Recommendations for Cardiac Point-of-Care Ultrasound Nomenclature.

Point-of-care ultrasound (POCUS) involves the acquisition, interpretation, and immediate clinical integration of ultrasonographic imaging performed by a treating clinician. The current state of cardiac POCUS terminology is heterogeneous and ambiguous, in part because it evolved through siloed specialty practices. In particular, the medical literature and colloquial medical conversation contain a wide variety of terms that equate to cardiac POCUS. While diverse terminology aided in the development and dissemination of cardiac POCUS throughout multiple specialties, it also contributes to confusion and raises patient safety concerns. This statement is the product of a diverse and inclusive Writing Group from multiple specialties, including medical linguistics, that employed an iterative process to contextualize and standardize a nomenclature for cardiac POCUS. We sought to establish a deliberate vocabulary that is sufficiently unrelated to any specialty, ultrasound equipment, or clinical setting to enhance consistency throughout the academic literature and patient care settings. This statement (1) reviews the evolution of cardiac POCUS-related terms; (2) outlines specific recommendations, distinguishing between intrinsic and practical differences in terminology; (3) addresses the implications of these recommendations for current practice; and (4) discusses the implications for novel technologies and future research.

Integrating PNPLA3 into clinical risk prediction.

The PNPLA3-rs738409-G variant was the first common variant associated with hepatic fat accumulation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, to date, the clinical translation of this discovery has been minimal because it has not yet been clearly demonstrated where the genetic information may play an independent and additional role in clinical risk prediction. In this mini-review, we will discuss the most relevant evidence regarding the potential integration of the PNPLA3 variant into scores and algorithms for liver disease diagnostics and risk stratification, specifically focusing on MASLD but also extending to liver diseases of other etiologies. The PNPLA3 variant adds little in diagnosing the current state of the disease, whether in terms of presence/absence of metabolic dysfunction-associated steatohepatitis or the stage of fibrosis. While it can play an important role in prediction, allowing for the early definition of risk profiles that enable tailored monitoring and interventions over time, this is most valuable when applied to populations with relatively high pre-test probability of having significant fibrosis based on either non-invasive tests (e.g. Fibrosis-4) or demographics (e.g. diabetes). Indeed, in this context, integrating FIB4 with the PNPLA3 genotype can refine risk stratification, though there is still no evidence that genetic information adds to liver stiffness determined by elastography. Similarly, in patients with known liver cirrhosis, knowing the PNPLA3 genotype can play a role in predicting the risk of hepatocellular carcinoma, while more doubts remain about the risk of decompensation.

Enabling Visible Light Sensitization of YbIII, NdIII and ErIII in Dimeric LnIII/GaIII Metallacrowns through Functionalization with RuII Complexes for NIR-II Multiplex Imaging.

Multiplex imaging in the second near-infrared window (NIR-II, 1000-1700 nm) provides exciting opportunities for more precise understanding of biological processes and more accurate diagnosis of diseases by enabling real-time acquisition of images with improved contrast and spatial resolution in deeper tissues. Today, the number of imaging agents suitable for this modality remains very scarce. In this work, we have synthesized and fully characterized, including theoretical calculations, a series of dimeric LnIII/GaIII metallacrowns bearing RuII polypyridyl complexes, LnRu-3 (Ln = YIII, YbIII, NdIII, ErIII). Relaxed structures of YRu-3 in the ground and the excited electronic states have been calculated using dispersion-corrected density functional theory methods. Detailed photophysical studies of LnRu-3 have demonstrated that characteristic emission signals of YbIII, NdIII and ErIII in the NIR-II range can be sensitized upon excitation in the visible range through RuII-centered metal-to-ligand charge transfer (MLCT) states. We have also showed that these NIR-II signals are unambiguously detected in an imaging experiment using capillaries and biological tissue-mimicking phantoms. This work opens unprecedented perspectives for NIR-II multiplex imaging using LnIII-based molecular compounds.

Identifying health and healthcare priorities in rural areas: A concept mapping study informed by consumers, health professionals and researchers.

BACKGROUND: It is vital that health service delivery and health interventions address patients' needs or preferences, are relevant for practice and can be implemented. Involving those who will use or deliver healthcare in priority-setting can lead to health service delivery and research that is more meaningful and impactful. This is particularly crucial in rural communities, where limited resources and disparities in healthcare and health outcomes are often more pronounced. The aim of this study was to determine the health and healthcare priorities in rural communities using a region-wide community engagement approach. METHODS: This multi-methods study was conducted in five rural communities in the Grampians region, Western Victoria, Australia. It involved six concept mapping steps: (1) preparation, (2) generation (brainstorming statements and identifying rating criteria), (3) structuring statements (sorting and rating statements), (4) representation of statements, (5) interpretation of the concept map and (6) utilization. Community forums, surveys and stakeholder consultations with community members and health professionals were used in Step 2. An innovative online group concept mapping platform, involving consumers, health professionals and researchers was used in Step 3. RESULTS: Overall, 117 community members and 70 health professionals identified 400 health and healthcare issues. Six stakeholder consultation sessions (with 16 community members and 16 health professionals) identified three key values for prioritizing health issues: equal access for equal need, effectiveness and impact (number of people affected). Actionable priorities for healthcare delivery were largely related to access issues, such as the challenges navigating the healthcare system, particularly for people with mental health issues; the lack of sufficient general practitioners and other health providers; the high travel costs; and poor internet coverage often impacting technology-based interventions for people in rural areas. CONCLUSIONS: This study identified actionable health and healthcare priorities from the perspective of healthcare service users and providers in rural communities in Western Victoria. Issues related to access, such as the inequities in healthcare costs, the perceived lack of quality and availability of services, particularly in mental health and disability, were identified as priorities. These insights can guide future research, policy-making and resource allocation efforts to improve healthcare access, quality and equity in rural communities.

Mortality outcomes in individuals with MASLD versus MASLD and increased alcohol intake.

BACKGROUND AND AIM: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a leading cause of chronic liver disease worldwide. A new entity termed MetALD has also been described and is defined as individuals with MASLD and increased alcohol intake. However, the natural history of MetALD compared with MASLD is unknown. We aimed to compare longitudinal outcomes in patients with MASLD versus MetALD. METHODS: This study was performed using data from the National Health and Nutrition Examination Survey from 2011 to 2018. MASLD patients (defined by the United States Fatty Liver Index > 30) who met cardiometabolic criteria including body mass index (BMI) > 25 (BMI > 23 in Asians), hypertension, diabetes mellitus, dyslipidemia, and hypertriglyceridemia were included. MetALD was defined as MASLD with increased alcohol intake (3-6 standard drinks per day in males; 2-5 standard drinks per day in females). A comparison of overall, cardiovascular, cancer-related, and other causes of mortality in patients with MASLD versus MetALD was performed. RESULTS: A total of 2838 individuals with MASLD and 2557 individuals with MetALD were included with a median follow-up time of 56 months. MetALD patients were at increased risk of cancer-related mortality compared with patients with MASLD (hazard ratio 1.32; 95% confidence interval 1.14-1.53; P < 0.01). However, there was no significant difference in overall, cardiovascular, and other causes of mortality. CONCLUSIONS: Patients with MetALD were at higher risk for cancer-related mortality than MASLD. Close attention to regular cancer surveillance and accurate classification of alcohol consumption in individuals with diagnosed MASLD is warranted to help improve patient care and outcome.

Association between vitamin D level and cataract: A systematic review and meta-analysis.

PURPOSE: The association between serum vitamin D level and cataract remains controversial. This study aims to evaluate the association between vitamin D level and cataract. METHODS: In this study, articles in the PubMed, Web of Science, and EMBASE databases were searched up to 30 August 2023 and 626 articles were screened. Four studies involving a total of 10,928 subjects with cataract and 10,117 control subjects met the inclusion criteria. RESULTS: Decreased serum vitamin D level was associated with higher incidence of cataract (P = 0.047; MD: -4.87; 95%CI: [-9.67, -0.07]). In the subgroup analysis by sex, a significant association was found between serum vitamin D level and cataract in both male (P = 0.01, MD: -2.15,95%CI: [-3.83, -0.46]) and female (P < 0.01; MD: -6.67,95%CI: [-8.20, -5.14]).In the subgroup analysis by the types of cataract, significant association was found between serum vitamin D level and nuclear (P < 0.01; MD: -10.48; 95%CI: [-12.72, -8.24]) and posterior subcapsular cataract (P = 0.02; MD: -6.05; 95%CI: [-11.30, -0.80]) but not in cortical cataract (P = 0.14; MD: -6.74; 95%CI: [-15.70, 2.22]). CONCLUSION: This meta-analysis revealed potential association between serum vitamin D level and cataract, more significant in female, and the subtypes of nuclear and posterior subcapsular cataract.

Revving up a Designed Copper Nitrite Reductase Using Non-Coded Active Site Ligands.

Herein, we report a three stranded coiled-coil (3SCC) de novo protein containing a type II copper center (CuT2) composed of 6-membered ring N-heterocycles. This design yields the most active homogenous copper nitrite reductase (CuNiR) mimic in water. We achieved this result by controlling three factors. First, previous studies with Nδ and Nε -Methyl Histidine had indicated that a ligand providing pyridine-like electronic character to the copper site was superior to the more donating Nδ for nitrite reduction. By substitution of the parent histidine with the non-coded amino acids pyridyl alanine (3'-Pyridine [3'Py] vs 4'-Pyridine [4'Py]), an authentic pyridine donor was employed without the complications of the coupling of both electronic and tautomeric effects of histidine or methylated histidine. Second, by changing the position of the nitrogen atom within the active site (4'-Pyridine vs. 3'Pyridine) a doubling of the enzyme's catalytic efficiency resulted. This effect was driven exclusivity by substrate binding to the copper site. Third, we replaced the leucine layer adjacent to the active site with an alanine, and the disparity between the 3'Py and 4'Py became more apparent. The decreased steric bulk minimally impacted the 3'Py derivative; however, the 4'Py K m decreased by an order of magnitude (600 mM to 50 mM), resulting in a 40-fold enhancement in the k cat/K m compared to the analogues histidine site and a 1500-fold improvement compared with the initially reported CuNiR catalyst of this family, TRIW-H. When combined with XANES/EXAFS data, the relaxing of the Cu(I) site to a more 2-coordinate Cu(I) like structure in the resting state increases the overall catalytic efficiency of nitrite reduction via the lowering of K m. This study illustrates how by combining advanced spectroscopic methods, detailed kinetic analysis, and a broad toolbox of amino acid side chain functionality, one can rationally design systems that optimize biomimetic catalysis.

MutaT7GDE: A Single Chimera for the Targeted, Balanced, Efficient, and Processive Installation of All Possible Transition Mutations In Vivo.

Deaminase-T7 RNA polymerase fusion (MutaT7) proteins are a growing class of synthetic biology tools used to diversify target genes during in vivo laboratory evolution. To date, MutaT7 chimeras comprise either a deoxyadenosine or deoxycytidine deaminase fused to a T7 RNA polymerase. Their expression drives targeted deoxyadenosine-to-deoxyguanosine or deoxycytidine-to-deoxythymidine mutagenesis, respectively. Here, we repurpose recently engineered substrate-promiscuous general deaminases (GDEs) to establish a substantially simplified system based on a single chimeric enzyme capable of targeting both deoxyadenosine and deoxycytidine. We assess on- and off-target mutagenesis, strand and context preference, and parity of deamination for four different MutaT7GDE constructs. We identify a single chimera that installs all possible transition mutations more efficiently than preexisting, more cumbersome MutaT7 tools. The optimized MutaT7GDE chimera reported herein is a next-generation hypermutator capable of mediating efficient and uniform target-gene diversification during in vivo directed evolution.

Thermal infrared directs host-seeking behaviour in Aedes aegypti mosquitoes.

Mosquito-borne diseases affect hundreds of millions of people annually and disproportionately impact the developing world1,2. One mosquito species, Aedes aegypti, is a primary vector of viruses that cause dengue, yellow fever and Zika. The attraction of Ae. aegypti female mosquitos to humans requires integrating multiple cues, including CO2 from breath, organic odours from skin and visual cues, all sensed at mid and long ranges, and other cues sensed at very close range3-6. Here we identify a cue that Ae. aegypti use as part of their sensory arsenal to find humans. We demonstrate that Ae. aegypti sense the infrared (IR) radiation emanating from their targets and use this information in combination with other cues for highly effective mid-range navigation. Detection of thermal IR requires the heat-activated channel TRPA1, which is expressed in neurons at the tip of the antenna. Two opsins are co-expressed with TRPA1 in these neurons and promote the detection of lower IR intensities. We propose that radiant energy causes local heating at the end of the antenna, thereby activating temperature-sensitive receptors in thermosensory neurons. The realization that thermal IR radiation is an outstanding mid-range directional cue expands our understanding as to how mosquitoes are exquisitely effective in locating hosts.

Estimated Exposure to 6 Potentially Hepatotoxic Botanicals in US Adults.

Importance: Use of herbal and dietary supplements (HDSs) accounts for an increasing proportion of drug hepatotoxicity cases. Turmeric or curcumin, green tea extract, Garcinia cambogia, black cohosh, red yeast rice, and ashwagandha are the most frequently reported hepatoxic botanicals, but their prevalence and reasons for use in the general population are unknown. Objective: To assess the prevalence and clinical characteristics of adult consumers of 6 potentially hepatoxic botanicals. Design, Setting, and Participants: This survey study analyzed nationally representative data from the National Health and Nutrition Examination Survey (NHANES), a nationally representative, cross-sectional survey of the general US population. Prescription drug and HDS exposure data in the past 30 days were analyzed, and 2020 US Census data were used for population estimates. Data were analyzed July 1, 2023, to February 1, 2024. Exposures: Adult NHANES participants enrolled between January 2017 and March 2020. Main Outcomes and Measures: Baseline weighted characteristics of HDS users and users of 6 potentially hepatotoxic botanical products were compared with non-HDS users. Multivariable analysis was undertaken to identify factors associated with HDS use or at-risk botanical use. Results: Among 9685 adults enrolled in this NHANES cohort, the mean (SE) age was 47.5 (0.5) years, and 51.8% (95% CI, 50.2%-53.4%) were female. The overall prevalence of HDS product use was 57.6% (95% CI, 55.9%-59.4%), while the prevalence of using the 6 botanicals of interest was 4.7% (95% CI, 3.9%-5.7%). Turmeric-containing botanicals were most commonly used (n = 236), followed by products containing green tea (n = 92), ashwagandha (n = 28), Garcinia cambogia (n = 20), red yeast rice (n = 20), and black cohosh (n = 19). Consumers of these 6 botanicals were significantly older (adjusted odds ratio [AOR], 2.36 [95% CI, 1.06-5.25]; P = .04 for 40-59 years of age and AOR, 3.96 [95% CI, 1.93-8.11]; P = .001 for ≥60 years of age), had a higher educational level (AOR, 4.78 [95% CI, 2.62-8.75]; P < .001), and were more likely to have arthritis (AOR, 2.27 [95% CI, 1.62-3.29]; P < .001) compared with non-HDS users. An estimated 15 584 599 (95% CI, 13 047 571-18 648 801) US adults used at least 1 of the 6 botanical products within the past 30 days, which was similar to the estimated number of patients prescribed potentially hepatotoxic drugs, including simvastatin (14 036 024 [95% CI, 11 202 460-17 594 452]) and nonsteroidal anti-inflammatory drugs (14 793 837 [95% CI, 13 014 623-16 671 897]). The most common reason for consuming turmeric and green tea was to improve or maintain health. Conclusions and Relevance: In this survey study, an estimated 15.6 million US adults consumed at least 1 botanical product with liver liability within the past 30 days, comparable with the number of people who consumed nonsteroidal anti-inflammatory drugs and a commonly prescribed hypolipidemic drug. Given a lack of regulatory oversight on the manufacturing and testing of botanical products, clinicians should be aware of possible adverse events from consumption of these largely unregulated products.

Regulation of the poly(A) Polymerase Star-PAP by a Nuclear Phosphoinositide Signalosome.

Star-PAP is a noncanonical poly(A) polymerase that controls gene expression. Star-PAP was previously reported to bind the phosphatidylinositol 4-phosphate 5-kinase PIPKI⍺ and its product phosphatidylinositol 4,5-bisphosphate, which regulate Star-PAP poly(A) polymerase activity and expression of specific genes. Recent studies have revealed a nuclear PI signaling pathway in which the PI transfer proteins PITP⍺/ß, PI kinases and phosphatases bind p53 to sequentially modify protein-linked phosphatidylinositol phosphates and regulate its function. Here we demonstrate that multiple phosphoinositides, including phosphatidylinositol 4-monophosphate and phosphatidylinositol 3,4,5-trisphosphate are also coupled to Star-PAP in response to stress. This is initiated by PITP⍺/ß binding to Star-PAP, while the Star-PAP-linked phosphoinositides are modified by PI4KII⍺, PIPKI⍺, IPMK, and PTEN recruited to Star- PAP. The phosphoinositide coupling enhances the association of the small heat shock proteins HSP27/⍺B-crystallin with Star-PAP. Knockdown of the PITPs, kinases, or HSP27 reduce the expression of Star-PAP targets. Our results demonstrate that the PITPs generate Star-PAP-PIPn complexes that are then modified by PI kinases/phosphatases and small heat shock proteins that regulate the linked phosphoinositide phosphorylation and Star-PAP activity in response to stress.

ER procollagen storage defect without coupled unfolded protein response drives precocious arthritis.

Collagenopathies are a group of clinically diverse disorders caused by defects in collagen folding and secretion. For example, mutations in the gene encoding collagen type-II, the primary collagen in cartilage, can lead to diverse chondrodysplasias. One example is the Gly1170Ser substitution in procollagen-II, which causes precocious osteoarthritis. Here, we biochemically and mechanistically characterize an induced pluripotent stem cell-based cartilage model of this disease, including both hetero- and homozygous genotypes. We show that Gly1170Ser procollagen-II is notably slow to fold and secrete. Instead, procollagen-II accumulates intracellularly, consistent with an endoplasmic reticulum (ER) storage disorder. Likely owing to the unique features of the collagen triple helix, this accumulation is not recognized by the unfolded protein response. Gly1170Ser procollagen-II interacts to a greater extent than wild-type with specific ER proteostasis network components, consistent with its slow folding. These findings provide mechanistic elucidation into the etiology of this disease. Moreover, the easily expandable cartilage model will enable rapid testing of therapeutic strategies to restore proteostasis in the collagenopathies.

Describing a medical school's rural activity footprint: setting selection and workforce distribution priorities.

CONTEXT: There is growing evidence supporting a shift towards 'grow your own' approaches to recruiting, training and retaining health professionals from and for rural communities. To achieve this, there is a need for sound methodologies by which universities can describe their area of geographic focus in a precise way that can be utilised to recruit students from their region and evaluate workforce outcomes for partner communities. In Australia, Deakin University operates a Rural Health Multidisciplinary Training (RHMT) program funded Rural Clinical School and University Department of Rural Health, with the purpose of producing a graduate health workforce through the provision of rural clinical placements in western and south-western Victoria. The desire to establish a dedicated Rural Training Stream within Deakin's Doctor of Medicine course acted as a catalyst for us to describe our 'rural footprint' in a way that could be used to prioritise local student recruitment as well as evaluate graduate workforce outcomes specifically for this region. ISSUE: In Australia, selection of rural students has relied on the Australian Statistical Geography Standard Remoteness Areas (ASGS-RA) or Modified Monash Model (MMM) to assign rural background status to medical course applicants, based on a standard definition provided by the RHMT program. Applicants meeting rural background criteria may be preferentially admitted to any medical school according to admission quotas or dedicated rural streams across the country. Until recently, evaluations of graduate workforce outcomes have also used these rurality classifications, but often without reference to particular geographic areas. Growing international evidence supports the importance of place-based connection and training, with medical graduates more likely to work in a region that they are from or in which they have trained. For universities to align rural student recruitment more strategically with training in specific geographic areas, there is a need to develop precise geographical definitions of areas of rural focus that can be applied during admissions processes. LESSONS LEARNED: As we strived to describe our rural activity area precisely, we modelled the application of several geographical and other frameworks, including the MMM, ASGS-RA, Primary Healthcare Networks (PHN), Local Government Areas (LGAs), postcodes and Statistical Areas. It became evident that there was no single geographical or rural framework that (1) accurately described our area of activity, (2) accurately described our desired workforce focus, (3) was practical to apply during the admissions process. We ultimately settled on a bespoke approach using a combination of the PHN and MMM to achieve the specificity required. This report provides an example of how a rural activity footprint can be accurately described and successfully employed to prioritise students from a geographical area for course admission. Lessons learned about the strengths and limitations of available geographical measures are shared. Applications of a precise footprint definition are described including student recruitment, evaluation of workforce outcomes for a geographic region, benefits to stakeholder relationships and an opportunity for more nuanced RHMT reporting.

Self-Assembled Tetranuclear Square Complex of Chromium(III) Bridged by Radical Pyrazine: A Molecular Model for Metal-Organic Magnets.

The attractive electronic properties of metal-pyrazine materials─electrical conductivity, magnetic order, and strong magnetic coupling─can be tuned in a wide range depending on the metal employed, as well as its ligand-imposed redox environment. Using solvent-directed synthesis to control the dimensionality of such systems, a discrete tetranuclear chromium(III) complex, exhibiting a rare example of bridging radical pyrazine, has been prepared from chromium(II) triflate and neutral pyrazine. The strong antiferromagnetic interaction between CrIII (S = 3/2) and radical pyrazine (S = 1/2) spins, theoretically estimated at about -932 K, leads to a thermally isolated ST = 4 ground state, which remains the only populated state observable even at room temperature.