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Older adults are at risk of adverse drug events during transition of care from hospital to community, thus optimal communication about medications at discharge is essential. Standardization of medication discharge plan (MDP) is lacking. This study aimed to (1) create a standardized MDP for older adults using consensus-based principles, (2) create a short-version MDP and (3) generate a practical guide. Modified Delphi was used to establish consensus on guiding principles for the MDP. Additionally, participants were asked about guiding principles deemed most essential, patient prioritization, the format and mode of transmission of the MDP. Twenty-six guiding principles reached consensus, with 17 prioritized for a short-version MDP. The practical guide includes explanations of the guiding principles, criteria for patient selection and recommendations on the format and mode of transmission. The results of this study will assist implementation of MDPs when older adults are discharged from hospital., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv ( CK-136 ), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound 1R , a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1R led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. In vivo echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138 . Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.

Currently, wearable technology is an emerging trend that offers remarkable access to our data through smart devices like smartphones, watches, fitness trackers and textiles. As such, wearable devices can enable health monitoring without disrupting our daily routines. In clinical settings, electrocardiograms (ECGs) and photoplethysmographies (PPGs) are used to monitor heart and respiratory behaviors. In more practical settings, accelerometers can be used to estimate the heart rate when they are attached to the chest. They can also help filter out some noise in ECG signals from movement. In this work, we compare the heart rate data extracted from the built-in accelerometer of a commercial smart pen equipped with sensors (STABILO's DigiPen) to standard ECG monitor readouts. We demonstrate that it is possible to accurately predict the heart rate from the smart pencil. The data collection is carried out with eight volunteers writing the alphabet continuously for five minutes. The signal is processed with a Butterworth filter to cut off noise. We achieve a mean-squared error (MSE) better than 6.685 × 10-3 comparing the DigiPen's computed Δt (time between pulses) with the reference ECG data. The peaks' timestamps for both signals all maintain a correlation higher than 0.99. All computed heart rates (HR =60Δt) from the pen accurately correlate with the reference ECG signals.

Background: Accurate and portable respiratory parameter measurements are critical for properly managing chronic obstructive pulmonary diseases (COPDs) such as asthma or sleep apnea, as well as controlling ventilation for patients in intensive care units, during surgical procedures, or when using a positive airway pressure device for sleep apnea., Objective: The purpose of this research is to develop a new nonprescription portable measurement device that utilizes relative humidity sensors (RHS) to accurately measure key respiratory parameters at a cost that is approximately 10 times less than the industry standard., Methods: We present the development, implementation, and assessment of a wearable respiratory measurement device using the commercial Bosch BME280 RHS. In the initial stage, the RHS was connected to the pneumotach (PNT) gold standard device via its external connector to gather breathing metrics. Data collection was facilitated using the Arduino platform with a Bluetooth Low Energy connection, and all measurements were taken in real time without any additional data processing. The device's efficacy was tested with 7 participants (5 men and 2 women), all in good health. In the subsequent phase, we specifically focused on comparing breathing cycle and respiratory rate measurements and determining the tidal volume by calculating the region between inhalation and exhalation peaks. Each participant's data were recorded over a span of 15 minutes. After the experiment, detailed statistical analysis was conducted using ANOVA and Bland-Altman to examine the accuracy and efficiency of our wearable device compared with the traditional methods., Results: The perfused air measured with the respiratory monitor enables clinicians to evaluate the absolute value of the tidal volume during ventilation of a patient. In contrast, directly connecting our RHS device to the surgical mask facilitates continuous lung volume monitoring. The results of the 1-way ANOVA showed high P values of .68 for respiratory volume and .89 for respiratory rate, which indicate that the group averages with the PNT standard are equivalent to those with our RHS platform, within the error margins of a typical instrument. Furthermore, analysis utilizing the Bland-Altman statistical method revealed a small bias of 0.03 with limits of agreement (LoAs) of -0.25 and 0.33. The RR bias was 0.018, and the LoAs were -1.89 and 1.89., Conclusions: Based on the encouraging results, we conclude that our proposed design can be a viable, low-cost wearable medical device for pulmonary parametric measurement to prevent and predict the progression of pulmonary diseases. We believe that this will encourage the research community to investigate the application of RHS for monitoring the pulmonary health of individuals., (©Fabrice Vaussenat, Abhiroop Bhattacharya, Julie Payette, Jaime A Benavides-Guerrero, Alexandre Perrotton, Luis Felipe Gerlein, Sylvain G Cloutier. Originally published in JMIR Biomedical Engineering (http://biomsedeng.jmir.org), 25.10.2023.)

Abstract: Gagnon, A, Payette, J, Park, M, Juras, K, and Slater, L. Relationship between pitch counts and shoulder strength in collegiate baseball players. J Strength Cond Res 37(9): 1860-1864, 2023-Large volumes of throwing leads to changes in shoulder strength that have been associated with increased risk of injury. The purpose of this study was to investigate the relationship between throwing volume and eccentric shoulder strength. Twelve NCAA Division I baseball pitchers volunteered to participate. Prepractice and postpractice eccentric shoulder strength was measured using a handheld dynamometer at 30°/second. Change in strength was calculated as the prepractice strength measure subtracted from the postpractice strength measure. After initial testing, subjects self-reported pitch counts before completing postpractice strength testing. Subjects were separated into high-strength and low-strength groups based on the median external rotation strength. Paired t -tests were used to compare change in shoulder strength and Pearson's r correlations were used to quantify the association between pitches and change in strength. There were no changes between prestrength and poststrength assessments in external rotation strength or internal rotation strength for the entire group. When divided into strength groups, correlations between strength and total pitches were nonsignificant for the high-strength group but were strong for both external rotation ( r = -0.87, p = 0.025) and internal rotation ( r = -0.91, p = 0.013) in the low-strength group. Pitchers with lower shoulder eccentric strength at baseline demonstrated greater declines in strength, whereas pitchers with higher shoulder eccentric strength did not demonstrate changes in strength. Changes in strength during practice could lead to compensatory movement that may predispose athletes to injury. Sport performance professionals may benefit from obtaining eccentric shoulder strength to assist with performance periodization and rehabilitation after injury., (Copyright © 2023 National Strength and Conditioning Association.)

In the upcoming years, artificial intelligence is going to transform the practice of medicine in most of its specialties. Deep learning can help achieve better and earlier problem detection, while reducing errors on diagnosis. By feeding a deep neural network (DNN) with the data from a low-cost and low-accuracy sensor array, we demonstrate that it becomes possible to significantly improve the measurements' precision and accuracy. The data collection is done with an array composed of 32 temperature sensors, including 16 analog and 16 digital sensors. All sensors have accuracies between [Formula: see text]. 800 vectors are extracted, covering a range from to 30 to [Formula: see text]. In order to improve the temperature readings, we use machine learning to perform a linear regression analysis through a DNN. In an attempt to minimize the model's complexity in order to eventually run inferences locally, the network with the best results involves only three layers using the hyperbolic tangent activation function and the Adam Stochastic Gradient Descent optimizer. The model is trained with a randomly-selected dataset using 640 vectors (80% of the data) and tested with 160 vectors (20%). Using the mean squared error as a loss function between the data and the model's prediction, we achieve a loss of only 1.47x10[Formula: see text] on the training set and 1.22x10[Formula: see text] on the test set. As such, we believe this appealing approach offers a new pathway towards significantly better datasets using readily-available ultra low-cost sensors., (© 2023. The Author(s).)

The record of the coevolution of oxygenic phototrophs and the environment is preserved in three forms: genomes of modern organisms, diverse geochemical signals of surface oxidation and diagnostic Proterozoic microfossils. When calibrated by fossils, genomic data form the basis of molecular clock analyses. However, different interpretations of the geochemical record, fossil calibrations and evolutionary models produce a wide range of age estimates that are often conflicting. Here, we show that multiple interpretations of the cyanobacterial fossil record are consistent with an Archean origin of crown-group Cyanobacteria. We further show that incorporating relative dating information from horizontal gene transfers greatly improves the precision of these age estimates, by both providing a novel empirical criterion for selecting evolutionary models, and increasing the stringency of sampling of posterior age estimates. Independent of any geochemical evidence or hypotheses, these results support oxygenic photosynthesis evolving at least several hundred million years before the Great Oxygenation Event (GOE), a rapid diversification of major cyanobacterial lineages around the time of the GOE, and a post-Cryogenian origin of extant marine picocyanobacterial diversity.

Epigenetic regulation of gene expression by DNA methylation plays a central role in the maintenance of cellular homeostasis. Here we present evidence implicating the DNA methylation program in the regulation of hypoxia-inducible factor (HIF) oxygen-sensing machinery and hypoxic cell metabolism. We show that DNA methyltransferase 3a (DNMT3a) methylates and silences the HIF-2α gene (EPAS1) in differentiated cells. Epigenetic silencing of EPAS1 prevents activation of the HIF-2α gene program associated with hypoxic cell growth, thereby limiting the proliferative capacity of adult cells under low oxygen tension. Naturally occurring defects in DNMT3a, observed in primary tumors and malignant cells, cause the unscheduled activation of EPAS1 in early dysplastic foci. This enables incipient cancer cells to exploit the HIF-2α pathway in the hypoxic tumor microenvironment necessary for the formation of cellular masses larger than the oxygen diffusion limit. Reintroduction of DNMT3a in DNMT3a-defective cells restores EPAS1 epigenetic silencing, prevents hypoxic cell growth, and suppresses tumorigenesis. These data support a tumor-suppressive role for DNMT3a as an epigenetic regulator of the HIF-2α oxygen-sensing pathway and the cellular response to hypoxia.

Objective: Musculoskeletal injuries related to training and operational missions frequently affect military personnel. A common treatment for these injuries is the PRICE (protection, rest, ice, compression, and elevation) method, which is time consuming and impractical in the field. Therefore, the primary objective of this study was to determine the effectiveness of the cryotherapy wrap compared to a traditional treatment in the management of acute ankle sprains., Methods: A randomized controlled clinical trial was conducted in a university research laboratory with 13 subjects (9 males and 4 females) with the following physical characteristics: age (yr) 20.6 ? 2.2, height (cm) 177.0 ? 14.3, weight (kg) 76.6 ? 20.6, and body mass index (kg/m2) 24.1 ? 3.7. Participants were instructed to perform PRICE with a traditional ice pack and compression wrap (control group) or with an Arctic Ease? cryotherapy wrap (test group) for 48 hours following enrollment in the study. The Numeric Pain Scale, Foot and Ankle Ability Measure, and ankle/foot volumetric measurement were performed at initial presentation and 24-hour, 48-hour, and 7-day follow-up intervals., Results: While the comparison of the Numeric Pain Scale scores, Foot and Ankle Ability Measure scores, and volumetric changes between groups revealed no statistically significant differences (p > 0.01), there was an 86% compliance rate for subjects in the cryotherapy wrap group compared to a 17% compliance rate of subjects in the control group., Conclusions: The cryotherapy wraps performed comparably to ice therapy and therefore may be especially applicable to military personnel required to operate in austere and hostile environments where traditional therapies are unrealistic. Although this pilot study did not demonstrate that the cryotherapy wraps produce statistically superior results, trends emerged in the data suggesting that subject compliance rate may be improved by using an alternative form of cryotherapy compression, which could lead to better management of pain, edema, and functional recovery. Future research should include a larger sample size to verify this claim., (2012.)

Study Design: Prospective cohort., Objectives: To identify the prevalence of neurocognitive and balance deficits in collegiate football players 48 hours following competition., Background: Neurocognitive testing, balance assessments, and subjective report of symptoms are a commonly used test battery in examining athletes when concussion is suspected. Previous literature suggests many concussions go unreported. Little research exists examining the prevalence of neurocognitive or balance deficits in athletes who do not report concussion-like symptoms to a health care provider., Methods: Forty-five Division IA collegiate football players participated in this study. Preseason baseline scores using the Balance Error Scoring System, the Immediate Post-Concussion Assessment and Cognitive Testing, and the Postconcussion Symptom Scale were compared to posttest results obtained 48 hours following a game. Prevalence of symptoms was analyzed and reported., Results: Thirty-two (71%) of the 45 athletes tested demonstrated at least 1 deficit in either the Postconcussion Symptom Scale, Balance Error Scoring System, or at least 1 composite score of the Immediate Post-Concussion Assessment and Cognitive Testing. Nineteen of the 32 subjects demonstrated a change in 2 or more categories of neurocognitive and balance function., Conclusion: In a cohort of football players tested 48 hours following their last game of the season, who did not seek medical attention related to a concussion, a significant number demonstrated limitations in neurocognitive and balance performance, suggesting that further research may need to be performed to improve recognition of an athlete's deficits and to improve the ability to assess concussion., Level of Evidence: Differential diagnosis/symptom prevalence, level 3b.

Protein synthesis involves the translation of ribonucleic acid information into proteins, the building blocks of life. The initial step of protein synthesis is the binding of the eukaryotic translation initiation factor 4E (eIF4E) to the 7-methylguanosine (m(7)-GpppG) 5' cap of messenger RNAs. Low oxygen tension (hypoxia) represses cap-mediated translation by sequestering eIF4E through mammalian target of rapamycin (mTOR)-dependent mechanisms. Although the internal ribosome entry site is an alternative translation initiation mechanism, this pathway alone cannot account for the translational capacity of hypoxic cells. This raises a fundamental question in biology as to how proteins are synthesized in periods of oxygen scarcity and eIF4E inhibition. Here we describe an oxygen-regulated translation initiation complex that mediates selective cap-dependent protein synthesis. We show that hypoxia stimulates the formation of a complex that includes the oxygen-regulated hypoxia-inducible factor 2α (HIF-2α), the RNA-binding protein RBM4 and the cap-binding eIF4E2, an eIF4E homologue. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis identified an RNA hypoxia response element (rHRE) that recruits this complex to a wide array of mRNAs, including that encoding the epidermal growth factor receptor. Once assembled at the rHRE, the HIF-2α-RBM4-eIF4E2 complex captures the 5' cap and targets mRNAs to polysomes for active translation, thereby evading hypoxia-induced repression of protein synthesis. These findings demonstrate that cells have evolved a program by which oxygen tension switches the basic translation initiation machinery.

Inappropriate expression of Ets-1 is observed in a variety of human cancers, and its forced expression in cultured cells results in transformation, autonomous proliferation, and tumor formation. The basis by which Ets-1 confers autonomous growth, one of the primary hallmarks of cancer cells and a critical component of persistent proliferation, has yet to be fully explained. Using a variety of cancer cell lines, we show that inhibition of Ets-1 blocks tumor formation and cell proliferation in vivo and autonomous growth in culture. A screen of multiple diffusible growth factors revealed that inhibition of Ets-1 results in the specific downregulation of transforming growth factor alpha (TGFalpha), the proximal promoter region of which contains multiple ETS family DNA binding sites that can be directly bound and regulated by Ets-1. Notably, rescuing TGFalpha expression in Ets-1-silenced cells was sufficient to restore tumor cell proliferation in vivo and autonomous growth in culture. These results reveal a previously unrecognized mechanism by which Ets-1 oncogenic activity can be explained in human cancer through its ability to regulate the important cellular mitogen TGFalpha.

Cancer development is a multistep process, driven by a series of genetic and environmental alterations, that endows cells with a set of hallmark traits required for tumorigenesis. It is broadly accepted that growth signal autonomy, the first hallmark of malignancies, can be acquired through multiple genetic mutations that activate an array of complex, cancer-specific growth circuits [Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57-70; Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789-799]. The superfluous nature of these pathways is thought to severely limit therapeutic approaches targeting tumor proliferation, and it has been suggested that this strategy be abandoned in favor of inhibiting more systemic hallmarks, including angiogenesis (Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: Mechanisms of anti-tumor activity. Nat Rev Cancer 8:579-591; Stommel JM, et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287-290; Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727-739; Kaiser J (2008) Cancer genetics: A detailed genetic portrait of the deadliest human cancers. Science 321:1280-1281]. Here, we report the unexpected observation that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2alpha, an element of the oxygen-sensing machinery. Inhibition of HIF-2alpha prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and non-small-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2alpha exerts its proliferative effects by endorsing these major pathways. Consistently, silencing these receptors phenocopies the loss of HIF-2alpha oncogenic activity, abrogating the serum-independent growth of human cancer cells in culture. Based on these data, we propose an alternative to the predominant view that cancers exploit independent autonomous growth pathways and reveal HIF-2alpha as a potentially universal culprit in promoting the persistent proliferation of neoplastic cells.

It is thought that degradation of nuclear proteins by the ubiquitylation system requires nuclear-cytoplasmic trafficking of E3 ubiquitin ligases. The von Hippel-Lindau (VHL) tumor suppressor protein is the substrate recognition component of a Cullin-2-containing E3 ubiquitin ligase that recruits hypoxia-inducible factor (HIF) for oxygen-dependent degradation. We demonstrated that VHL engages in nuclear-cytoplasmic trafficking that requires ongoing transcription to promote efficient HIF degradation. Here, we report the identification of a discreet motif, DXGX(2)DX(2)L, that directs transcription-dependent nuclear export of VHL and which is targeted by naturally occurring mutations associated with renal carcinoma and polycythemia in humans. The DXGX(2)DX(2)L motif is also found in other proteins, including poly(A)-binding protein 1, to direct its transcription-dependent nuclear export. We define DXGX(2)DX(2)L as TD-NEM (transcription-dependent nuclear export motif), since inhibition of transcription by actinomycin D or 5,6-dichlorobenzimidazole abrogates its nuclear export activity. Disease-causing mutations of key residues of TD-NEM restrain the ability of VHL to efficiently mediate oxygen-dependent degradation of HIF by altering its nuclear export dynamics without affecting interaction with its substrate. These results identify a novel nuclear export motif, further highlight the role of nuclear-cytoplasmic shuttling of E3 ligases in degradation of nuclear substrates, and provide evidence that disease-causing mutations can target subcellular trafficking.

The demineralization of enamel that is associated with early caries formation affects the optical properties of the enamel. Polarized Raman spectroscopy and optical coherence tomography have been used to detect these changes and potentially offer a means to detect and monitor early caries development. The total optical attenuation coefficient as measured by optical coherence tomography and the polarization anisotropy of the Raman peak arising from the symmetric nu(1) vibration of PO4(3-) at approximately 959 cm(-1) have been demonstrated as being sensitive markers of early caries. This ex vivo study on extracted human teeth demonstrates that these measurements can be made with reasonable precision with concomitantly good repeatability and reproducibility in sound enamel. Such reliability is crucial for these techniques to have a practical clinical value.

Background/aims: The visualization of skin hemodynamics and tissue water content has important implications in a number of areas of dermatology, plastic surgery, and clinical skin evaluation. The aim of this study was to develop instrumentation and techniques for infrared spectroscopic imaging, and to evaluate whether they can be used to make objective assessments of skin health, perhaps even before clinical signs are evident., Methods: A liquid-crystal tunable filter was mounted on the front of the objective lens of an infrared-sensitive charge-coupled device digital camera. Sets of narrow-band images of skin were acquired in vivo at wavelength intervals of 10 nm from 650 to 1050 nm, under computer control. The data processing techniques used to extract interpretable clinical information from the raw image sets included normalization, ratios, and multivariate analysis., Results: To highlight the capabilities of these techniques, results are presented of two studies that generated spectroscopic images. One examined a volunteer's forearm subjected to short interruptions of blood flow, and the other followed changes in a skin flap elevated on a rat model. The data sets were processed in different ways to determine several skin and blood parameters, in particular hemoglobin oxygen saturation, blood volume, and skin hydration. Variations in these parameters were followed non-invasively as a function of time and location to study the skin's response to blood flow changes, and to predict the viability of the skin., Conclusion: Near-infrared reflectance spectroscopic imaging is demonstrated to be a powerful augmentation to the standard clinical assessment of skin.

Visible-near infrared multispectral reflectance image sets were acquired from the dorsal surface of rats both before and after elevation of reversed McFarlane skin flaps. Raw images were dominated by uneven surface illumination and shadowing along with the variation associated with instrument response. These interfering features obscured variation associated with a change in tissue reflectance, which is related to the degree of flap perfusion. Logarithmic residual preprocessing followed by principal component analysis of multispectral images could clearly detect a difference in the optical properties between the base and distal section of the flap. The difference in the reflectance properties correlates with the varying degree of tissue perfusion. Principal component analysis detected this optical difference between the well-perfused base of the skin flap and the compromised distal section of the flap immediately following surgery. The first visual signs of compromised tissue perfusion appeared only 6 or more hours after surgery. The results from this study indicate that the application of principal component analysis to discrete wavelength near infrared multispectral reflectance images of skin flaps can effectively distinguish reflectance changes related to the degree of tissue perfusion immediately following surgical elevation of the reversed McFarlane skin flap. © 1999 Society of Photo-Optical Instrumentation Engineers.

Near-infrared reflectance spectroscopy and imaging were used to assess tissue hydration following elevation of reverse McFarlane dorsal rat skin flaps (N = 6). A quantitative measure of tissue water content was derived using the integrated intensities of the strong absorption bands of water centered at 970 and 1450 nm. Near-infrared spectroscopy monitored tissue hydration at discrete locations, while imaging provided hydration maps of cutaneous tissues. Both methods were rapid and noninvasive. The near-infrared results were compared to laser Doppler flux measurements. Significant changes in tissue hydration were observed upon surgical elevation with substantial regional variation along the skin flap. These results indicate the potential of near-infrared spectroscopy and imaging to monitor tissue hydration changes in the skin following surgery.

Clinically, skin color, temperature, and capillary perfusion are used to assess tissue viability following microvascular tissue transfer. However, clinical signs that arise as a consequence of poor perfusion become evident only after several hours of compromised perfusion. This study demonstrates the potential usefulness of optical/infrared multispectral imaging in the prognosis of tissue viability immediately post-surgery. Multispectral images of a skin flap model acquired within 1 h of surgical elevation are analyzed in comparison to the final 72-h clinical outcome with a high degree of correlation. Regional changes in tissue perfusion and oxygenation present immediately following surgery are differentiated using fuzzy clustering and image processing algorithms. These methodologies reduce the intersubject variability inherent in infrared imaging methods such that the changes in perfusion are reproducible and clearly distinguishable across all subjects. Clinically, an early prognostic indicator of viability such as this would allow for a more timely intervention following surgery in the event of compromised microvasculature.