Barriers to the Use of Insulin Therapy and Potential Solutions: A Narrative Review of Perspectives from the Asia-Pacific Region.

The rising prevalence of type 2 diabetes (T2D) is posing major challenges for the healthcare systems of many countries, particularly in the Asia-Pacific Region, in which T2D can present at younger ages and lower body mass index when compared with Western nations. There is an important role for insulin therapy in the management of T2D in these nations, but available evidence suggests that insulin is under-utilized and often delayed, to the detriment of patient prognosis. The authors of this article gathered as an advisory panel (representative of some of the larger Asia-Pacific nations) to identify their local barriers to insulin use in T2D, and to discuss ways in which to address these barriers, with their outputs summarized herein. Many of the key barriers identified are well-documented issues of global significance, including a lack of healthcare resources or of an integrated structure, insufficient patient education, and patient misconceptions about insulin therapy. Barriers identified as more innate to Asian countries included local inabilities of patients to afford or gain access to insulin therapy, a tendency for some patients to be more influenced by social media and local traditions than by the medical profession, and a willingness to switch care providers and seek alternative therapies. Strategies to address some of these barriers are provided, with hypothetical illustrative case histories.

Structure and tethering mechanism of dynein-2 intermediate chains in intraflagellar transport.

Dynein-2 is a large multiprotein complex that powers retrograde intraflagellar transport (IFT) of cargoes within cilia/flagella, but the molecular mechanism underlying this function is still emerging. Distinctively, dynein-2 contains two identical force-generating heavy chains that interact with two different intermediate chains (WDR34 and WDR60). Here, we dissect regulation of dynein-2 function by WDR34 and WDR60 using an integrative approach including cryo-electron microscopy and CRISPR/Cas9-enabled cell biology. A 3.9 Å resolution structure shows how WDR34 and WDR60 use surprisingly different interactions to engage equivalent sites of the two heavy chains. We show that cilia can assemble in the absence of either WDR34 or WDR60 individually, but not both subunits. Dynein-2-dependent distribution of cargoes depends more strongly on WDR60, because the unique N-terminal extension of WDR60 facilitates dynein-2 targeting to cilia. Strikingly, this N-terminal extension can be transplanted onto WDR34 and retain function, suggesting it acts as a flexible tether to the IFT "trains" that assemble at the ciliary base. We discuss how use of unstructured tethers represents an emerging theme in IFT train interactions.

Impact of Atrial Fibrillation Burden on Health Care Costs and Utilization.

BACKGROUND: Integrating patient-specific cardiac implantable electronic device (CIED)-detected atrial fibrillation (AF) burden with measures of health care cost and utilization allows for an accurate assessment of the AF-related impact on health care use. OBJECTIVES: The goal of this study was to assess the incremental cost of device-recognized AF vs no AF; compare relative costs of paroxysmal atrial fibrillation (pAF), persistent atrial fibrillation (PeAF), and permanent atrial fibrillation (PermAF) AF; and evaluate rates and sources of health care utilization between cohorts. METHODS: Using the de-identified Optum Clinformatics U.S. claims database (2015-2020) linked with the Medtronic CareLink database, CIED patients were identified who transmitted data ≥6 months postimplantation. Annualized per-patient costs in follow-up were analyzed from insurance claims and adjusted to 2020 U.S. dollars. Costs and rates of health care utilization were compared between patients with no AF and those with device-recognized pAF, PeAF, and PermAF. Analyses were adjusted for geographical region, insurance type, CHA2DS2-VASc score, and implantation year. RESULTS: Of 21,391 patients (mean age 72.9 ± 10.9 years; 56.3% male) analyzed, 7,798 (36.5%) had device-recognized AF. The incremental annualized increased cost in those with AF was $12,789 ± $161,749 per patient, driven by increased rates of health care encounters, adverse clinical events associated with AF, and AF-specific interventions. Among those with AF, PeAF was associated with the highest cost, driven by increased rates of inpatient and outpatient hospitalization encounters, heart failure hospitalizations, and AF-specific interventions. CONCLUSIONS: Presence of device-recognized AF was associated with increased health care cost. Among those with AF, patients with PeAF had the highest health care costs. Mechanisms for cost differentials include both disease-specific consequences and physician-directed interventions.

Roles for CEP170 in cilia function and dynein-2 assembly.

Primary cilia are essential eukaryotic organelles required for signalling and secretion. Dynein-2 is a microtubule-motor protein complex and is required for ciliogenesis via its role in facilitating retrograde intraflagellar transport from the cilia tip to the cell body. Dynein-2 must be assembled and loaded onto IFT-trains for entry into cilia for this process to occur but how dynein-2 is assembled and how it is recycled back into a cilium remain poorly understood. Here, we identify Centrosomal Protein of 170 kDa (CEP170) as a dynein-2 interacting protein. We show that loss of CEP170 perturbs intraflagellar transport, Hedgehog signalling, and alters the stability of dynein-2 holoenzyme complex. Together, our data indicate a role for CEP170 in supporting cilia function and dynein-2 assembly.

The prevalence of developmental defects of enamel in a cohort of adults with cystic fibrosis - A cross sectional study.

OBJECTIVES: Cystic Fibrosis is an autosomal recessive condition. It is a multisystem disease treated with a broad range of pharmacological therapies, diet and nutrition, and physiotherapy. Previous studies suggest that people with cystic fibrosis have a higher prevalence of developmental defects of enamel which may place this population at a greater risk of developing oral diseases such as caries. The aim of this study was to assess a cohort of people with cystic fibrosis (PwCF) for the presence of developmental defects of enamel and compare the results with a control group of people without cystic fibrosis. METHODS: A cross sectional study involving 92 participants with cystic fibrosis and 92 controls was conducted in Cork University Dental School & Hospital. All participants completed a detailed questionnaire prior to undergoing a full clinical examination. The Developmental Defect of Enamel Index was used as a measurement index. All data was statistically analysed with the help of statisticians from Cystic Fibrosis Registry of Ireland. RESULTS: 64 % (n = 59) of PwCF had enamel defects compared to just 30 % (n = 28) of people without cystic fibrosis. The median number of teeth affected by enamel defects in the study group was 1.5, compared to 0 in the control group. CONCLUSION: In this study the cohort of PwCF had more enamel defects than people without CF. Further research is required to investigate the aetiology of these findings. CLINICAL SIGNIFICANCE: Clinicians should be vigilant after teeth have erupted in PwCF as they may have an increased susceptibility to developmental defects of enamel.

Periodontal disease prevalence and oral hygiene status of adults with cystic fibrosis: A case-control study.

AIM: To investigate the prevalence of gingivitis and periodontitis, and the oral hygiene status of adults with cystic fibrosis (CF) in the Republic of Ireland. MATERIALS AND METHODS: A case-control study in the form of a clinical examination of 92 adults with a diagnosis of CF was carried out in the adult CF unit in Cork University Hospital. A 40-item questionnaire was used to capture socio-demographic variables and medical and dental information. Two calibrated examiners carried out a periodontal assessment on participants, using the WHO-recommended CPI-modified index, and oral hygiene status was measured using the Greene-Vermillion index. The results were compared with a population-based control group of similar socio-demographic profile. RESULTS: Oral hygiene levels (plaque and calculus) were significantly worse in people with CF, with a median plaque index of 0.83 (interquartile range [IQR] 0.333-1.542) in the CF group compared with 0.5 (IQR 0.167-0.667) in the non-CF group. Calculus index in the CF group was 0.33 (IQR 0.17-0.83) compared with 0.33 (IQR 0.125-0.33) in the non-CF group. However, periodontal disease levels were significantly lower in the CF group. Gingivitis (bleeding on probing ≥ 10% sites) was seen in 67.4% of the CF group, compared with 83.7% of the non-CF group, OR 0.365 (95% confidence interval [CI] 0.181-0.736), relative risk (RR) 0.779 (95% CI 0.655-0.928). Mild periodontitis (periodontal probing depth [PPD] < 5 mm) was seen in 15.2% of the CF group, compared with 31.5% of the non-CF group, OR 0.390 (CI 0.190-0.800), RR 0.483 (95% CI 0.273-0.852). Severe periodontitis (PPD ≥ 6 mm) was seen in 0% of the CF group, compared with 9.8% of the non-CF group. There was a tendency, albeit non-significant, towards reduced periodontitis in PWCF who regularly took antibiotics, particularly azithromycin. CONCLUSIONS: In this study, adults with CF had poor oral hygiene practices, with high levels of plaque and calculus. Despite this finding, adults with CF had lower levels of clinical gingivitis and periodontitis than seen in a non-CF control group. Further study is required to examine the causes of this phenomenon.

Current practices and attitudes of dental practitioners regarding the provision of dental treatment for patients with solid organ transplants.

BACKGROUND: Solid organ transplant provides a lifeline for people with end stage organ failure. Each year the number of individuals in receipt of a solid organ transplant is increasing. Prevention of post-transplant sepsis and infection are critical for transplant success. The oral cavity contains more than 700 different species of bacteria and is a potential reservoir for disease causing pathogens. Prior to undergoing solid organ transplant, individuals must receive a certification of dental health from a dental practitioner. There are currently no guidelines or protocols for dental practitioners to follow when certifying a patient as dentally fit. This allows for a wide variation of the term 'dentally fit'. This survey was conducted as part of a larger study assessing the oral health of adults with cystic fibrosis ongoing in Cork University Dental School and Hospital. The aim of the study was to ascertain current practices and attitudes of dental practitioners regarding the provision of dental treatment pre and post solid organ transplantation. METHODS: An anonymous cross sectional survey of dental practitioners in Ireland was conducted. RESULTS: The data collected showed a wide variation in the provision of treatment for patient undergoing or in receipt of a solid organ transplant. CONCLUSION: It demonstrates a need for further research to be conducted to ascertain the full impact solid organ transplant has on oral health, so that guidelines can be developed to aid both dental and medical professionals in the treatment of this vulnerable cohort.

Optimisation of a Multi-Functional Piezoelectric Component for a Climbing Robot.

Force sensors on climbing robots give important information to the robot control system, however, off-the-shelf sensors can be both heavy and bulky. We investigate the optimisation of a lightweight integrated force sensor made of piezoelectric material for the multi-limbed climbing robot MAGNETO. We focus on three design objectives for this piezoelectric component. The first is to develop a lightweight component with minimal compliance that can be embedded in the foot of the climbing robot. The second objective is to ensure that the component has sensing capability to replace the off-the-shelf force sensor. Finally, the component should be robust for a range of climbing configurations. To this end, we focus on a compliance minimisation problem with constrained voltage and volume fraction. We present structurally optimised designs that satisfy the three main design criteria and improve upon baseline results from a reference component. Our computational study demonstrates that the optimisation of embedded robotic components with piezoelectric sensing is worthy of future investigation.

Developing procedural metrics for training in class II posterior composite resin restorations: Outcomes from an international Delphi panel.

OBJECTIVE: The objective of this study was to develop and operationally define procedural performance metrics for the Class II posterior composite resin restoration procedure and to obtain face and content validity through a consensus meeting. METHODS: A Metrics Group consisting of 4 experienced Consultants in Restorative Dentistry, an experienced member of staff from the Restorative Dentistry department in CUDSH and a senior behavioural scientist and education/training expert deconstructed the performance of the Class II posterior composite resin restoration and defined performance metrics. At a modified Delphi meeting, 20 experts in the field of Restorative Dentistry from 11 different Dental Institutions critiqued these metrics and their operational definitions before reaching consensus. RESULTS: Initially performance metrics consisting of 15 Phases, 45 steps, 42 errors and 34 critical errors were identified that characterize the performance of the Class II posterior resin composite procedure. During the Delphi panel these were modified and consensus was reached on 15 Phases (with a change to the initial sequence) with 46 Steps (1 added, 13 modified), 37 Errors (2 added, 1 deleted, 6 reclassified as Critical Error), and 43 Critical Errors (9 added). Consensus on the resulting metrics was obtained and face and content validity verified. CONCLUSIONS: It is possible to develop and objectively define performance metrics that comprehensively characterize a Class II posterior composite resin restoration. It is also possible to achieve consensus on the metrics from a Delphi panel of experts and to confirm the face and content validity of those procedure metrics.

Oral care considerations for people with cystic fibrosis: a cross-sectional qualitative study.

OBJECTIVES: To investigate the attitudes of adults with Cystic Fibrosis (CF) towards dental attendance and any perceived barriers to treatment. METHODS: A cross sectional survey in the form of a structured, anonymous questionnaire was used to obtain information regarding adults with CF's feelings towards dentists and dental treatment. The final version of the questionnaire was based on a collaborative effort between researchers at Cork University Dental School and Hospital and Cystic Fibrosis (CF) patient advocates from CF Ireland. Participants were recruited via CF Ireland's mailing list and social media channels. The responses underwent descriptive statistical analysis and inductive thematic analysis. RESULTS: A total of 71 people (33 Male: 38 Female) over the age of 18 living with CF in the Republic of Ireland responded to the survey. 54.9% of respondents were unhappy with their teeth. 63.4% felt that CF had an impact on oral health. 33.8% were anxious about attending their dentist. Respondents believed that CF has impacted on their oral health due to the medications and dietary requirements involved, as well as tiredness and other side effects of CF. Reasons for being anxious about attending the dentist included cross infection concerns, issues with the dentist, with tolerating treatment, and with the teeth themselves. Respondents wanted dentists to be aware of the practicalities of dental treatment for people with CF, especially their discomfort with lying back. They also want the dentist to be aware of the impact that their medication, treatment and diet has on their oral health. CONCLUSIONS: Over one third of adults with CF reported anxiety about attending the dentist. Reasons for this included fear, embarrassment, cross infection concerns and problems with treatment, especially being in the supine position. Adults with CF want dentists to be aware of the impact that CF can have upon dental treatment and oral health care.

Disease-associated mutations in WDR34 lead to diverse impacts on the assembly and function of dynein-2.

The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport in the primary cilium result in ciliopathies, a group of genetic disorders that commonly lead to the malformation of organs such as the kidney, liver and eyes and skeletal dysplasias. The motor proteins dynein-2 and kinesin-2 mediate retrograde and anterograde transport, respectively, in the cilium. WDR34 (also known as DYNC2I2), a dynein-2 intermediate chain, is required for the maintenance of cilia function. Here, we investigated WDR34 mutations identified in Jeune syndrome, short-rib polydactyly syndrome and asphyxiating thoracic dysplasia patients. There is a poor correlation between genotype and phenotype in these cases, making diagnosis and treatment highly complex. We set out to define the biological impacts on cilia formation and function of WDR34 mutations by stably expressing the mutant proteins in WDR34-knockout cells. WDR34 mutations led to different spectrums of phenotypes. Quantitative proteomics demonstrated changes in dynein-2 assembly, whereas initiation and extension of the axoneme, localization of intraflagellar transport complex-B proteins, transition zone integrity and Hedgehog signalling were also affected.

Self-reported dental attendance, oral hygiene habits, and dietary habits of adults with cystic fibrosis.

AIMS: To evaluate the dental attendance, oral hygiene habits, and dietary habits of adults with Cystic Fibrosis in the Republic of Ireland. METHODS AND RESULTS: A cross-sectional study was carried out using a structured anonymous questionnaire. A total of 71 adults with Cystic Fibrosis responded. While the majority of respondents (66.2%) saw a dentist in the preceding year, 15.5% had not attended a dentist for over 2 years. Smoking and alcohol consumption levels were low. 63.4% brushed twice or more daily, with 70.4% using a Fluoride containing toothpaste. 62% did not use any interdental cleaning aid. 5.6% changed their toothbrush at least once a month, but for 22.5% it was over 6 months. 70.4% used fluoride toothpaste. 38% snacked three or more times daily and 29.5% consumed fizzy drinks at least once daily. CONCLUSIONS: The alcohol and tobacco consumption in this study group was low. However, a large proportion frequently consumed sugar-rich foods, and they did not change their toothbrush, brush their teeth, or attend the dentist as regularly as is advised. More targeted advice may be necessary to improve the oral hygiene habits of adults with Cystic Fibrosis.

Migratory connectivity of North American waterfowl across administrative flyways.

Management of waterfowl that migrate seasonally across North America occurs within four flyways that were delineated in the early 1900s to include the annual movements of populations. Movements may have changed over the past century since the administrative flyways were established, and may do so while management plans are in use, so information about transitions among flyways through time can illustrate how management assumptions may change. Today there are more than 12 million records from 60 years of migratory waterfowl band recoveries to assess adaptive management approaches that will be most effective when they account for movements within and between flyways. We examined how much the movement of North American waterfowl occurs between flyways, whether those movements have changed through time, and whether movements of mallards are representative of multiple species, as suggested by current harvest management strategies. We estimated the probability a duck would transition from one flyway to another and the strength of migratory connectivity (MC) for each species within and among flyways. We used capture-mark-recovery models to estimate population-specific movement within and among flyways (transition probabilities) for 15 migratory waterfowl species that were banded during breeding and recovered during winter. We developed new functionality in the R package MigConnectivity to estimate the species-specific strength of MC using transition probability samples from the capture-mark-recovery models. We found the regular movement of duck populations among flyways, overall weak MC, and no consistent change in migratory movements through time. Mallard movements were median among all duck species, but significantly different from many species, particularly diving ducks. Despite the significant movement between flyways, our work suggests flyway management of waterfowl matches many of the seasonal movements of these species when considering mid-continent flyway management. We recommend models accounting for all transition probabilities between populations and regularly estimating harvest derivations, transition probabilities, and MC metrics to verify that the current movements match model assumptions.

IFT-A structure reveals carriages for membrane protein transport into cilia.

Intraflagellar transport (IFT) trains are massive molecular machines that traffic proteins between cilia and the cell body. Each IFT train is a dynamic polymer of two large complexes (IFT-A and -B) and motor proteins, posing a formidable challenge to mechanistic understanding. Here, we reconstituted the complete human IFT-A complex and obtained its structure using cryo-EM. Combined with AlphaFold prediction and genome-editing studies, our results illuminate how IFT-A polymerizes, interacts with IFT-B, and uses an array of ß-propeller and TPR domains to create "carriages" of the IFT train that engage TULP adaptor proteins. We show that IFT-A⋅TULP carriages are essential for cilia localization of diverse membrane proteins, as well as ICK-the key kinase regulating IFT train turnaround. These data establish a structural link between IFT-A's distinct functions, provide a blueprint for IFT-A in the train, and shed light on how IFT evolved from a proto-coatomer ancestor.

Geographic Variation in Influenza Vaccination Disparities Between Hispanic and Non-Hispanic White US Nursing Home Residents.

Background: Disparities in influenza vaccination exist between Hispanic and non-Hispanic White US nursing home (NH) residents, but the geographic areas with the largest disparities remain unknown. We examined how these racial/ethnic disparities differ across states and hospital referral regions (HRRs). Methods: This retrospective cohort study included >14 million short-stay and long-stay US NH resident-seasons over 7 influenza seasons from October 1, 2011, to March 31, 2018, where residents could contribute to 1 or more seasons. Residents were aged ≥65 years and enrolled in Medicare fee-for-service. We used the Medicare Beneficiary Summary File to ascertain race/ethnicity and Minimum Data Set assessments for influenza vaccination. We calculated age- and sex-standardized percentage point (pp) differences in the proportions vaccinated between non-Hispanic White and Hispanic (any race) resident-seasons. Positive pp differences were considered disparities, where the proportion of non-Hispanic White residents vaccinated was greater than the proportion of Hispanic residents vaccinated. States and HRRs with ≥100 resident-seasons per age-sex stratum per racial/ethnic group were included in analyses. Results: Among 7 442 241 short-stay resident-seasons (94.1% non-Hispanic White, 5.9% Hispanic), the median standardized disparities in influenza vaccination were 4.3 pp (minimum, maximum: 0.3, 19.2; n = 22 states) and 2.8 pp (minimum, maximum: -3.6, 10.3; n = 49 HRRs). Among 6 758 616 long-stay resident-seasons (93.7% non-Hispanic White, 6.5% Hispanic), the median standardized differences were -0.1 pp (minimum, maximum: -4.1, 11.4; n = 18 states) and -1.8 pp (minimum, maximum: -6.5, 7.6; n = 34 HRRs). Conclusions: Wide geographic variation in influenza vaccination disparities existed across US states and HRRs. Localized interventions targeted toward areas with high disparities may be a more effective strategy to promote health equity than one-size-fits-all national interventions.

Mechanochemical tuning of a kinesin motor essential for malaria parasite transmission.

Plasmodium species cause malaria and kill hundreds of thousands annually. The microtubule-based motor kinesin-8B is required for development of the flagellated Plasmodium male gamete, and its absence completely blocks parasite transmission. To understand the molecular basis of kinesin-8B's essential role, we characterised the in vitro properties of kinesin-8B motor domains from P. berghei and P. falciparum. Both motors drive ATP-dependent microtubule gliding, but also catalyse ATP-dependent microtubule depolymerisation. We determined these motors' microtubule-bound structures using cryo-electron microscopy, which showed very similar modes of microtubule interaction in which Plasmodium-distinct sequences at the microtubule-kinesin interface influence motor function. Intriguingly however, P. berghei kinesin-8B exhibits a non-canonical structural response to ATP analogue binding such that neck linker docking is not induced. Nevertheless, the neck linker region is required for motility and depolymerisation activities of these motors. These data suggest that the mechanochemistry of Plasmodium kinesin-8Bs is functionally tuned to support flagella formation.

Cooperative amyloid fibre binding and disassembly by the Hsp70 disaggregase.

Although amyloid fibres are highly stable protein aggregates, a specific combination of human Hsp70 system chaperones can disassemble them, including fibres formed of α-synuclein, huntingtin, or Tau. Disaggregation requires the ATPase activity of the constitutively expressed Hsp70 family member, Hsc70, together with the J domain protein DNAJB1 and the nucleotide exchange factor Apg2. Clustering of Hsc70 on the fibrils appears to be necessary for disassembly. Here we use atomic force microscopy to show that segments of in vitro assembled α-synuclein fibrils are first coated with chaperones and then undergo bursts of rapid, unidirectional disassembly. Cryo-electron tomography and total internal reflection fluorescence microscopy reveal fibrils with regions of densely bound chaperones, preferentially at one end of the fibre. Sub-stoichiometric amounts of Apg2 relative to Hsc70 dramatically increase recruitment of Hsc70 to the fibres, creating localised active zones that then undergo rapid disassembly at a rate of ~ 4 subunits per second. The observed unidirectional bursts of Hsc70 loading and unravelling may be explained by differences between the two ends of the polar fibre structure.

Smartphone technology for communications between clinicians - A scoping review.

OBJECTIVES: This scoping review aims to review explore, assess, and map the literature to inform clinical practice regarding communication between clinicians. Specific Apps/channels used were identified and assessed with a focus on data security with key concepts and knowledge gaps identified. DATA: The Joanna Briggs Institute framework is followed, with search results reported as per the PRISMA ScR for scoping reviews guidelines. SOURCES: A systematic search strategy encompassing EBSCO and OneSearch databases was conducted - two identical searches, (June and October 2020) limited to English language articles published 2016-2020. A narrative synthesis was used to integrate and report the findings. STUDY SELECTION: Sixty-six publications were selected. Twelve from EBSCO, thirty-five from OneSearch, nineteen were hand searched. Sixteen of the publications were research studies, nine were literature reviews, twenty-six were editorial, one was a newspaper article and fourteen were grey literature. Instant Messaging (40%, n = 23), image sharing (41%, n = 24), and video conferencing (19%, n = 11) were functions most popular with clinicians. WhatsApp, generic instant messaging, Facebook messenger, ZOOM, and Skype are evidenced as channels for communication between clinicians within the EU. A sizeable proportion of the publications (38%; n = 25) failed to identify or adequately address technical security concerns and requirements around privacy and data protection. CONCLUSIONS: Clinicians use smartphones /Apps to communicate clinical information with each other. The security and privacy issues arising from their communication of sensitive data is absent or only superficially acknowledged within the literature. CLINICAL SIGNIFICANCE: Clinician's need clearer guidance on the use of smartphone technology for clinical communications.