Association of insulin resistance with the accumulation of saturated intramyocellular lipid: A comparison with other fat stores.

It has been shown using proton magnetic resonance spectroscopy (1H MRS) that, in a group of females, whole-body insulin resistance was more closely related to accumulation of saturated intramyocellular lipid (IMCL) than to IMCL concentration alone. This has not been investigated in males. We investigated whether age- and body mass index-matched healthy males differ from the previously reported females in IMCL composition (measured as CH2:CH3) and IMCL concentration (measured as CH3), and in their associations with insulin resistance. We ask whether saturated IMCL accumulation is more strongly associated with insulin resistance than other ectopic and adipose tissue lipid pools and remains a significant predictor when these other pools are taken into account. In this group of males, who had similar overall insulin sensitivity to the females, IMCL was similar between sexes. The males demonstrated similar and even stronger associations of IMCL with insulin resistance, supporting the idea that a marker reflecting the accumulation of saturated IMCL is more strongly associated with whole-body insulin resistance than IMCL concentration alone. However, this marker ceased to be a significant predictor of whole-body insulin resistance after consideration of other lipid pools, which implies that this measure carries no more information in practice than the other predictors we found, such as intrahepatic lipid and visceral adipose tissue. As the marker of saturated IMCL accumulation appears to be related to these two predictors and has a much smaller dynamic range, this finding does not rule out a role for it in the pathogenesis of insulin resistance.

The utility of nasal nitric oxide in the diagnostic evaluation of primary ciliary dyskinesia.

BACKGROUND: There is no gold-standard test for primary ciliary dyskinesia (PCD), rather American Thoracic Society guidelines recommend starting with nasal nitric oxide (nNO) in children ≥5 years old and confirming the diagnosis with genetic testing or ciliary biopsy with transmission electron microscopy (TEM). These guidelines have not been studied in a clinical setting. We present a case series describing the PCD diagnostic process at our pediatric PCD center. METHODS: Diagnostic data from 131 patients undergoing PCD consultation were reviewed. RESULTS: In all participants ≥ 5 years old and who completed nNO using resistor methodology, the first diagnostic test performed was nNO in 77% (73/95), genetic testing in 14% (13/95), and TEM in <1% (9/95). nNO was the only diagnostic test performed in 75% (55/73) of participants who completed nNO first. Seventy-five percent (55/73) had a single above the cutoff nNO value and PCD was determined to be unlikely in 91% (50/55) without performing additional confirmatory testing. Eleven percent (8/73) had multiple below the cutoff nNO values, with 38% (3/8) being diagnosed with PCD by confirmatory testing and 50% (4/8) with negative confirmatory testing, but being managed as PCD. The genetic testing positivity rate was 50% in participants who completed nNO first and 8% when genetic testing was completed first. CONCLUSION: nNO is useful in three situations: an initial above the cutoff nNO value makes PCD unlikely and prevents additional confirmatory testing, repetitively below the cutoff nNO values without positive confirmatory testing suggests a probable PCD diagnosis and the yield of genetic testing is higher when nNO is performed first.

Dental and temporomandibular joint pathology of the red fox (Vulpes vulpes).

Skulls from 305 red foxes (Vulpes vulpes) were examined using predefined criteria to assess for the presence and severity of dental and temporomandibular joint (TMJ) pathology. Of the 305 specimens examined, 131 were male (42.9%), 103 were female (33.4%), 71 were of unknown sex (23.3%), 238 were adults (78.03%) and 67 were young adults (21.97%), with juveniles excluded from the study. Of a maximum of 12,810 possible teeth, 12,355 (96.5%) were present for examination, 72 (0.6%) were absent congenitally, 97 (0.8%) were acquired tooth loss and 280 (2.2%) were absent artefactually. Eight teeth (0.06%) in five specimens (1.6%) had abnormal tooth form and four (0.03%) supernumerary teeth were present across four (1.3%) specimens. Ten persistent deciduous teeth were present in seven (2.3%) specimens and six (0.05%) unerupted teeth were found in four (1.1%) specimens. Root number variation was present in 51 (0.4%) teeth, predominantly premolar teeth. Twenty-one (6.9%) specimens had lesions consistent with enamel hypoplasia and 42 (13.8%) showed root fenestrations in the maxillary alveolar bone. Periodontitis and attrition/abrasion were present in most specimens (56.7% and 96.1%, respectively). Three-hundred and eighty (3.1%) teeth were fractured, with the most common fracture type being root fractures. Eleven periapical lesions were found in nine (0.03%) specimens. Six-hundred and eight TMJs were evaluated and many specimens (11.5%) had evidence of low-grade TMJ osteoarthritis. Overall, these red foxes share similar dental pathology to other foxes, but had a higher prevalence of congenital tooth absence, persistent deciduous teeth, TMJ pathology and enamel hypoplasia.

Centile reference chart for resting metabolic rate through the life course.

OBJECTIVE: Reference centile charts are widely used for the assessment of growth and have progressed from describing height and weight to include body composition variables such as fat and lean mass. Here, we present centile charts for an index of resting energy expenditure (REE) or metabolic rate, adjusted for lean mass versus age, including both children and adults across the life course. DESIGN, PARTICIPANTS AND INTERVENTION: Measurements of REE by indirect calorimetry and body composition using dual-energy X-ray absorptiometry were made in 411 healthy children and adults (age range 6-64 years) and serially in a patient with resistance to thyroid hormone α (RTHα) between age 15 and 21 years during thyroxine therapy. SETTING: NIHR Cambridge Clinical Research Facility, UK. RESULTS: The centile chart indicates substantial variability, with the REE index ranging between 0.41 and 0.59 units at age 6 years, and 0.28 and 0.40 units at age 25 years (2nd and 98th centile, respectively). The 50th centile of the index ranged from 0.49 units (age 6 years) to 0.34 units (age 25 years). Over 6 years, the REE index of the patient with RTHα varied from 0.35 units (25th centile) to 0.28 units (<2nd centile), depending on changes in lean mass and adherence to treatment. CONCLUSION: We have developed a reference centile chart for an index of resting metabolic rate in childhood and adults, and shown its clinical utility in assessing response to therapy of an endocrine disorder during a patient's transition from childhood to adult.

Economic evaluations of interventions to prevent and control health-care-associated infections: a systematic review.

Almost 9 million health-care-associated infections have been estimated to occur each year in European hospitals and long-term care facilities, and these lead to an increase in morbidity, mortality, bed occupancy, and duration of hospital stay. The aim of this systematic review was to review the cost-effectiveness of interventions to limit the spread of health-care-associated infections), framed by WHO infection prevention and control core components. The Embase, National Health Service Economic Evaluation Database, Database of Abstracts of Reviews of Effects, Health Technology Assessment, Cinahl, Scopus, Pediatric Economic Database Evaluation, and Global Index Medicus databases, plus grey literature were searched for studies between Jan 1, 2009, and Aug 10, 2022. Studies were included if they reported interventions including hand hygiene, personal protective equipment, national-level or facility-level infection prevention and control programmes, education and training programmes, environmental cleaning, and surveillance. The British Medical Journal checklist was used to assess the quality of economic evaluations. 67 studies were included in the review. 25 studies evaluated methicillin-resistant Staphylococcus aureus outcomes. 31 studies evaluated screening strategies. The assessed studies that met the minimum quality criteria consisted of economic models. There was some evidence that hand hygiene, environmental cleaning, surveillance, and multimodal interventions were cost-effective. There were few or no studies investigating education and training, personal protective equipment or monitoring, and evaluation of interventions. This Review provides a map of cost-effectiveness data, so that policy makers and researchers can identify the relevant data and then assess the quality and generalisability for their setting.

Case series of pediatric mediastinal granuloma related to histoplasmosis.

INTRODUCTION: Mediastinal granuloma (MG) is a postinfectious complication of histoplasmosis that remains a rare diagnosis in the pediatric literature. This case series presents a well phenotyped population to further characterize this disease process. METHODS: Thirty cases of MG in children under 21 years-of-age presenting over a 16-year period were retrospectively analyzed. RESULTS: Seventy-five percent of patients presented with respiratory symptoms. Histoplasma antigen was negative in 90%. Histoplasma antibody was positive in 100%. Fine needle aspirates were positive for histoplasma in 31% whereas excisional biopsy was positive in 71%. Bronchoalveolar lavage (BAL) was negative for histoplasma in all cases where performed. Computed tomography revealed 53% of MGs were right paratracheal, 60% had internal calcifications, and 23% had splenic calcifications. Sixteen patients (53%) were managed with medical therapies only, with 7 (44%) treated with steroids and antifungals and 7 (44%) with antifungals alone. The remaining 14 patients (47%) underwent surgical excision and 9 were also treated with antifungals (64%). Bronchial compression was the most common comorbidity within the medically managed only group whereas vascular compression and fistulation were most common within the surgically managed group. CONCLUSION: Respiratory symptoms should raise suspicion for MG. Diagnostic evidence of MG includes positive histoplasma serologies, right paratracheal location, internal calcifications, and splenic calcifications. Bronchoscopy, BAL and needle biopsies provide minimal diagnostic benefit. Antifungals are used in the majority of cases, whereas steroids are used most often in non-surgically managed patients with airway compression. Indications for surgical resection are less defined, but include vascular compression and fistulation unresponsive to medical treatment.

A systematic review of the quality and scope of decision modelling studies in child oral health research.

BACKGROUND: Decision analytic models are often used in economic evaluations to estimate long-term costs and effects of treatment which span beyond the time-frame of a clinical trial, therefore providing a better understanding of the long-term implications of decisions that conventional trial-based economic evaluations fail to provide. This is particularly relevant for considering oral health interventions in children as treatments may affect adult oral health. However, in the field of child oral health there has not been an evaluation of the quality and scope of decision analytical models which extend into adulthood. The aim of this review is to examine the scope and quality of decision modelling studies, with horizons extending into adulthood, within the field of child oral health. METHODS: The following databases were searched: NHS Economic Evaluation Database (CRD York), MEDLINE, EMBASE, CINAHL, Web of Science, Scopus, the Cochrane Library and Econlit. Full economic evaluations, in the field of child oral health, published after 1997 which included a decision model with a horizon that extended beyond the age of 18 years old were included. Included studies were appraised against the Drummond checklist and the Consolidated Health Economic Evaluation Reporting Standards by calibrated reviewers. RESULTS: Four hundred studies were identified, of which nine met the inclusion criteria. Of the nine, eight were cost-effectiveness models. The majority focussed on the prevention or management of dental caries. The mean percentage of applicable Drummond checklist criteria met by the studies in this review was 82% (median = 85%, range = 54-100%). Discounting of costs and performing an incremental analysis were noted as key methodological weaknesses. The mean percentage of applicable CHEERS criteria met by each study was 82% (median = 87%, range = 32-96%). Justifying the type of model, analytical methods used, and sources of funding were most commonly unreported. CONCLUSIONS: There is a paucity of decision analytical models in the field of child oral health. Most of those that are available are of high methodological and reporting quality.

An Examination of Consistency in the Incremental Approach to Willingness to Pay: Evidence Using Societal Values for NHS Dental Services.

INTRODUCTION: Willingness to pay (WTP) is used to generate information about value. However, when comparing 2 or more services using standard WTP techniques, the amounts elicited from participants for the services are often similar, even when individuals state a clear preference for one service over another. An incremental approach has been suggested, in which individuals are asked to first rank interventions and provide a WTP value for their lowest-ranked intervention followed by then asking how much more they are willing to pay for their next preferred choice and so on. To date, evaluation of this approach has disregarded protest responses, which may give information on consistency between stated and implicit rankings. METHODS: A representative sample of the English population (n = 790) were asked to value 5 dental services adopting a societal perspective, using a payment vehicle of additional household taxation per year. The sample was randomized to either the standard or the incremental approach. Performance for both methods is assessed on discrimination between values for interventions and consistency between implicit and stated ranks. The data analysis is the first to retain protest responses when considering consistency between ranks. RESULTS: The results indicate that neither approach provides values that discriminate between interventions. Retaining protest responses reveals inconsistencies between the stated and implicit ranks are present in both approaches but much reduced in the incremental approach. CONCLUSION: The incremental approach does not improve discrimination between values, yet there is less inconsistency between ranks. The protest responses indicate that objections to giving values to the dental interventions are dependent on a multitude of factors beyond the elicitation process.

The Importance of Hydration in Body Composition Assessment in Children Aged 6-16 Years.

Body composition is associated with many noncommunicable diseases. The accuracy of many simple techniques used for the assessment of body composition is influenced by the fact that they do not take into account tissue hydration and this can be particularly problematic in paediatric populations. The aims of this study were: (1) to assess the agreement of two dual energy X-ray absorptiometry (DXA) systems for determining total and regional (arms, legs, trunk) fat, lean, and bone mass and (2) to compare lean soft tissue (LST) hydration correction methods in children. One hundred and twenty four healthy children aged between 6 and 16 years old underwent DXA scans using 2 GE healthcare Lunar systems (iDXA and Prodigy). Tissue hydration was either calculated by dividing total body water (TBW), by 4-component model derived fat free mass (HFFMTBW) or by using the age and sex specific coefficients of Lohman, 1986 (HFFMLohman) and used to correct LST. Regression analysis was performed to develop cross-calibration equations between DXA systems and a paired samples t-test was conducted to assess the difference between LST hydration correction methods. iDXA resulted in significantly lower estimates of total and regional fat and lean mass, compared to Prodigy. HFFMTBW showed a much larger age/sex related variability than HFFMLohman. A 2.0 % difference in LST was observed in the boys (34.5 kg vs 33.8 kg respectively, p < 0.05) and a 2.5% difference in the girls (28.2 kg vs 27.5 kg respectively, p < 0.05) when corrected using either HFFMTBW or HFFMLohman. Care needs to be exercised when combining data from iDXA and Prodigy, as total and regional estimates of body composition can differ significantly. Furthermore, tissue hydration should be taken into account when assessing body composition as it can vary considerably within a healthy paediatric population even within specific age and/or sex groups.

Exploring readiness for implementing best practices: A mixed methods study.

RATIONALE: Evidence-based practice (EBP) can improve health care in underprivileged countries. Bolivia's EBP movement is nascent and the factors contributing to better implementation in nursing are unknown. AIM: To explore Bolivian nurses' readiness to engage in EBP while highlighting the facilitators and barriers for pursuing EBP. METHOD: The study used a sequential explanatory mixed methods study. First, general trends were disclosed via a survey of 170 nurses in La Paz, Bolivia, holding at least a baccalaureate regarding their perceived beliefs about EBP. The survey identified facilitators and barriers for implementing EBP in acute and ambulatory settings. Second, qualitative data was gathered via a focus group of nine nurses with the purpose of enhancing the survey results. RESULTS: The survey results showed that nurses believe that engaging in EBP can improve their clinical practice. However, the nurses' research behaviors were found to be infrequent. Lack of support from the nurses' clinics and hospitals and from non-nursing professionals were identified as barriers for engaging in EBP. The qualitative results revealed underlying limitations to nurses' clinical practice, including "feeling undervalued". CONCLUSIONS: There is a dearth of EBP knowledge among Bolivian nurses stemming from a lack of preparation in EBP environments, including EBP training opportunities. This situation affects nurses' professional dimensions of relational work, power, and collaboration. Collaborative research among educators, professional nursing societies, and local and international organizations could provide initiatives for implementing EBP, based on local health profiles.

My Coronavirus Experience.

A nurse-midwife describes her experience being ill with COVID-19.

Nek7 conformational flexibility and inhibitor binding probed through protein engineering of the R-spine.

Nek7 is a serine/threonine-protein kinase required for proper spindle formation and cytokinesis. Elevated Nek7 levels have been observed in several cancers, and inhibition of Nek7 might provide a route to the development of cancer therapeutics. To date, no selective and potent Nek7 inhibitors have been identified. Nek7 crystal structures exhibit an improperly formed regulatory-spine (R-spine), characteristic of an inactive kinase. We reasoned that the preference of Nek7 to crystallise in this inactive conformation might hinder attempts to capture Nek7 in complex with Type I inhibitors. Here, we have introduced aromatic residues into the R-spine of Nek7 with the aim to stabilise the active conformation of the kinase through R-spine stacking. The strong R-spine mutant Nek7SRS retained catalytic activity and was crystallised in complex with compound 51, an ATP-competitive inhibitor of Nek2 and Nek7. Subsequently, we obtained the same crystal form for wild-type Nek7WT in apo form and bound to compound 51. The R-spines of the three well-ordered Nek7WT molecules exhibit variable conformations while the R-spines of the Nek7SRS molecules all have the same, partially stacked configuration. Compound 51 bound to Nek2 and Nek7 in similar modes, but differences in the precise orientation of a substituent highlights features that could be exploited in designing inhibitors that are selective for particular Nek family members. Although the SRS mutations are not required to obtain a Nek7-inhibitor structure, we conclude that it is a useful strategy for restraining the conformation of a kinase in order to promote crystallogenesis.

Army Antimalarial Drug Development: An Advanced Development Case Study for Tafenoquine.

Malaria is classified as a top-tier infectious disease threat associated with a high risk for mortality among U.S. service members deployed overseas. As malarial drug resistance degrades the efficacy of current gold standard drugs for malarial prophylaxis and treatment, it is vitally important to maintain a robust drug pipeline to discover and develop improved, next-generation antimalarial prevention and treatment tools. The U.S. Army Medical Materiel Development Activity (USAMMDA) manages the medical product development of the malarial drug tafenoquine for malarial prophylaxis to address the threat to U.S. service members. Tafenoquine is an effective prophylactic drug against all parasite life cycle stages and all malaria species that infect humans. Thus, it provides broad capabilities in a single drug for malarial prophylaxis and treatment. Partnerships with industry are a crucial part of USAMMDA's medical product development strategy, by leveraging their drug development experience and manufacturing capabilities to achieve licensure and commercial availability. Additionally, these partnerships capitalize on expertise in the commercial market and help ensure that USAMMDA successfully translates a Department of Defense capability gap into a commercially available product. This article will highlight the strategies used to move this critical antimalarial drug through the development pipeline.

A borane-mediated palladium-catalyzed reductive allylic alkylation of α,ß-unsaturated carbonyl compounds.

The development of the palladium-catalyzed allylic alkylation of in situ generated boron enolates via tandem 1,4-hydroboration is reported. Investigation of the reaction revealed insights into specific catalyst electronic features as well as a profound leaving group effect that proved crucial for achieving efficient allylic alkylation of ester enolates at room temperature and ultimately a highly preparatively useful synthesis of notoriously challenging acyclic all-carbon quaternary stereocenters. The method demonstrates boron enolates as viable pro-nucleophiles in transition-metal catalyzed allylic alkylation, potentially opening up further transformations outside their traditional use.

Quantifying energy expenditure in childhood: utility in managing pediatric metabolic disorders.

BACKGROUND: Energy expenditure prediction equations are used to estimate energy intake based on general population measures. However, when using equations to compare with a disease cohort with known metabolic abnormalities, it is important to derive one's own equations based on measurement conditions matching the disease cohort. OBJECTIVE: We aimed to use newly developed prediction equations based on a healthy pediatric population to describe and predict resting energy expenditure (REE) in a cohort of pediatric patients with thyroid disorders. METHODS: Body composition was measured by DXA and REE was assessed by indirect calorimetry in 201 healthy participants. A prediction equation for REE was derived in 100 healthy participants using multiple linear regression and z scores were calculated. The equation was validated in 101 healthy participants. This method was applied to participants with resistance to thyroid hormone (RTH) disorders, due to mutations in either thyroid hormone receptor ß or α (ß: female n = 17, male n = 9; α: female n = 1, male n = 1), with deviation of REE in patients compared with the healthy population presented by the difference in z scores. RESULTS: The prediction equation for REE = 0.061 * Lean soft tissue (kg) - 0.138 * Sex (0 male, 1 female) + 2.41 (R2 = 0.816). The mean ± SD of the residuals is -0.02 ± 0.44 kJ/min. Mean ± SD REE z scores for RTHß patients are -0.02 ± 1.26. z Scores of -1.69 and -2.05 were recorded in male (n = 1) and female ( n = 1) RTHα patients. CONCLUSIONS: We have described methodology whereby differences in REE between patients with a metabolic disorder and healthy participants can be expressed as a z score. This approach also enables change in REE after a clinical intervention (e.g., thyroxine treatment of RTHα) to be monitored.

How does priority setting for resource allocation happen in commissioning dental services in a nationally led, regionally delivered system: a qualitative study using semistructured interviews with NHS England dental commissioners.

OBJECTIVES: To understand approaches to priority setting for healthcare service resource allocation at an operational level in a nationally commissioned but regionally delivered service. DESIGN: Qualitative study using semistructured interviews and a Framework analysis. SETTING: National Health Service dentistry commissioning teams within subregional offices in England. PARTICIPANTS: All 31 individuals holding the relevant role (dental lead commissioner in subregional offices) were approached directly and from this 14 participants were recruited, with 12 interviews completed. Both male and female genders and all regions were represented in the final sample. RESULTS: Three major themes arose. First, 'Methods of priority setting and barriers to explicit approaches' was a common theme, specifically identifying the main methods as: perpetuating historical allocations, pressure from politicians and clinicians and use of needs assessments while barriers were time and skill deficits, a lack of national guidance and an inflexible contracting arrangements stopping resource allocation. Second, 'Relationships with key stakeholders and advisors' were discussed, showing the important nature of relationships with clinical advisors but variation in the quality of these relationships was noted. Finally, 'Tensions between national and local responsibilities' were illustrated, where there was confusion about where power and autonomy lay. CONCLUSIONS: Commissioners recognised a need for resource allocation but relied on clinical advice and needs assessment in order to set priorities. More explicit priority setting was prevented by structure of the commissioning system and standard national contracts with providers. Further research is required to embed and simplify adoption of tools to aid priority setting.

Resource allocation in NHS dentistry: recognition of societal preferences (RAINDROP): study protocol.

BACKGROUND: Resources in any healthcare systems are scarce relative to need and therefore choices need to be made which often involve difficult decisions about the best allocation of these resources. One pragmatic and robust tool to aid resource allocation is Programme Budgeting and Marginal Analysis (PBMA), but there is mixed evidence on its uptake and effectiveness. Furthermore, there is also no evidence on the incorporation of the preferences of a large and representative sample of the general public into such a process. The study therefore aims to undertake, evaluate and refine a PBMA process within the exemplar of NHS dentistry in England whilst also using an established methodology (Willingness to Pay (WTP)) to systematically gather views from a representative sample of the public. METHODS: Stakeholders including service buyers (commissioners), dentists, dental public health representatives and patient representatives will be recruited to participate in a PBMA process involving defining current spend, agreeing criteria to judge services/interventions, defining areas for investment and disinvestment, rating these areas against the criteria and making final recommendations. The process will be refined based on participatory action research principles and evaluated through semi-structured interviews, focus groups and observation of the process by the research team. In parallel a representative sample of English adults will be recruited to complete a series of four surveys including WTP valuations of programmes being considered by the PBMA panel. In addition a methodological experiment comparing two ways of eliciting WTP will be undertaken. DISCUSSION: The project will allow the PBMA process and particularly the use of WTP within it to be investigated and developed. There will be challenges around engagement with the task by the panel undertaking it and with the outputs by stakeholders but careful relationship building will help to mitigate this. The large volume of data will be managed through careful segmenting of the analysis and the use of the well-established Framework approach to qualitative data analysis. WTP has various potential biases but the elicitation will be carefully designed to minimise these and some methodological investigation will take place.

United States Model Midwifery Legislation and Regulation: Development of a Consensus Document.

INTRODUCTION: Midwifery is defined and regulated across all 50 United States. However, states' regulations vary markedly, creating confusion for policy makers and consumers, and can limit services to women. In 2011, the International Confederation of Midwives released Global Standards for Midwifery Education, Regulation, and Association, providing guidance for international midwifery for the first time. US organizations representing midwifery education, regulation, and professional associations (US MERA) agreed to work together on common goals. METHODS: The purpose of this modified Delphi study, conducted by US MERA, was to develop a consensus document on principles of model US midwifery legislation and regulation. Expert panelists (N = 51) across maternal and child health care professions and consumer groups participated over several iterative rounds. RESULTS: The final document establishes guiding principles for US midwifery regulation, including regulatory authority, education, qualifications, regulation, registration and licensure, standards of practice and conduct, complaints, and third-party payment for services. DISCUSSION: As more US states recognize and license midwives of all credentials and in every practice setting, we can envision a time when equity, informed choice, safety, and seamless access to quality midwifery care will be the right of every birthing family.