countries does not guarantee their use. This study aims to identify factors associated with the uptake of referrals in order to investigate barriers to service use. METHODS: Children with impairments identified in two districts of Bangladesh were invited to attend screening camps where their condition was confirmed; they were provided with referrals for rehabilitation and treatment services. Predictors of referral uptake were identified using logistic regression. RESULTS: Overall referral uptake was 47%, 32% in Sirajganj and 61% in Natore. There was no association between age or gender and referral uptake. Factors predictive of referral uptake were higher income in Sirajganj (OR=2.6 95%CI 1.4-5.0), and the districts combined (OR=1.6 95%CI 1.1-2.1); maternal literacy in Natore (OR=1.6 95%CI 1.0-2.5); and epilepsy in all three models (Sirajganj: OR=2.6 95%CI 1.7-4.0; Natore: OR=13.5 95%CI 6.5-28.3; Combined: OR=4.6 95%CI 3.3-6.5). Physical impairment was associated with increased odds of uptake in Sirajganj and in the combined model (OR=2.7 95%CI 1.8-4.1; OR=3.34 95%CI 2.2-5.2). CONCLUSIONS: Even when some logistical and financial assistance is available, children with impairment from low-income families may require additional support to take up referrals. There may be greater willingness to accept treatment that is locally provided, such as medication for epilepsy or therapy at village level.

Hierarchies of damage induced loss of mechanical properties in calcified bone after in vivo fatigue loading of rat ulnae.

During fatigue loading of whole bone, damage to bone tissue accumulates, coalesces and leads to fractures. Whether damage affects tissue material properties similarly at the nanoscale (less than 1 µm), microscale (less than 1 mm), and whole bone scale has not been fully evaluated. Therefore, in this study, we examine scale-dependent loss of calcified tissue material properties in rat ulnae, after fatigue loading of rat forearms using the forearm compression model. In vivo fatigue loading was conducted on the right forearms until a displacement end-point was reached. The non-fatigued left forearms served as contralateral controls. Subsequently, three-point bending tests to failure on excised ulnae demonstrated a 41% and 49% reduction in the stiffness and ultimate strength as compared to contralateral control ulnae, respectively. Depth-sensing microindentation demonstrated an average decrease in material properties, such as elastic modulus and hardness, of 28% and 29% respectively. Nanoindentation measured elastic modulus and hardness were reduced by 26% and 29% in damaged bone relative to contralateral controls, respectively. The increased loss of whole bone material properties compared to tissue material properties measured using indentation is mainly attributed to the presence of a macrocrack located in the medial compressive region at the site of peak strains. The similar magnitude of changes in material properties by microindentation and nanoindentation is attributed to damage that may originate at an even smaller scale, as inferred from 10% differences in connectivity of osteocyte canaliculi in damaged bone.

Effect of the presence or absence of J chain on expression of recombinant anti-Kell immunoglobulin M.

The aim of this study was to determine the effect of expressing a recombinant anti-Kell immunoglobulin (Ig) M from two cell lines, CH0 and NS0, on its ability to function as a diagnostic antibody. As a polymeric immunoglobulin, IgM is able to directly agglutinate red blood cells (RBCs), making it a useful blood grouping reagent. To simplify expression, recombinant human IgM (rIgM) from NS0 (a mouse myeloma line) and CHO (Chinese hamster ovary line) cells was expressed in the absence of human J chain. Whereas NS0 expresses mouse J chain, rIgM expressed from CH0 cells lack J chain. Although the ability to polymerize resides within the tailpiece of IgM heavy chain, J chain can influence the polymeric state. This in turn could affect the ability of rIgM to bind its antigen. The variable region of the heavy chain of an anti-Kell IgG was grafted onto the constant region of human IgM and co-expressed with light chain derived from the same antibody. rIgM was purified from each cell line and the strength of direct agglutination assessed. Both cell lines produced polymeric rIgM that was able to specifically bind the target antigen and to directly agglutinate RBCs to the same degree. The presence or absence of J chain did not affect the ability of the rIgM to bind the Kell antigen or the strength of agglutination. The presence of J chain is not required for the production of a functional rIgM for use as a diagnostic reagent. CHO and NS0 lines are both suitable for production of such a reagent.

Indications for and anticipated difficulty of third molar surgery: a comparison between a dental hospital and a specialist high street practice.

OBJECTIVE: To investigate the indications for and anticipated difficulty of third molar surgery between two different referral settings. DESIGN: A prospective study involving completion of a proforma pre- and post-operatively. SETTING: A dental teaching hospital and a specialist surgical dentistry practice in 2003. SUBJECTS AND METHODS: Patients referred for the assessment of their third molars were recruited. Details of the clinical and radiographical assessment for each patient were recorded pre-operatively and the extent of surgery required post-operatively. RESULTS: The main indication for referral for third molar extraction was pericoronitis in both centres. A larger number of patients were assessed and treated in a shorter period of time at the surgical dentist compared with the dental hospital. The surgical dentist was accurate in his assessment of the difficulty of surgery 96% of the time compared with 66% for the dental hospital staff. CONCLUSIONS: This study highlights the benefits for patients in being treated by a surgical dentist. As dental students require exposure to surgical dentistry in order to attain a level of competence, a reduction in the number of patients being referred to dental hospitals may impact upon students' ability to both assess and perform surgical procedures. This may mean that undergraduates will be less able to fulfil the recommendations of the General Dental Council. An outreach programme for final year dental students to surgical dentistry practices would benefit all concerned.

Comparative positions of kinetoplasts in Trypanosoma musculi and Trypanosoma lewisi during development in vitro.

The development of Trypanosoma musculi and Trypanosoma lewisi were studied in vitro in the presence of adherent splenic cells. Both parasites developed only when attached by their flagellar tips to adherent splenic cells. During the proliferation of T. musculi, the kinetoplast migrated towards the nucleus, and once in the vicinity of the nucleus, the nuclear division was triggered. The kinetoplast of T. lewisi did not migrate towards the nucleus, but remained at its original location. The nucleus and kinetoplast divided at the same time in both parasites, and parasites started dividing from their flagellar ends and T. musculi and T. lewisi daughter cells were formed within 48 h. The unavailability of the adherent splenic cells in vitro led the parasites to transform into round/oval nonviable forms.

Effects of selenium deficiency in the development of trypanosomes and humoral immune responses in mice infected with Trypanosoma musculi.

The selenium-deficient mouse-trypanosome system was used to study the effects of selenium deficiency in Swiss Webster mice infected with Trypanosoma musculi. In selenium-deficient mice, a low parasitemia was observed and infection was cleared by day 16 post-inoculation (PI), whereas control mice sustained the parasitemia until day 24 PI. There were no significant differences in size variability of the trypanosomes; however the range of variability in the length of parasites differed significantly between the three groups. In comparison to mice on complete or pair-fed diets, the selenium-deficient mice produced lower concentrations of IgG(1), IgG(2b), IgG(3), and IgM. The levels of IgG(2a) and IgA were lower than normal controls. The results of the present study indicated that there was a severe depression in primary and secondary antibody responses to sheep red blood cells in all inoculated mice. However, these responses were significantly less depressed in selenium-deficient mice.

Genomic organization of human TCF12 gene and spliced mRNA variants producing isoforms of transcription factor HTF4.

The human TCF12 gene, mapping to 15q21, encodes the helix-loop-helix transcription factor 4 (HTF4). A detailed analysis of this genomic region established the organization of the TCF12 gene. The gene includes 21 exons and is significantly larger than an average human gene. Preceding the second exon, two alternative acceptor sites for mRNA splicing yield two distinguishable transcripts (HTF4a and HTF4b) which differ in their 5' untranslated region but share identical coding sequences. Differential utilization of exon 15 in the TCF12 gene may reflect a mechanism producing a cell-type-specific protein (HTF4c). In addition, intron 5 in the TCF12 gene corresponds to the region involved in a translocation, t(9;15)(q22;q21), that results in a form of extraskeletal myxoid chondrosarcoma.

Development and proliferation of Trypanosoma musculi in the presence of adherent splenic cells.

The development and proliferation of Trypanosoma musculi parasites were studied in vitro in the presence of adherent splenic cells. The parasites grew and proliferated only when attached by their flagellar tips to adherent splenic cells. Analyses of excretory-secretory products of the adherent cells-parasites did not indicate any detectable soluble growth factor that might be responsible for the growth of these trypanosomes. During the proliferation, the kinetoplast migrated toward the nucleus, and once in the vicinity of the nucleus, nuclear division was triggered. The nucleus and kinetoplast divided at the same time Trypanosoma musculi parasites started dividing from their flagellar ends, and daughter cells were formed within 48 hr. In the absence of adherent splenic cells in vitro, the parasites were transformed into round nonviable forms.

Trypanosome infection rate in cattle at Nguruman, Kenya.

Trypanosome infection rate in cattle at Nguruman was investigated in a study conducted in 1984-1986. Shifting pastoralism significantly reduced trypanosome infections in cattle. The cattle were more heavily infected with Trypanosoma congolense (16.5%) than Trypanosoma vivax (4.95%) and Trypanosoma brucei (0.19%). Trypanosoma theileri was observed only once among the cattle examined. Mixed trypanosome infections in cattle were observed to be 2.75% and 0.014% for T. congolense/T. vivax and T. congolense/T. brucei, respectively. The duration of infection in the cattle was 55 days for T. congolense and 79 days for T. vivax. High infections in cattle were observed 2 months after the rains, which were concomitant with high tsetse densities.

Dynamic holographic imaging of the beating human heart

Background--Currently, the reporting and archiving of echocardiographic data suffer from the difficulty of representing heart motion on printable 2-dimensional (2D) media. Methods and Results--We studied the capability of holography to integrate motion into 2D echocardiographic prints. Images of normal human hearts and of a variety of mitral valve function abnormalities (mitral valve prolapse, systolic anterior motion of the mitral leaflets, and obstruction of the mitral valve by a myxoma) were acquired digitally on standard echocardiographic machines. Images were processed into a data format suitable for holographic printing. Angularly multiplexed holograms were then printed on a prototype holographic "laser" printer, with integration of time in vertical parallax, so that heart motion became visible when the hologram was tilted up and down. The resulting holograms displayed the anatomy with the same resolution as the original acquisition and allowed detailed study of valve motion with side-by-side comparison of normal and abnormal findings. Comparison of standard echocardiographic measurements in original echo frames and corresponding hologram views showed an excellent correlation of both methods (P<0.0001, r2=0.979, mean bias=2.76 mm). In this feasibility study, both 2D and 3D holographic images were produced. The equipment needed to view these holograms consists of only a simple point-light source. Conclusions--Holographic representation of myocardial and valve motion from echocardiographic data is feasible and allows the printing on a 2D medium of the complete heart cycle. Combined with the recent development of online holographic printing, this novel technique has the potential to improve reporting, visualization, and archiving of echocardiographic imaging.

First Report of Mimosa Wilt Disease of Silk Tree (Albizia julibrissin) in California Caused by Fusarium oxysporum f. sp. Perniciosum.

A Fusarium sp. was isolated from a 12-year-old Silk Tree (Albizia julibrissin) in a residential area of Redlands, CA. The scaffold branches and trunk exhibited gummosis, the sap oozing from fissures or intact bark. Internally the wood exhibited brown to black broad streaks of discoloration from the scaffold branches down into lateral roots below the root crown, similar to symptoms observed in Virginia (2). Wilted and dried foliage remained on the scaffold branches. Two-week-old cultures of the isolate grown on Komada (1) and acidified potato dextrose agar media developed short conidiophores, macroconidia, and colony morphology typical of Fusarium oxysporum. To complete Koch's postulates, 1-month-old seedlings were root-dip inoculated with a water suspension of macro- and microconidia (106 per ml). Two weeks after inoculation, typical Fusarium wilt symptoms developed in all inoculated seedlings. The fungus was reisolated from symptomatic seedlings. This is the first report of mimosa wilt disease in California. The disease has the potential to adversely impact California's nursery and landscape industry. References: (1) H. Komada. Rev. Plant Prot. Res. 8:114, 1975. (2) R. J. Stipes and P. M. Phipps. Phytopathology 65:188, 1975.

The natural history and clinical consequences of aspiration in acute stroke.

Sixty consecutive patients admitted to a teaching hospital with acute stroke were studied prospectively for 3 months to define the natural history and consequences of lung aspiration. Using videofluoroscopy, aspiration was identified in 25 patients (42%) within 72 h of stroke onset, and had resolved in all but three patients (8%) after 3 months. It was closely related to the presence of dysphagia, which itself resolved within 2 weeks in all but the persistent aspirators. Lower respiratory tract infection (LRTI) was more common in aspirating patients (68%) than non-aspirators (6%). The use of intravenous fluids without oral intake did not appear to prevent LRTI in aspirating patients who were also dysphagic. Pneumonia occurred after 2 weeks in the three patients subsequently found to aspirate persistently. Aspiration is a transient phenomenon in most cases of acute stroke; it is associated with a high incidence of LRTI, but mortality in this series was not significantly associated either with respiratory tract infection or aspiration itself.

Development of a culturally, theoretically and developmentally based survey instrument for assessing risk behaviors among African-American early adolescents living in urban low-income neighborhoods.

The creation of developmentally and culturally appropriate data-gathering instruments is necessary as health researchers and interventionists expand their investigations to community-based minority adolescent populations. The creation of such instruments is a complex process, requiring the integration of multiple data-gathering and analytic approaches. Recent efforts have delineated several issues to be considered in survey design for minority populations: community collaboration; problem conceptualization; application of the presumed model of behavioral change; and dialect and format of delivery. This paper describes the process of creating a culturally and developmentally appropriate, theoretically grounded instrument for use in monitoring the impact of an AIDS educational intervention on the behavior and health outcomes of urban African-American pre-adolescents and early adolescents. Three phases of research were involved: preliminary (and ongoing) ethnographic research including extensive participant observation, as well as, focus group and individual interviews with 65 youths; construction and testing of the preliminary instrument involving two waves of pilot testing (N1 = 57; N2 = 45); and, finalization of the instrument including reliability testing and assessment of tool constructs and selection of the mode of delivery (involving 2 additional waves of pilot testing (N3 = 91; N4 = 351). The essential role played by the community in all phases of instrument development is underscored.

Aspiration in acute stroke: a clinical study with videofluoroscopy.

To assess the incidence of lung aspiration in acute stroke, and attempt to identify factors which render such patients at risk of aspiration, consecutive patients admitted to hospital within 24 h of their first symptomatic stroke were studied prospectively. Sixty patients who were conscious, and who did not have any preceding neurological or other cause of dysphagia, were assessed clinically and underwent a bedside water-swallowing test and videofluoroscopy within 72 h of stroke. Twenty-five patients (42%) were seen to aspirate at videofluoroscopy; of these 20% did not have overt dysphagia as detected by a simple water-swallowing test. Factors found to be significantly associated with aspiration were reduced pharyngeal sensation, dysphagia and stroke severity. Aspiration is common in the early period following acute stroke; disordered pharyngeal sensation is an important concomitant of this and should be carefully tested in each patient admitted with acute stroke.

Stability studies of gabapentin in aqueous solutions.

Gabapentin is a gamma-aminobutyric acid analogue, which has been shown to be an effective antiepileptic. The solution stability of gabapentin in buffered systems was studied in order to facilitate the formulation of a liquid product. The degradation of the drug was followed as a function of pH, buffer concentration, ionic strength, and temperature. The results indicated that the rate of degradation was proportional to the buffer concentration and temperature. The pH-rate profile of gabapentin degradation showed that the rate of degradation was minimum at an approximate pH of 6.0. Further, the data suggested a slower solvent-catalyzed degradation rate for the zwitterionic species compared to the cationic or anionic species in the pH range of 4.5 to 7.0. There was no influence of ionic strength on the rate of degradation. Arrhenius plots of the data indicated that a shelf life of 2 years or more at room temperature may be obtained in an aqueous solution at a pH value of 6.0.

Gastrointestinal behavior of orally administered radiolabeled erythromycin pellets in man as determined by gamma scintigraphy.

The behavior of single 250-mg doses of a multiparticulate form of erythromycin base (ERYC(R)), each including five pellets radiolabeled with neutron-activated samarium-153, was observed by gamma scintigraphy in seven male subjects under fasting and nonfasting conditions. The residence time and locus of radiolabeled pellets within regions of the gastrointestinal tract were determined and were correlated with plasma concentrations of erythromycin at coincident time points. Administration of food 30 minutes postdosing reduced fasting plasma erythromycin Cmax and area under the plasma erythromycin versus time curve (AUC) values by 43% and 54%, respectively. Mean peak plasma concentration of erythromycin (Cmax) in the fasting state was 1.64 micrograms/mL versus 0.94 micrograms/mL in the nonfasting state. Total oral bioavailability, as determined by mean AUC (0-infinity) of the plasma erythromycin concentration versus time curve, was 7.6 hr/micrograms/mL in the fasted state, versus 3.5 hr/micrograms/mL in the nonfasting state. Mean time to peak plasma erythromycin concentration (tmax) in the fasting state was 3.3 hours, versus 2.3 hours in the nonfasting state. Plasma concentrations of erythromycin in both fasting and nonfasting states were within acceptable therapeutic ranges. Evidence provided by this study: 1) indicates that pellet erosion and absorption of active erythromycin base begins when the enteric-coated pellets reach the highly vascular mucosa of the jejunum and proximal ileum, and is essentially completed within the ileum, with a significant portion absorbed in the medial-to-distal ileum; 2) confirms that acceptable therapeutic plasma levels of erythromycin are attained in nonfasting subjects (Cmax = 0.94 microgram/mL) and that superior plasma erythromycin concentrations (Cmax = 1.64 micrograms/mL) are achieved by administration of the dose on an empty stomach 1 to 2 hours before or after meals; 3) corroborates other comparative studies reporting greater fasting bioavailability with this multiparticulate dosage form of erythromycin base than with reference single tablet or particle-in-tablet formulations; and 4) indicates that neutron activation of stable isotopes incorporated as a normal excipient in industrially-produced formulations provides an effective means for in vivo evaluation of dosage forms through gamma scintigraphy.

Manufacture and properties of erythromycin beads containing neutron-activated erbium-171.

To evaluate the effects of a neutron activation radiolabeling technique on an enteric-coated multiparticulate formulation of erythromycin, test quantities were produced under industrial pilot scale conditions. The pellets contained the stable isotope erbium oxide (Er-170), which was later converted by neutron activation into the short-lived gamma ray-emitting radionuclide, erbium-171. In vitro studies indicated that the dissolution profile, acid resistance, and enteric-coated surface of the pellets were minimally affected by the irradiation procedure. Antimicrobial potency was also unaffected, as determined by microbiological assay. Neutron activation thus appears to simplify the radiolabeling of complex pharmaceutical dosage forms for in vivo study by external gamma scintigraphy.