The intricacies of tooth enamel: Embryonic origin, development and human genetics.

Tooth enamel is a fascinating tissue with exceptional biomechanical properties that allow it to last for a lifetime. In this mini review, we discuss the unique embryonic origin of this highly mineralized tissue, the complex differentiation process that leads to its "construction" (amelogenesis), and the various genetic conditions that lead to impaired enamel development in humans (amelogenesis imperfecta). Tremendous progress was made in the last 30 years in understanding the molecular and cellular mechanism that leads to normal and pathologic enamel development. However, several aspects of amelogenesis remain to be elucidated and the function of many genes associated with amelogenesis imperfecta still needs to be decoded.

Tropical forest cover, oil palm plantations, and precipitation drive flooding events in Aceh, Indonesia, and hit the poorest people hardest.

Tropical forest loss and degradation in watersheds disrupt essential ecosystem services that regulate water flow, often causing devastating floods that impact agricultural productivity and impoverish downstream communities. Despite its importance, evaluations of the interconnectedness between the depletion of hydrological services and flooding lack an evidence-base in the Global South and, therefore, have little influence on policy dialogue. In this study, we focus on the forest-rich province of Aceh, Indonesia, using local and national newspaper articles to compile information on flood events between 2011 and 2018. We explored spatio-temporal flood patterns with a combination of climatic, topographic, and environmental factors. We compiled 2,029 reported flood events in mainland Aceh located in 20 of the 21 districts/cities, with a disproportionately high occurrence (71%) in four districts. The trend of flood events exhibited an increasing pattern between 2011 and 2018. Over this period, floods displaced ~158,000 people and damaged ~24,500 houses and ~11,500 ha of agricultural land. Our generalized linear mixed-effect model found that reported flood events were more likely to occur in areas with lower tree cover, more oil palm plantations, and higher precipitation. Areas with a lower human population density and higher poverty rates were found to be most susceptible to flooding events. Our findings highlight the critical link between forest preservation and flood prevention, and the irreplaceable role that forests play in ensuring the well-being of local communities, especially those affected by poverty. Our study underscores the importance of considering these interconnected factors in future land use and economic development plans and policies.

Acute hyperlipidemia has transient effects on large-scale bone regeneration in male mice.

Excessive dietary fat intake increases plasma lipid levels and has been associated with reduced bone mineral density (BMD) and increased risk of osteoporotic fracture, especially in older postmenopausal women. The objective of this study was to investigate whether there are sex-related differences in lipid metabolism that could have an impact on large-scale bone regeneration. Because ribs provide a unique exception as the only bones capable of completely regenerating large-scale defects, we used a rib resection mouse model in which human features are recapitulated. After 10 days of exposure to a low-fat diet or high-fat diet (HFD), we performed large-scale rib resection surgeries on male and female mice (6-7 weeks old) with deletion of the low-density lipoprotein (LDL) receptor (Ldlr-/-) and age- and sex-matched wild-type (WT) mice were used as controls. Plasma analysis showed that short-term exposure to HFD significantly increases total cholesterol, LDL cholesterol, and triglycerides levels in Ldlr-/- mice but not in WT, with no differences between males and females. However, under HFD, callus bone volume was significantly reduced exclusively in male Ldlr-/- mice when compared to WT, although these differences were no longer apparent by 21 days after resection. Regardless of diet or genotype, BMD of regenerated ribs did not differ significantly between groups, although male mice typically had lower average BMD values. Together, these results suggest that short-term hyperlipidemia has transient effects on large-scale bone regeneration exclusively in male mice.

Paving the way for affordable and equitable liposomal amphotericin B access worldwide.

Amphotericin B has long been crucial for treating many serious infectious diseases, such as invasive fungal infections and visceral leishmaniasis, particularly for patients who are immunocompromised, including those with advanced HIV infection. The conventional amphotericin B deoxycholate formulation has largely been replaced in high-income countries with liposomal amphotericin B (LAmB), which has many advantages, including lower rates of adverse events, such as nephrotoxicity and anaemia. Despite an evident need for LAmB in low-income and middle-income countries, where mortality from invasive fungal infections is still substantial, many low-income and middle-income countries still often use the amphotericin B deoxycholate formulation because of a small number of generic formulations and the high price of the originator LAmB. The pricing of LAmB is also highly variable between countries. Overcoming supply barriers through the availability of additional quality-assured, generic formulations of LAmB at accessible prices would substantially facilitate equitable access and have a substantial effect on mortality attributable to deadly fungal infections.

Ocular findings in Jansen metaphyseal chondrodysplasia.

Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by germline heterozygous PTHR1 variants resulting in constitutive activation of parathyroid hormone type 1 receptor. A description of ocular manifestations of the disease is lacking. Six patients with JMC underwent a detailed ophthalmic evaluation, spectral-domain optical coherence tomography (OCT), visual field testing, and craniofacial CT scans. Five of 6 patients had good visual acuity. All patients had widely spaced eyes; 5/6 had downslanted palpebral fissures. One patient had proptosis, and another had bilateral ptosis. Two patients had incomplete closure of the eyelids (lagophthalmos), one had a history of progressive right facial nerve palsy with profuse epiphora, while the second had advanced optic nerve atrophy with corresponding retinal nerve fiber layer (RNFL) thinning on OCT and significant bilateral optic canal narrowing on CT scan. Additionally, this patient also had central visual field defects and abnormal color vision. A third patient had normal visual acuity, subtle temporal pallor of the optic nerve head, normal average RNFL, but decreased temporal RNFL and retinal ganglion cell layer analysis (GCA) on OCT. GCA was decreased in 4/6 patients indicating a subclinical optic nerve atrophic process. None of the patients had glaucoma or high myopia. These data represent the first comprehensive report of ophthalmic findings in JMC. Patients with JMC have significant eye findings associated with optic canal narrowing due to extensive skull base dysplastic bone overgrowth that appear to be more prevalent and pronounced with age. Progressive optic neuropathy from optic canal narrowing may be a feature of JMC, and OCT GCA can serve as a useful biomarker for progression in the setting of optic canal narrowing. We suggest that patients with JMC should undergo regular ophthalmic examination including color vision, OCT, visual field testing, orbital, and craniofacial imaging.

Integrin signalling in joint development, homeostasis and osteoarthritis.

Integrins are key regulators of cell-matrix interactions during joint development and joint tissue homeostasis, as well as in the development of osteoarthritis (OA). The signalling cascades initiated by the interactions of integrins with a complex network of extracellular matrix (ECM) components and intracellular adaptor proteins orchestrate cellular responses necessary for maintaining joint tissue integrity. Dysregulated integrin signalling, triggered by matrix degradation products such as matrikines, disrupts this delicate balance, tipping the scales towards an environment conducive to OA pathogenesis. The interplay between integrin signalling and growth factor pathways further underscores the multifaceted nature of OA. Moreover, emerging insights into the role of endocytic trafficking in regulating integrin signalling add a new layer of complexity to the understanding of OA development. To harness the therapeutic potential of targeting integrins for mitigation of OA, comprehensive understanding of their molecular mechanisms across joint tissues is imperative. Ultimately, deciphering the complexities of integrin signalling will advance the ability to treat OA and alleviate its global burden.

Explainable deep learning and biomechanical modeling for TMJ disorder morphological risk factors.

Clarifying multifactorial musculoskeletal disorder etiologies supports risk analysis, development of targeted prevention, and treatment modalities. Deep learning enables comprehensive risk factor identification through systematic analyses of disease data sets but does not provide sufficient context for mechanistic understanding, limiting clinical applicability for etiological investigations. Conversely, multiscale biomechanical modeling can evaluate mechanistic etiology within the relevant biomechanical and physiological context. We propose a hybrid approach combining 3D explainable deep learning and multiscale biomechanical modeling; we applied this approach to investigate temporomandibular joint (TMJ) disorder etiology by systematically identifying risk factors and elucidating mechanistic relationships between risk factors and TMJ biomechanics and mechanobiology. Our 3D convolutional neural network recognized TMJ disorder patients through participant-specific morphological features in condylar, ramus, and chin. Driven by deep learning model outputs, biomechanical modeling revealed that small mandibular size and flat condylar shape were associated with increased TMJ disorder risk through increased joint force, decreased tissue nutrient availability and cell ATP production, and increased TMJ disc strain energy density. Combining explainable deep learning and multiscale biomechanical modeling addresses the "mechanism unknown" limitation undermining translational confidence in clinical applications of deep learning and increases methodological accessibility for smaller clinical data sets by providing the crucial biomechanical context.

Single-cell and spatially resolved interactomics of tooth-associated keratinocytes in periodontitis.

Periodontitis affects billions of people worldwide. To address relationships of periodontal niche cell types and microbes in periodontitis, we generated an integrated single-cell RNA sequencing (scRNAseq) atlas of human periodontium (34-sample, 105918-cell), including sulcular and junctional keratinocytes (SK/JKs). SK/JKs displayed altered differentiation states and were enriched for effector cytokines in periodontitis. Single-cell metagenomics revealed 37 bacterial species with cell-specific tropism. Fluorescence in situ hybridization detected intracellular 16 S and mRNA signals of multiple species and correlated with SK/JK proinflammatory phenotypes in situ. Cell-cell communication analysis predicted keratinocyte-specific innate and adaptive immune interactions. Highly multiplexed immunofluorescence (33-antibody) revealed peri-epithelial immune foci, with innate cells often spatially constrained around JKs. Spatial phenotyping revealed immunosuppressed JK-microniches and SK-localized tertiary lymphoid structures in periodontitis. Here, we demonstrate impacts on and predicted interactomics of SK and JK cells in health and periodontitis, which requires further investigation to support precision periodontal interventions in states of chronic inflammation.

Broad proteomics analysis of seeding-induced aggregation of α-synuclein in M83 neurons reveals remodeling of proteostasis mechanisms that might contribute to Parkinson's disease pathogenesis.

Aggregation of misfolded α-synuclein (α-syn) is a key characteristic feature of Parkinson's disease (PD) and related synucleinopathies. The nature of these aggregates and their contribution to cellular dysfunction is still not clearly elucidated. We employed mass spectrometry-based total and phospho-proteomics to characterize the underlying molecular and biological changes due to α-syn aggregation using the M83 mouse primary neuronal model of PD. We identified gross changes in the proteome that coincided with the formation of large Lewy body-like α-syn aggregates in these neurons. We used protein-protein interaction (PPI)-based network analysis to identify key protein clusters modulating specific biological pathways that may be dysregulated and identified several mechanisms that regulate protein homeostasis (proteostasis). The observed changes in the proteome may include both homeostatic compensation and dysregulation due to α-syn aggregation and a greater understanding of both processes and their role in α-syn-related proteostasis may lead to improved therapeutic options for patients with PD and related disorders.

Oral Health-Related Quality of Life in Rare Disorders of Congenital Facial Weakness.

Congenital facial weakness (CFW) encompasses a heterogenous set of rare disorders presenting with decreased facial movement from birth, secondary to impaired function of the facial musculature. The aim of the present study is to provide an analysis of subject-reported oral health-related quality of life (OHRQoL) in congenital facial weakness (CFW) disorders. Forty-four subjects with CFW and age- and sex- matched controls were enrolled in an Institutional Review Board (IRB)-approved study. Demographic data, medical and surgical history, comprehensive oral examination, and the Oral Health Impact Profile (OHIP-14) were obtained. Compared to unaffected controls, subjects with CFW had higher OHIP-14 scores overall (mean ± SD: 13.11 ± 8.11 vs. 4.46 ± 4.98, p < 0.0001) and within five of seven oral health domains, indicating decreased OHRQoL. Although subjects with Moebius syndrome (MBS) were noted to have higher OHIP-14 scores than those with Hereditary Congenital Facial Paresis (HCFP), there was no significant correlation in OHIP-14 score to age, sex, or specific diagnosis. An increase in OHIP-14 scores in subjects was detected in those who had undergone reanimation surgery. In conclusion, subjects with CFW had poorer OHRQoL compared to controls, and subjects with MBS had poorer OHRQoL than subjects with HCFP. This study provides better understanding of oral health care needs and quality of life in a CFW cohort and suggests that guidelines for dental treatment are required.

Examining the associations between microglia genetic capacity, early life exposures and white matter development at the level of the individual.

There are inter-individual differences in susceptibility to the influence of early life experiences for which the underlying neurobiological mechanisms are poorly understood. Microglia play a role in environmental surveillance and may influence individual susceptibility to environmental factors. As an index of neurodevelopment, we estimated individual slopes of mean white matter fractional anisotropy (WM-FA) across three time-points (age 4.5, 6.0, and 7.5 years) for 351 participants. Individual variation in microglia reactivity was derived from an expression-based polygenic score(ePGS) comprised of Single Nucleotide Polymorphisms (SNPs) functionally related to the expression of microglia-enriched genes.A higher ePGS denotes an increased genetic capacity for the expression of microglia-related genes, and thus may confer a greater capacity to respond to the early environment and to influence brain development. We hypothesized that this ePGS would associate with the WM-FA index of neurodevelopment and moderate the influence of early environmental factors.Our findings show sex dependency, where a significant association between WM-FA and microglia ePGS was only obtained for females.We then examined associations with perinatal factors known to decrease (optimal birth outcomes and familial conditions) or increase (systemic inflammation) the risk for later mental health problems.In females, individuals with high microglia ePGS showed a negative association between systemic inflammation and WM-FA and a positive association between more advantageous environmental conditions and WM-FA. The microglia ePGS in females thus accounted for variations in the influence of the quality of the early environment on WM-FA.Finally, WM-FA slopes mediated the association of microglia ePGS with interpersonal problems and social hostility in females. Our findings suggest the genetic capacity for microglia function as a potential factor underlying differential susceptibility to early life exposuresthrough influences on neurodevelopment.

The National Institutes of Health Lasker Clinical Research Scholars Program: A Decade of Launching Clinician-Scientist Careers.

PURPOSE: In response to the decades-long decrease in U.S. clinician-scientists, the National Institutes of Health (NIH) and the Albert and Mary Lasker Foundation launched the Lasker Clinical Research Scholars Program in academic year 2011 to 2012. The investigators examined the early outcomes of this program. METHOD: Thirty-nine scholars have matriculated into the program as of May 2023. Productivity was assessed for all scholars who joined the program before October 2020 (n = 31). Extramural early-stage investigators (ESIs) were used as a control group, and coarsened exact matching was used to compare the groups. The scholars were compared with the matched ESIs on 4 productivity metrics: publication count, weighted relative citation ratio, clinical impact, and approximate potential to translate. Publication records for both groups were compiled using the NIH Office of Portfolio Analysis' name disambiguation method and manually curated to ensure integrity of the data set. RESULTS: Of the 39 scholars, 29 were compared with 121 matched extramural ESIs. Five years before matriculation, the 2 groups had comparable numbers of publications, but scholars had a higher median weighted relative citation ratio, clinical impact, and approximate potential to translate score. Five years after matriculation, the scholars had a higher median number of publications than the ESIs, and the gap between scholars and ESIs, with scholars having higher scores, had widened for all metrics except approximate potential to translate scores. Of 10 of the 39 scholars at or approaching tenure eligibility, 6 have attained tenure (3 at NIH and 3 in academic institutions), and 4 are on track to attain tenure at NIH. CONCLUSIONS: All the Lasker clinical research scholars are substantially involved in clinical and translational research. Their productivity matches or exceeds that of a matched cohort of ESIs at U.S. academic institutions.

Cardiometabolic risk factors in social housing residents: A multi-site cross-sectional survey in older adults from Ontario, Canada.

OBJECTIVE: This study describes cardiometabolic diseases and related risk factors in vulnerable older adults residing in social housing, aiming to inform primary care initiatives to reduce health inequities. Associations between sociodemographic variables, modifiable risk factors (clinical and behavioural), health-related quality of life and self-reported cardiometabolic diseases were investigated. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study with an interviewer-administered questionnaire. Data was collected from residents aged 55 years and older residing in 30 social housing apartment buildings in five regions in Ontario, Canada. OUTCOME MEASURES: The proportion of cardiometabolic diseases and modifiable risk factors (e.g., clinical, behavioural, health status) in this population was calculated. RESULTS: Questionnaires were completed with 1065 residents: mean age 72.4 years (SD = 8.87), 77.3% were female, 87.2% were white; 48.2% had less than high school education; 22.70% self-reported cardiovascular disease (CVD), 10.54% diabetes, 59.12% hypertension, 43.59% high cholesterol. These proportions were higher than the general population. Greater age was associated with overweight, high cholesterol, high blood pressure and CVD. Poor health-related quality of life was associated with self-reported CVD and diabetes. CONCLUSIONS: Older adults residing in social housing in Ontario have higher proportion of cardiovascular disease and modifiable risk factors compared to the general population. This vulnerable population should be considered at high risk of cardiometabolic disease. Primary care interventions appropriate for this population should be implemented to reduce individual and societal burdens of cardiometabolic disease.

Essential and Toxic Elements in Infant Cereal in Brazil: Exposure Risk Assessment.

Infant cereals, one of the first solid foods introduced to infants, have been reported to pose risks to human health because they contain toxic elements and an excess of essential elements. The objective of this study was to assess the cancer and non-cancer risk of exposure to essential and toxic elements in infant cereal in Brazil. In our analyses, we included data from 18 samples of infant cereals made from different raw materials and estimated the incremental lifetime cancer risks and non-cancer hazard quotients (HQs) for their consumption. Rice cereal is particularly concerning because it is immensely popular and usually contains high levels of inorganic arsenic. In addition to arsenic, we assessed aluminum, boron, barium, cadmium, chromium, copper, lead, manganese, nickel, selenium, silver, strontium, and zinc. The cancer risk was highest for rice cereal, which was also found to have an HQ > 1 for most of the tested elements. Inorganic As was the element associated with the highest cancer risk in infant cereal. All of the infant cereals included in this research contained at least one element with an HQ > 1. The essential and non-essential elements that presented HQ > 1 more frequently were zinc and cadmium, respectively. The cancer and non-cancer risks could potentially be decreased by reducing the amount of toxic and essential elements (when in excess), and public policies could have a positive influence on risk management in this complex scenario.

How to conduct an annual literature update for top articles relevant to clinical practice in geriatrics: A scoping review.

BACKGROUND: Clinical educators in geriatrics are often tasked with presenting a literature update at annual conferences and scientific meetings, which is a highly regarded continuing medical education (CME) activity. Preparation of an annual literature update cannot rely on bibliometric analysis due to time lag and poor correlation between bibliometrics and expert opinion on clinical relevance. The methodology of how top research articles of the year are selected and presented is not often reported. METHODS: We conducted a scoping review for published reports of a curated selection of recent articles critically appraised for high impact to clinical practice in general geriatrics, published from 2010 to 2022. RESULTS: Six annual literature updates were included for study. Three updates detailed their article sources, ranging from a survey of clinicians, consulting seven individual journals, searching up to four bibliographic databases, scanning social media outlets, and reviewing previous literature updates. One update reported a detailed method of article selection and consensus development. Critical appraisal of articles followed a structured reporting of clinical context, methods, results, and a statement of clinical implication or bottom line. Three of the six updates' results were disseminated in an annual conference update and did not evaluate learning outcomes of the audience. We mapped the results on a four-step framework of article search, selection, critical appraisal, and dissemination of knowledge. CONCLUSIONS: Educators in geriatrics consult numerous article sources spanning multiple journals, databases, social media, and peer suggestions to create an annual literature update. The methodology of article search and selection is inconsistently described. In this exciting area of CME, we encourage educators to develop a framework for conducting annual literature updates in geriatrics and expand its scholarship.

Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis.

BACKGROUND: The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. METHODS AND FINDINGS: We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies. CONCLUSIONS: Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance. TRIAL REGISTRATION: ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

An Update on the Role of MRI in Treatment Stratification of Patients with Cervical Cancer.

Cervical cancer is the fourth most common cancer in women worldwide and the most common gynaecological malignancy. The FIGO staging system is the most commonly utilised classification system for cervical cancer worldwide. Prior to the most recent update in the FIGO staging in 2018, the staging was dependent upon clinical assessment alone. Concordance between the surgical and clinical FIGO staging decreases rapidly as the tumour becomes more advanced. MRI now plays a central role in patients diagnosed with cervical cancer and enables accurate staging, which is essential to determining the most appropriate treatment. MRI is the best imaging option for the assessment of tumour size, location, and parametrial and sidewall invasion. Notably, the presence of parametrial invasion precludes surgical options, and the patient will be triaged to chemoradiotherapy. As imaging is intrinsic to the new 2018 FIGO staging system, nodal metastases have been included within the classification as stage IIIC disease. The presence of lymph node metastases within the pelvis or abdomen is associated with a poorer prognosis, which previously could not be included in the staging classification as these could not be reliably detected on clinical examination. MRI findings corresponding to the 2018 revised FIGO staging of cervical cancers and their impact on treatment selection will be described.

Three-Dimensional Cephalometric Landmark Annotation Demonstration on Human Cone Beam Computed Tomography Scans.

Craniofacial cephalometric analysis is a diagnostic tool used for the assessment of the relationship of various bones and soft tissues in the head and face. Cephalometric analysis has been traditionally conducted with the use of 2D radiographs and landmark sets and restricted to size, linear and angular measurements, and 2D relationships. The increasing use of 3D cone beam computed tomography (CBCT) scans in the dental field dictates the need for the evolution to 3D cephalometric analysis, which incorporates shape and a more realistic analysis of longitudinal development in all three planes. This study is a demonstration of 3D cephalometric analysis with the use of a validated set of skeletal tissue landmarks on human CBCT scans. Detailed instructions for the annotation of each landmark on a 3D volume are provided as part of a step-by-step protocol. The generated measurements and 3D coordinates of the landmarks can be exported and used both for clinical and research purposes. The introduction of 3D cephalometric analysis in basic and clinical craniofacial studies will lead to future advancements in the field of craniofacial growth and development.

Multidrug Aerosol Delivery During Mechanical Ventilation.

Background: In the critically ill, pulmonary vasodilators are often provided off label to intubated patients using continuous nebulization. If additional aerosol therapies such as bronchodilators or antibiotics are needed, vasodilator therapy may be interrupted. This study assesses aerosol systems designed for simultaneous delivery of two aerosols using continuous nebulization and bolus injection without interruption or circuit disconnection. Methods: One i-AIRE dual-port breath-enhanced jet nebulizer (BEJN) or two Aerogen® Solo vibrating mesh nebulizers (VMNs) were installed on the dry side of the humidifier. VMN were stacked; one for infusion and the second for bolus drug delivery. The BEJN was powered by air at 3.5 L/min, 50 psig. Radiolabeled saline was infused at 5 and 10 mL/h with radiolabeled 3 and 6 mL bolus injections at 30 and 120 minutes, respectively. Two adult breathing patterns (duty cycle 0.13 and 0.34) were tested with an infusion time of 4 hours. Inhaled mass (IM) expressed as % of initial syringe activity (IM%/min) was monitored in real time with a ratemeter. All delivered radioaerosol was collected on a filter at the airway opening. Transients in aerosol delivery were measured by calibrated ratemeter. Results: IM%/h during continuous infusion was linear and predictable, mean ± standard deviation (SD): 2.12 ± 1.45%/h, 2.47 ± 0.863%/h for BEJN and VMN, respectively. BEJN functioned without incident. VMN continuous aerosol delivery stopped spontaneously in 3 of 8 runs (38%); bolus delivery stopped spontaneously in 3 of 16 runs (19%). Tapping restarted VMN function during continuous and bolus delivery runs. Bolus delivery IM% (mean ± SD): 20.90% ± 7.01%, 30.40% ± 11.10% for BEJN and VMN, respectively. Conclusion: Simultaneous continuous and bolus nebulization without circuit disconnection is possible for both jet and mesh technology. Monitoring of VMN devices may be necessary in case of spontaneous interruption of nebulization.