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This study was performed to investigate the relationship between heart rate (HR) as a percentage of peak HR and oxygen uptake (VO2) as a percentage of peak (VO2) in older adults while performing deep water running (DWR). Twenty-three (14 male and 9 female) apparently healthy older adults, age 50 to 70 years, volunteered. Deep water running to VO2peak was performed in 3-min stages at leg speeds controlled by a metronome beginning at 60 strides per minute and increasing 12 strides per minute each additional stage. Oxygen uptake and HR were continuously monitored by open-circuit spirometry and radiotelemetry, respectively. Simple linear regression analysis was used to establish the relationship between the physiological variables. The relationship between %VO2peak and %HRpeak was statistically significant, with the male (VO2peak = 1.5301 [%HRpeak] 54.4932 [r =.96, SEE 6.0%]) and female (%VO2peak = 1.5904 [%HRpeak 62.3935 [r = .91, SEE 6.9%1) regression equations being significantly different (p < .05). The regression equations of older adults and those for college-aged males (%VO2peak 1.4634 [%HR peak] - 49.619) and females %VO2peak = 1.6649 [%HR peak 67.862) were not significantly different. [ABSTRACT FROM AUTHOR]

Background: The 2010 international guidelines for cardiopulmonary resuscitation recently recommended an increase in the minimum compression depth from 38 to 50 mm, although there are limited human data to support this. We sought to study patterns of cardiopulmonary resuscitation compression depth and their associations with patient outcomes in out-of-hospital cardiac arrest cases treated by the 2005 guideline standards.Design: Prospective cohort.Setting: Seven U.S. and Canadian urban regions.Patients: We studied emergency medical services treated out-of-hospital cardiac arrest patients from the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest for whom electronic cardiopulmonary resuscitation compression depth data were available, from May 2006 to June 2009.Measurements: We calculated anterior chest wall depression in millimeters and the period of active cardiopulmonary resuscitation (chest compression fraction) for each minute of cardiopulmonary resuscitation. We controlled for covariates including compression rate and calculated adjusted odds ratios for any return of spontaneous circulation, 1-day survival, and hospital discharge.Main Results: We included 1029 adult patients from seven U.S. and Canadian cities with the following characteristics: Mean age 68 yrs; male 62%; bystander witnessed 40%; bystander cardiopulmonary resuscitation 37%; initial rhythms: Ventricular fibrillation/ventricular tachycardia 24%, pulseless electrical activity 16%, asystole 48%, other nonshockable 12%; outcomes: Return of spontaneous circulation 26%, 1-day survival 18%, discharge 5%. For all patients, median compression rate was 106 per minute, median compression fraction 0.65, and median compression depth 37.3 mm with 52.8% of cases having depth <38 mm and 91.6% having depth <50 mm. We found an inverse association between depth and compression rate ( p < .001). Adjusted odds ratios for all depth measures (mean values, categories, and range) showed strong trends toward better outcomes with increased depth for all three survival measures.Conclusions: We found suboptimal compression depth in half of patients by 2005 guideline standards and almost all by 2010 standards as well as an inverse association between compression depth and rate. We found a strong association between survival outcomes and increased compression depth but no clear evidence to support or refute the 2010 recommendations of >50 mm. Although compression depth is an important component of cardiopulmonary resuscitation and should be measured routinely, the most effective depth is currently unknown. [ABSTRACT FROM AUTHOR]

Abstract Purpose To describe a pilot study for a novel preclinical model used to test human tissue-based therapies in the setting of cutaneous radiation injury. Methods A protocol was designed to irradiate the skin of athymic rats while sparing the body and internal organs by utilizing a non-occlusive skin clamp along with an x-ray image guided stereotactic irradiator. Each rat was irradiated both on the right and the left flank with a circular field at a 20 cm source-to-surface distance (SSD). Single fractions of 30.4 Gy, 41.5 Gy, 52.6 Gy, 65.5 Gy, and 76.5 Gy were applied in a dose-finding trial. Eight additional wounds were created using the 41.5 Gy dose level. Each wound was photographed and the percentage of the irradiated area ulcerated at given time points was analyzed using ImageJ software. Results No systemic or lethal sequelae occurred in any animals, and all irradiated skin areas in the multi-dose trial underwent ulceration. Greater than 60% of skin within each irradiated zone underwent ulceration within ten days, with peak ulceration ranging from 62.1% to 79.8%. Peak ulceration showed a weak correlation with radiation dose (r = 0.664). Mean ulceration rate over the study period is more closely correlated to dose (r = 0.753). With the highest dose excluded due to contraction-related distortions, correlation between dose and average ulceration showed a stronger relationship (r = 0.895). Eight additional wounds created using 41.5 Gy all reached peak ulceration above 50%, with all healing significantly but incompletely by the 65-day endpoint. Conclusions We developed a functional preclinical model which is currently used to evaluate human tissue-based therapies in the setting of cutaneous radiation injury. Similar models may be widely applicable and useful the development of novel therapies which may improve radiotherapy management over a broad clinical spectrum.

Background: Despite prophylactic platelet transfusions, hypoproliferative thrombocytopenia is associated with bleeding; historical risk factors include hematocrit (HCT) ≤ 25%, activated partial thromboplastin time ≥ 30 s, international normalized ratio ≥ 1.2, and platelets ≤ 5000/μL., Methods: We performed a post hoc analysis of bleeding outcomes and risk factors in participants with hematologic malignancy and hypoproliferative thrombocytopenia enrolled in the American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (A-TREAT) and randomized to receive either tranexamic acid (TXA) or placebo., Results: World Health Organization (WHO) grade 2+ bleeding occurred in 46% of 330 participants, with no difference between the TXA (44%) and placebo (47%) groups (p = 0.66). Overall, the most common sites of bleeding were oronasal (18%), skin (17%), gastrointestinal (11%), and genitourinary (11%). Among participants of childbearing potential, 28% experienced vaginal bleeding. Platelets ≤5000/μL and HCT < 21% (after adjusting for severe thrombocytopenia) were independently associated with increased bleeding risk (HR 3.78, 95% CI 2.16-6.61; HR 2.67, 95% CI 1.35-5.27, respectively). Allogeneic stem cell transplant was associated with nonsignificant increased risk of bleeding versus chemotherapy alone (HR 1.34, 95% CI 0.94-1.91)., Discussion: The overall rate of WHO grade 2+ bleeding was similar to previous reports, albeit with lower rates of gastrointestinal bleeding. Vaginal bleeding was common in participants of childbearing potential. Platelets ≤5000/μL remained a risk factor for bleeding. Regardless of platelet count, bleeding risk increased with HCT < 21%, suggesting a red blood cell transfusion threshold above 21% should be considered to mitigate bleeding. More investigation is needed on strategies to reduce bleeding in this population., (© 2024 The Author(s). Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

The brain helps us survive by forming internal representations of the external world 1,2 . Excitatory cortical neurons are often precisely tuned to specific external stimuli 3,4 . However, inhibitory neurons, such as parvalbumin-positive (PV) interneurons, are generally less selective 5 . PV interneurons differ from excitatory neurons in their neurotransmitter receptor subtypes, including AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) 6,7 . Excitatory neurons express calcium-impermeable AMPARs that contain the GluA2 subunit (encoded by GRIA2), whereas PV interneurons express receptors that lack the GluA2 subunit and are calcium-permeable (CP-AMPARs). Here we demonstrate a causal relationship between CP-AMPAR expression and the low feature selectivity of PV interneurons. We find low expression stoichiometry of GRIA2 mRNA relative to other subunits in PV interneurons that is conserved across ferrets, rodents, marmosets and humans, and causes abundant CP-AMPAR expression. Replacing CP-AMPARs in PV interneurons with calcium-impermeable AMPARs increased their orientation selectivity in the visual cortex. Manipulations to induce sparse CP-AMPAR expression demonstrated that this increase was cell-autonomous and could occur with changes beyond development. Notably, excitatory-PV interneuron connectivity rates and unitary synaptic strength were unaltered by CP-AMPAR removal, which suggested that the selectivity of PV interneurons can be altered without markedly changing connectivity. In Gria2-knockout mice, in which all AMPARs are calcium-permeable, excitatory neurons showed significantly degraded orientation selectivity, which suggested that CP-AMPARs are sufficient to drive lower selectivity regardless of cell type. Moreover, hippocampal PV interneurons, which usually exhibit low spatial tuning, became more spatially selective after removing CP-AMPARs, which indicated that CP-AMPARs suppress the feature selectivity of PV interneurons independent of modality. These results reveal a new role of CP-AMPARs in maintaining low-selectivity sensory representation in PV interneurons and implicate a conserved molecular mechanism that distinguishes this cell type in the neocortex., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Autosomal dominant mutations in FGF14 , which encodes intracellular fibroblast growth factor 14 (iFGF14), underlie spinocerebellar ataxia type 27A (SCA27A), a devastating multisystem disorder resulting in progressive deficits in motor coordination and cognitive function. Mice lacking iFGF14 ( Fgf14 -/- ) exhibit similar phenotypes, which have been linked to iFGF14-mediated modulation of the voltage-gated sodium (Nav) channels that control the high frequency repetitive firing of Purkinje neurons, the main output neurons of the cerebellar cortex. To investigate the pathophysiological mechanisms underlying SCA27A, we developed a targeted knock-in strategy to introduce the first point mutation identified in FGF14 into the mouse Fgf14 locus ( Fgf14 F145S ), we determined the impact of in vivo expression of the mutant Fgf14 F145S allele on the motor performance of adult animals and on the firing properties of mature Purkinje neurons in acute cerebellar slices. Electrophysiological experiments revealed that repetitive firing rates are attenuated in adult Fgf14 F145S/+ cerebellar Purkinje neurons, attributed to a hyperpolarizing shift in the voltage-dependence of steady-state inactivation of Nav channels. More severe effects on firing properties and Nav channel inactivation were observed in homozygous Fgf14 F145S/F145S Purkinje neurons. Interestingly, the electrophysiological phenotypes identified in adult Fgf14 F145S/+ and Fgf14 F145S/F145S cerebellar Purkinje neurons mirror those observed in heterozygous Fgf14 +/- and homozygous Fgf14 -/- Purkinje neurons, respectively, suggesting that the mutation results in the loss of the iFGF14 protein. Western blot analysis of lysates from adult heterozygous Fgf14 F145S/+ and homozygous Fgf14 F145S/F145S animals revealed reduced or undetectable, respectively, iFGF14 expression, supporting the hypothesis that the mutant allele results in loss of the iFGF14 protein and that haploinsufficiency underlies SCA27A neurological phenotypes.

There is a striking sex bias in the prevalence and severity of autism spectrum disorder (ASD) with 80% of diagnoses occurring in males. Because the molecular etiology of ASD is likely combinatorial, including interactions across multiple genetic and environmental factors, it is difficult to investigate the physiological mechanisms driving sex-specific differences. Loss of function mutations in TSC1 result in dysregulated mTORC1 signaling and underlie a multi-system disorder known as tuberous sclerosis (TSC). Interestingly, more than 50% of individuals diagnosed with TSC are also diagnosed with ASD, making TSC mutations one of the most prevalent monogenic causes of ASD. Mice harboring targeted deletion of Tsc1 selectively in cerebellar Purkinje neurons, referred to here as Tsc1 mut/mut , have multiple ASD-linked behavioral impairments, including deficits in social interactions, motor coordination, and vocalizations. However, these ASD-linked behavioral deficits have only been investigated using male Tsc1 mut/mut animals. Here, we used cohorts of male and female Tsc1 mut/mut animals to determine if behavioral impairments, previously identified in this model, are similar across sex. Specifically, we measured balance and motor coordination and social interaction behaviors in two age groups across sex. W e determined balance and motor coordination deficits are similar in male and female Tsc1 mut/mut mice, and that deficits in the firing of Tsc1 mut/mut Purkinje neurons located in the cerebellar vermis are also similar across sex. However, impairments in social approach behavior were found to be significantly more severe in Tsc1 mut/mut males compared to females. These results indicate the selective deletion of Tsc1 in Purkinje neurons differentially impairs cerebellar circuits based on sex.

The resurgent sodium current (I NaR ) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, I NaR is thought to drive high rates of repetitive neuronal firing. However, I NaR is often studied in combination with the persistent or noninactivating portion of sodium currents (I NaP ). We used dynamic clamp to test how I NaR and I NaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned I NaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages and that subthreshold I NaP is critical in regulating neuronal firing rate. Adjustments to the voltage-gated sodium conductance model used in these studies revealed I NaP and I NaR can be inversely scaled by adjusting occupancy in the slow-inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune I NaP and Purkinje neuron repetitive firing rates., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Recent media coverage of high-profile cases of cervical artery dissection (CAD) has ignited the discussion about the role of cervical spine manipulation (CSM) in causing cervical artery dissection. However, research does not support a causal association between cervical spine manipulation and cervical artery dissection in a healthy cervical spine. The objective of this study was to review the 10 most recent case reports of cervical spine manipulation and cervical artery dissection for convincing evidence of the causation of cervical artery dissection by cervical spine manipulation. Nine of 10 case reports showed no convincing evidence of a causal relationship between cervical spine manipulation and cervical artery dissection. The 10th case report was exceptional as the CSM was contraindicated by pre-existing cervical spine pathology. We conclude that these 10 case reports provide no convincing evidence of the causation of cervical artery dissection by cervical spine manipulation in a healthy cervical spine. One case report demonstrated that cervical spine manipulation can cause cervical artery dissection when performed in the presence of pre-existing cervical spine pathology. Therefore, we conclude that practitioners should exclude cervical spine pathology before performing cervical spine manipulation., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Brown et al.)

We present a case report of diagnosis of cervical spine multiple sclerosis by a chiropractic physician. This unique case contributes an account of a challenging differential diagnosis to the literature. A 30-year-old male presented with a three-year history of diffuse left upper extremity motor strength deficits and paresthesia (numbness and tingling). The patient had seen multiple physicians for these symptoms with no diagnosis of multiple sclerosis and no advanced imaging. The differential diagnosis included lower cervical spine nerve root compression or neurological disorders such as amyotrophic lateral sclerosis, cerebral lesion, motor neuropathy, multiple sclerosis, or spinal cord lesion. MRI of the cervical spine with and without IV contrast revealed evidence of spinal cord multiple sclerosis. The patient was referred to a neurologist where the diagnosis of multiple sclerosis was confirmed. A 10-year follow-up showed the patient was controlling his condition with medications and had no disability. This case underscores the importance for physicians to consider neurological conditions and advanced imaging in the presence of diffuse motor strength deficits and paresthesia in the absence of injury, pain, or any other symptoms., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Brown et al.)

Where there are bacteria, there will be bacteriophages. These viruses are known to be important players in shaping the wider microbial community in which they are embedded, with potential implications for human health. On the other hand, bacteria possess a range of distinct immune mechanisms that provide protection against bacteriophages, including the mutation or complete loss of the phage receptor, and CRISPR-Cas adaptive immunity. While our previous work showed how a microbial community may impact phage resistance evolution, little is known about the inverse, namely how interactions between phages and these different phage resistance mechanisms affect the wider microbial community in which they are embedded. Here, we conducted a 10-day, fully factorial evolution experiment to examine how phage impact the structure and dynamics of an artificial four-species bacterial community that includes either Pseudomonas aeruginosa wild-type or an isogenic mutant unable to evolve phage resistance through CRISPR-Cas. Additionally, we used mathematical modelling to explore the ecological interactions underlying full community behaviour, as well as to identify general principles governing the impacts of phage on community dynamics. Our results show that the microbial community structure is drastically altered by the addition of phage, with Acinetobacter baumannii becoming the dominant species and P. aeruginosa being driven nearly extinct, whereas P. aeruginosa outcompetes the other species in the absence of phage. Moreover, we find that a P. aeruginosa strain with the ability to evolve CRISPR-based resistance generally does better when in the presence of A. baumannii, but that this benefit is largely lost over time as phage is driven extinct. Finally, we show that pairwise data alone is insufficient when modelling our microbial community, both with and without phage, highlighting the importance of higher order interactions in governing multispecies dynamics in complex communities. Combined, our data clearly illustrate how phage targeting a dominant species allows for the competitive release of the strongest competitor while also contributing to community diversity maintenance and potentially preventing the reinvasion of the target species, and underline the importance of mapping community composition before therapeutically applying phage., Competing Interests: E.R.W. is inventor on patent GB2303034.9., (Copyright: © 2024 Alseth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

It has been proposed that cervical spine manipulation (CSM) can cause dissection in healthy cervical arteries, with resultant immediate stroke. However, research does not support a causal association between CSM and cervical artery dissection (CAD) in healthy cervical arteries. The objective of this study was to review the literature to identify plausible mechanisms of causation of immediate stroke by CSM. Immediate stroke is defined as a stroke occurring within seconds or minutes of CSM. Our review found plausible thromboembolic and thrombotic mechanisms of causation of immediate stroke by CSM in the literature. The common premise of these mechanisms is CAD being present before CSM, not occurring as a result of CSM. These mechanisms of causation have clinical and medicolegal implications for physicians performing CSM., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Brown et al.)

The Δδ regression approach of Blade et al. [ J. Phys. Chem. A 2020, 124(43), 8959-8977] for accurately discriminating between solid forms using a combination of experimental solution- and solid-state NMR data with density functional theory (DFT) calculation is here extended to molecules with multiple conformational degrees of freedom, using furosemide polymorphs as an exemplar. As before, the differences in measured 1 H and 13 C chemical shifts between solution-state NMR and solid-state magic-angle spinning (MAS) NMR (Δδ experimental ) are compared to those determined by gauge-including projector augmented wave (GIPAW) calculations (Δδ calculated ) by regression analysis and a t -test, allowing the correct furosemide polymorph to be precisely identified. Monte Carlo random sampling is used to calculate solution-state NMR chemical shifts, reducing computation times by avoiding the need to systematically sample the multidimensional conformational landscape that furosemide occupies in solution. The solvent conditions should be chosen to match the molecule's charge state between the solution and solid states. The Δδ regression approach indicates whether or not correlations between Δδ experimental and Δδ calculated are statistically significant; the approach is differently sensitive to the popular root mean squared error (RMSE) method, being shown to exhibit a much greater dynamic range. An alternative method for estimating solution-state NMR chemical shifts by approximating the measured solution-state dynamic 3D behavior with an ensemble of 54 furosemide crystal structures (polymorphs and cocrystals) from the Cambridge Structural Database (CSD) was also successful in this case, suggesting new avenues for this method that may overcome its current dependency on the prior determination of solution dynamic 3D structures.

Background: Tranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding in a multitude of clinical settings from postpartum hemorrhage to trauma. TXA may have clinical effects unrelated to bleeding; plasminogen, the target of TXA, alters immune responses, and TXA appears to decrease the risk of infection in patients undergoing cardiac surgery, as well as joint arthroplasty., Objectives: To address whether TXA alters rates of infection and inflammatory outcomes in patients with hematologic malignancies., Methods: We performed a post hoc analysis of outcomes of patients randomized to receive either TXA or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (Clinicaltrials.gov identifier: NCT02578901)., Results: TXA did not change the overall rate of infections, but the rate of severe infections (Common Toxicology Criteria for Adverse Events grade 3+) was lower in patients who received TXA compared with the placebo group. Patients who experienced grade 3+ infections had higher rates of World Health Organization grade 2+ bleeding and red blood cell transfusion requirements than patients who did not experience a grade 3+ infection, irrespective of treatment group. TXA did not impact other inflammatory outcomes such as mucositis, rash, or graft vs host disease., Conclusion: Patients with hematologic malignancies who received TXA had less severe infections than those who received placebo with no difference in overall rate of infection or other inflammatory outcomes. Further investigation is needed on the impact of TXA on infections in this population., (© 2024 The Author(s).)

Purpose: Physical activity (PA) and body fat percentage (%BF) are independently associated with arterial stiffness, but it has not been explored if there is an associative pathway among these variables. This study examined whether %BF mediates the relationship between PA or sedentary behavior levels with arterial stiffness., Methods: Fifty adults (1:1 men:women; age 28 ± 11 year) had carotid-femoral pulse wave velocity (CF-PWV) measured by applanation tonometry, %BF by bioelectrical impedance, and PA levels by accelerometry. Accelerometer data determined minutes per day spent in sedentary, light, moderate-to-vigorous physical activity (MVPA), and Total PA., Results: Pearson correlation indicated statistically significant associations among age, %BF, CF-PWV, MVPA, and Total PA (r = 0.34-0.65, p < 0.05). Sedentary and light PA were not associated with CF-PWV. Mediation analysis indicated significant total effects of MVPA (β = - 0.34, p = 0.044) and age (β = 0.65, p < 0.001) on CF-PWV. %BF mediated the relationship between Total PA and CF-PWV due to indirect effect of Total PA on %BF (β = - 0.34, p = 0.02) and %BF on CF-PWV (β = 0.44, p = 0.002), and partially mediated the relationship between age and CF-PWV (β = 0.54, p < 0.001). Total PA retained its significant effect on %BF (β = - 0.28, p = 0.04) and the effect of %BF on CF-PWV remained significant (β = 0.26, p = 0.03), despite age having a significant effect on both %BF (β = 0.31, p = 0.023) and CF-PWV (β = 0.54, p < 0.001)., Conclusions: %BF mediated the relationship between Total PA and arterial stiffness, even after accounting for age. Engagement in more Total PA may help to reduce %BF, resulting in decreased arterial stiffness., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Sedentary behaviour (SB) among adults with Down syndrome (DS) may differ based on personal or environmental factors., Objective: Investigate differences in SB levels and patterns of adults with DS based on sex, age, and residence-type across weekdays and weekends., Methods: Thirty-four adults with DS (15 men; 37 ± 12 years) underwent accelerometry-based measurements of sedentary time, bouts, and breaks for 7 days. We evaluated differences with 2 × 2 mixed-model (group-by-day) ANOVA., Results: Younger (19-36 years) individuals had less sedentary time (p = .042), and shorter (p = .048) and fewer (p = .012) bouts than older (37-60 years) individuals. Group home residents had more bouts on weekends than adults living with parent/guardians (p = .015)., Conclusions: Adults with DS spent half their waking hours in SB of short bouts. Age and residence may influence SB., (© 2023 John Wiley & Sons Ltd.)

When grown on agar surfaces, microbes can produce distinct multicellular spatial structures called colonies, which contain characteristic sizes, shapes, edges, textures, and degrees of opacity and color. For over one hundred years, researchers have used these morphology cues to classify bacteria and guide more targeted treatment of pathogens. Advances in genome sequencing technology have revolutionized our ability to classify bacterial isolates and while genomic methods are in the ascendancy, morphological characterization of bacterial species has made a resurgence due to increased computing capacities and widespread application of machine learning tools. In this paper, we revisit the topic of colony morphotype on the within-species scale and apply concepts from image processing, computer vision, and deep learning to a dataset of 69 environmental and clinical Pseudomonas aeruginosa strains. We find that colony morphology and complexity under common laboratory conditions is a robust, repeatable phenotype on the level of individual strains, and therefore forms a potential basis for strain classification. We then use a deep convolutional neural network approach with a combination of data augmentation and transfer learning to overcome the typical data starvation problem in biological applications of deep learning. Using a train/validation/test split, our results achieve an average validation accuracy of 92.9% and an average test accuracy of 90.7% for the classification of individual strains. These results indicate that bacterial strains have characteristic visual 'fingerprints' that can serve as the basis of classification on a sub-species level. Our work illustrates the potential of image-based classification of bacterial pathogens and highlights the potential to use similar approaches to predict medically relevant strain characteristics like antibiotic resistance and virulence from colony data., Competing Interests: The authors declare no competing interests., (Copyright: © 2023 Rattray et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Streptococcus pneumoniae is an opportunistic pathogen that, while usually carried asymptomatically, can cause severe invasive diseases like meningitis and bacteremic pneumonia. A central goal in S. pneumoniae public health management is to identify which serotypes (immunologically distinct strains) pose the most risk of invasive disease. The most common invasiveness metrics use cross-sectional data (i.e., invasive odds ratios (IOR)), or longitudinal data (i.e., attack rates (AR)). To assess the reliability of these metrics we developed an epidemiological model of carriage and invasive disease. Our mathematical analyses illustrate qualitative failures with the IOR metric (e.g., IOR can decline with increasing invasiveness parameters). Fitting the model to both longitudinal and cross-sectional data, our analysis supports previous work indicating that invasion risk is maximal at or near time of colonization. This pattern of early invasive disease risk leads to substantial (up to 5-fold) biases when estimating underlying differences in invasiveness from IOR metrics, due to the impact of carriage duration on IOR. Together, these results raise serious concerns with the IOR metric as a basis for public health decision-making and lend support for multiple alternate metrics including AR., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier B.V.)

Despite being corrosion-resistant, plastic potable water pipes might accumulate heavy metals on their surface if they convey metal-contaminated tap water. This study examined the influence of water pH and flow conditions on lead (Pb) release from new and biofilm-laden potable water pipes to provide insights regarding decontamination. For this purpose, biofilms were grown onto new crosslinked polyethylene (PEX-A), high-density polyethylene (HDPE), and copper pipes for three months. Lead was then deposited onto the new and biofilm-laden pipes through 5 d exposure experiments under flow conditions. After that, lead release experiments were conducted by exposing the lead-accumulated pipes to lead-free synthetic tap water for 5 d, under both stagnant and water flow conditions. The metal accumulation study showed no significant difference in lead uptake by new pipes and their biofilm-laden counterparts under flow conditions. This could be attributed to the detachment of biofilms that have accumulated lead as water flows through the pipes. Water flow conditions significantly influenced the lead release from new and biofilm-laden water pipes. A lower water pH of 5.0 increased the release of lead from plastic pipes into the contact water, compared to pH 6.0 and 7.8. The greatest percentage of lead was released from biofilm-laden HDPE pipes (5.3%, 120 h) compared to biofilm-laden copper pipes (3.9%, 6 h) and PEX-A (3.7%, 120 h) and after exposure to lead-free synthetic tap water at pH 5.0, under stagnant conditions. On the other hand, under water flow conditions, the greatest lead release was found for new PEX-A pipes (4.4%, 120 h), new HDPE pipes (2.7%, 120 h), and biofilm-laden copper pipes (3.7%, 2 h)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cystic fibrosis (CF) is widely known as a disease of the lung, even though it is in truth a systemic disease, whose symptoms typically manifest in gastrointestinal dysfunction first. CF ultimately impairs not only the pancreas and intestine but also the lungs, gonads, liver, kidneys, bones, and the cardiovascular system. It is caused by one of several mutations in the gene of the epithelial ion channel protein CFTR. Intense research and improved antimicrobial treatments during the past eight decades have steadily increased the predicted life expectancy of a person with CF (pwCF) from a few weeks to over 50 years. Moreover, several drugs ameliorating the sequelae of the disease have become available in recent years, and notable treatments of the root cause of the disease have recently generated substantial improvements in health for some but not all pwCF. Yet, numerous fundamental questions remain unanswered. Complicating CF, for instance in the lung, is the fact that the associated insufficient chloride secretion typically perturbs the electrochemical balance across epithelia and, in the airways, leads to the accumulation of thick, viscous mucus and mucus plaques that cannot be cleared effectively and provide a rich breeding ground for a spectrum of bacterial and fungal communities. The subsequent infections often become chronic and respond poorly to antibiotic treatments, with outcomes sometimes only weakly correlated with the drug susceptibility of the target pathogen. Furthermore, in contrast to rapidly resolved acute infections with a single target pathogen, chronic infections commonly involve multi-species bacterial communities, called "infection microbiomes," that develop their own ecological and evolutionary dynamics. It is presently impossible to devise mathematical models of CF in its entirety, but it is feasible to design models for many of the distinct drivers of the disease. Building upon these growing yet isolated modeling efforts, we discuss in the following the feasibility of a multi-scale modeling framework, known as template-and-anchor modeling, that allows the gradual integration of refined sub-models with different granularity. The article first reviews the most important biomedical aspects of CF and subsequently describes mathematical modeling approaches that already exist or have the potential to deepen our understanding of the multitude aspects of the disease and their interrelationships. The conceptual ideas behind the approaches proposed here do not only pertain to CF but are translatable to other systemic diseases. This article is categorized under: Congenital Diseases > Computational Models., (© 2023 Wiley Periodicals LLC.)

Heavy metals' interactions with plumbing materials are complicated due to the differential formation of biofilms within pipes that can modulate, transform, and/or sequester heavy metals. This research aims to elucidate the mechanistic role of biofilm presence on Lead (Pb) accumulation onto crosslinked polyethylene (PEX-A), high-density polyethylene (HDPE), and copper potable water pipes. For this purpose, biofilms were grown on new pipes for three months. Five-day Pb exposure experiments were conducted to examine the kinetics of Pb accumulation onto the new and biofilm-laden pipes. Additionally, the influence of Pb initial concentration on the rate of its accumulation onto the pipes was examined. The results revealed greater biofilm biomass on the PEX-A pipes compared to the copper and HDPE pipes. More negative zeta potential was found for the biofilm-laden plastic pipes compared to the new plastic pipes. After five days of Pb exposure under stagnant conditions, the biofilm-laden PEX-A (980 μg m -2 ) and HDPE (1170 μg m -2 ) pipes accumulated more than three times the Pb surface loading compared to the new PEX-A (265 μg m -2 ) and HDPE pipes (329 μg m -2 ), respectively. However, under flow conditions, Pb accumulation on biofilm-laden plastic pipes was lower than on the new pipes. Moreover, with increasing the initial Pb concentration, greater rates of Pb surface accumulation were found for the biofilm-laden pipes compared to the new pipes under stagnant conditions. First-order kinetics model best described the Pb accumulation onto both new and biofilm-laden water pipes under both stagnant and flow conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Illustration of life-histories of phages and plasmids through horizontal and vertical transmission (see Figure 1 for more information)., (© 2023 European Society for Evolutionary Biology.)

Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. However, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, is not fully understood. Here, we report that in mice, adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in a model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings suggest the microglial Cnr1 may contribute to adverse effect of cannabis exposure in genetically vulnerable individuals., (© 2023. Springer Nature Limited.)

Background: Suicide is a leading cause of death in adolescents and adults in the US. Follow-up support delivered when patients return home after an emergency department (ED) or primary care encounter can significantly reduce suicidal ideation and attempts. Two follow-up models to augment usual care including the Safety Planning Intervention have high efficacy: Instrumental Support Calls (ISC) and Caring Contacts (CC) two-way text messages, but they have never been compared to assess which works best. This protocol for the Suicide Prevention Among Recipients of Care (SPARC) Trial aims to determine which model is most effective for adolescents and adults with suicide risk., Methods: The SPARC Trial is a pragmatic randomized controlled trial comparing the effectiveness of ISC versus CC. The sample includes 720 adolescents (12-17 years) and 790 adults (18+ years) who screen positive for suicide risk during an ED or primary care encounter. All participants receive usual care and are randomized 1:1 to ISC or CC. The state suicide hotline delivers both follow-up interventions. The trial is single-masked, with participants unaware of the alternative treatment, and is stratified by adolescents/adults. The primary outcome is suicidal ideation and behavior, measured using the Columbia Suicide Severity Rating Scale (C-SSRS) screener at 6 months. Secondary outcomes include C-SSRS at 12 months, and loneliness, return to crisis care for suicidality, and utilization of outpatient mental health services at 6 and 12 months., Discussion: Directly comparing ISC and CC will determine which follow-up intervention is most effective for suicide prevention in adolescents and adults., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023. Published by Elsevier Inc.)

Lorlatinib is an active pharmaceutical ingredient (API) used in the treatment of lung cancer. Here, an NMR crystallography analysis is presented whereby the single-crystal X-ray diffraction structure (CSD: 2205098) determination is complemented by multinuclear ( 1 H, 13 C, 14 / 15 N, 19 F) magic-angle spinning (MAS) solid-state NMR and gauge-including projector augmented wave (GIPAW) calculation of NMR chemical shifts. Lorlatinib crystallises in the P2 1 space group, with two distinct molecules in the asymmetric unit cell, Z' = 2. Three of the four NH 2 hydrogen atoms form intermolecular hydrogen bonds, N30-H…N15 between the two distinct molecules and N30-H…O2 between two equivalent molecules. This is reflected in one of the NH 2 1 H chemical shifts being significantly lower, 4.0 ppm compared to 7.0 ppm. Two-dimensional 1 H- 13 C, 14 N- 1 H and 1 H (double-quantum, DQ)- 1 H (single-quantum, SQ) MAS NMR spectra are presented. The 1 H resonances are assigned and specific HH proximities corresponding to the observed DQ peaks are identified. The resolution enhancement at a 1 H Larmor frequency of 1 GHz as compared to 500 or 600 MHz is demonstrated., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lorlatinib is marketed by Pfizer, with co-authors from Pfizer on the paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

1 H-detected 14 N heteronuclear multiple-quantum coherence (HMQC) magic-angle-spinning (MAS) NMR experiments performed at fast magic-angle spinning (≥50 kHz) are finding increasing application, e.g., to pharmaceuticals. Of importance to the efficacy of these techniques is the recoupling technique applied to reintroduce the 1 H- 14 N dipolar coupling. In this paper, we compare, by experiment and 2-spin density matrix simulations, two classes of recoupling scheme: first, those based on n = 2 rotary resonance, namely R 3 and spin-polarisation inversion SPI-R 3 , and the symmetry based SR4 1 2 method and, second, the TRAPDOR method. Both classes require optimisation depending on the magnitude of the quadrupolar interaction, and thus there is a compromise choice for samples with more than one nitrogen site, as is the case for the studied dipeptide β-AspAla that contains two nitrogen sites with a small and large quadrupolar coupling constant. Considering this, we observe better sensitivity for the TRAPDOR method, though noting the marked sensitivity of TRAPDOR to the 14 N transmitter offset, with both SPI-R 3 and SR4 1 2 giving similar recoupling performance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Caring Contacts can effectively reduce suicide ideation, attempts, and death. In published clinical trials, Caring Contacts were sent by someone who knew the recipient. At scale, Caring Contacts programs rarely introduce the recipient and sender. It is not known whether receiving Caring Contacts from someone unknown is as effective as messages from someone the recipient has met., Methods: Pragmatic randomized controlled trial comparing Caring Contacts with (CC+) versus without an introductory phone call (CC). Recruitment occurred January-July 2021, with outcomes assessed at 6 months. Participants were primary care patients or healthcare providers/staff reporting adverse mental health outcomes on a qualifying survey. Participants were sent 11 standardized caring text messages over 6 months; when participants replied, they received personalized unscripted responses. CC+ calls were semi-structured. The primary outcome was loneliness (NIH Toolkit)., Results: Participants included 331 patients (mean [SD] age: 45.5 [16.4], 78.9 % female) and 335 healthcare providers/staff (mean [SD] age: 40.9 [11.8], 86.6 % female). There were no significant differences in loneliness at 6 months by treatment arm in either stratum. In patients, mean (SD) loneliness was 61.9 (10.7) in CC, and 60.8 (10.3) in CC+, adjusted mean difference of -1.0 (95 % CI: -3.0, 1.0); p-value = 0.31. In providers/staff, mean (SD) loneliness was 61.2 (11) in CC, and 61.3 (11.1) in CC+, adjusted mean difference of 0.2 (95 % CI: -1.8, 2.2); p-value = 0.83., Limitations: Study population was 93 % white which may limit generalizability., Conclusions: Including an initial phone call added operational complexity without significantly improving the effectiveness of a Caring Contacts program., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Solid-state nuclear spin diffusion is the coherent and reversible process through which spin order is transferred via dipolar couplings. With the recent increases in magic-angle spinning (MAS) frequencies and magnetic fields becoming routinely applied in solid-state nuclear magnetic resonance, understanding how the increased 1H resolution obtained affects spin diffusion is necessary for interpretation of several common experiments. To investigate the coherent contributions to spin diffusion with fast MAS, we have developed a low-order correlation in Liouville space model based on the work of Dumez et al. (J. Chem. Phys. 33, 224501, 2010). Specifically, we introduce a new method for basis set selection, which accounts for the resonance-offset dependence at fast MAS. Furthermore, we consider the necessity of including chemical shift, both isotropic and anisotropic, in the modeling of spin diffusion. Using this model, we explore how different experimental factors change the nature of spin diffusion. Then, we show case studies to exemplify the issues that arise in using spin diffusion techniques at fast spinning. We show that the efficiency of polarization transfer via spin diffusion occurring within a deuterated and 100% back-exchanged protein sample at 60 kHz MAS is almost entirely dependent on resonance offset. We additionally identify temperature-dependent magnetization transfer in beta-aspartyl L-alanine, which could be explained by the influence of an incoherent relaxation-based nuclear Overhauser effect., (© 2023 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)