Impacts of a Dysphagia Screening Questionnaire on Speech Pathology Input Using a Transdisciplinary Approach for Patients with Chronic Obstructive Pulmonary Disease in a Pulmonary Rehabilitation Program.

Patients with chronic obstructive pulmonary disease (COPD) in pulmonary rehabilitation programs (PRPs) are not routinely screened for dysphagia. An Australian regional health service audit revealed that patients with COPD are frequently referred to speech pathology during acute admissions, rather than proactively to mitigate the risk of dysphagia-related consequences. Referral patterns to speech pathology using a novel transdisciplinary approach for identifying at risk for dysphagia patients in a PRP were explored. The aim of this study was to investigate the impact of a transdisciplinary dysphagia screening questionnaire on speech pathology referrals within a cohort of patients with COPD enrolled in a PRP. This quasi-experimental study introduced a dysphagia screening questionnaire in a PRP using a transdisciplinary approach. A retrospective audit of PRP patients (n = 563) between 01/01/2014 and 31/12/2018 was conducted to identify the frequency of referrals to speech pathology for dysphagia. Data was compared to a cohort of patients (n = 50) enrolled in the PRP (from 01/02/21 to 30/11/21) after introduction of the questionnaire using Fisher's exact test. Less than 1% (n = 4/563) of PRP patients were referred to speech pathology prior to implementation of the questionnaire. Following the implementation, referrals to speech pathology significantly increased to 16% (8/50) (X2 = 7.72, P < 0.05; odds ratio = 7.89 95% CI [1.94, 32.1]). Introducing a dysphagia screening questionnaire increased referrals to speech pathology from a PRP. This study demonstrated the potential for a transdisciplinary approach in early screening for patients at risk of dysphagia for patients with COPD. Further research is encouraged to explore patient motivation towards speech pathology input with COPD-related dysphagia and clinicians' perceived self-efficacy in using the questionnaire.

Parental Education for the Prevention of Plagiocephaly.

INTRODUCTION: The American Academy of Pediatrics Back-to-Sleep Campaign significantly reduced infant mortality from sudden infant death syndrome. As a result of prolonged supine positioning, the incidence of deformational plagiocephaly has also risen 5-fold since its adoption. We aimed to improve the current educational paradigm for new parents with the goal of reducing the incidence of plagiocephaly within the confines of the Back-to-Sleep Campaign. We hypothesized that the early addition of plagiocephaly focused education for parents would reduce cephalic index, the ratio of head width to length, used as an easily measured objective proxy for positional plagiocephaly. METHODS: Children were screened at their newborn visit. Premature newborns and those diagnosed with craniofacial disorders were excluded. For those enrolled, biparietal and anteroposterior measurements of the head were obtained using manual calipers to obtain cephalic index. Subjects randomly assigned to the intervention group were shown a 2-minute video and given an educational pamphlet on methods to prevent plagiocephaly. Unpaired 2-sample t tests comparing mean differences in intervention and control were performed. RESULTS: Thirty-nine subjects were enrolled as of November 2023 with variable lengths of follow-up completed. The average baseline cephalic index for subjects in the control group was 82.7 and 83.8 for intervention group. Unpaired 2-sample t tests were performed at 2-, 4-, and 6-month time points to analyze the difference between groups. At 4 months, average cephalic index for subjects in the control and treatment group, respectively, was 90.6 and 83.4 (P = 0.02). SIGNIFICANCE: Parental education at the newborn visit led to decreases in cephalic index, a proxy for positional plagiocephaly, compared with control patients. This simple intervention has the potential to reduce parental stress and healthcare costs associated with the evaluation and treatment of plagiocephaly.

Bone Deformities through the Prism of the International Classification of Functioning, Disability and Health in Ambulant Children with Cerebral Palsy: A Systematic Review.

(1) Aim: The aim of this study was to determine the relationship between lower limb bone deformities and body functions, activity, and participation in ambulant children with CP and whether changing bone morphology affects outcomes in these domains. (2) Methods: A systematic literature search (PROSPERO CRD42020208416) of studies reporting correlations between measures of lower limb bone deformities and measures of body function, activity or participation, or post-surgical outcomes in these domains was conducted from 1990 to 2023 in Medline, Scopus, and Cochrane Library. We assessed study quality with the Checklist for Case Series (CCS) and a quality assessment developed by Quebec University Hospital. Meta-analysis was not possible; therefore, descriptive synthesis was performed. (3) Results: A total of 12 of 3373 screened articles were included. No studies evaluated the relationships between bone deformities and activity or participation, or the effect of isolated bone surgery on these domains. Correlations between bone deformities and body functions were poor-to-moderate. Internal hip rotation during gait improved after femoral derotation osteotomy. (4) Conclusions: A shift in paradigm is urgently required for the research and management of bone deformities in children with CP to include the activity and participation domains of the ICF, as well as consider more psychological aspects such as self-image.

NF-κB signaling in neoplastic transition from epithelial to mesenchymal phenotype.

NF-κB transcription factors are critical regulators of innate and adaptive immunity and major mediators of inflammatory signaling. The NF-κB signaling is dysregulated in a significant number of cancers and drives malignant transformation through maintenance of constitutive pro-survival signaling and downregulation of apoptosis. Overactive NF-κB signaling results in overexpression of pro-inflammatory cytokines, chemokines and/or growth factors leading to accumulation of proliferative signals together with activation of innate and select adaptive immune cells. This state of chronic inflammation is now thought to be linked to induction of malignant transformation, angiogenesis, metastasis, subversion of adaptive immunity, and therapy resistance. Moreover, accumulating evidence indicates the involvement of NF-κB signaling in induction and maintenance of invasive phenotypes linked to epithelial to mesenchymal transition (EMT) and metastasis. In this review we summarize reported links of NF-κB signaling to sequential steps of transition from epithelial to mesenchymal phenotypes. Understanding the involvement of NF-κB in EMT regulation may contribute to formulating optimized therapeutic strategies in cancer. Video Abstract.

JNK Signalling Regulates Self-Renewal of Proliferative Urine-Derived Renal Progenitor Cells via Inhibition of Ferroptosis.

With a global increase in chronic kidney disease patients, alternatives to dialysis and organ transplantation are needed. Stem cell-based therapies could be one possibility to treat chronic kidney disease. Here, we used multipotent urine-derived renal progenitor cells (UdRPCs) to study nephrogenesis. UdRPCs treated with the JNK inhibitor-AEG3482 displayed decreased proliferation and downregulated transcription of cell cycle-associated genes as well as the kidney progenitor markers-SIX2, SALL1 and VCAM1. In addition, levels of activated SMAD2/3, which is associated with the maintenance of self-renewal in UdRPCs, were decreased. JNK inhibition resulted in less efficient oxidative phosphorylation and more lipid peroxidation via ferroptosis, an iron-dependent non-apoptotic cell death pathway linked to various forms of kidney disease. Our study is the first to describe the importance of JNK signalling as a link between maintenance of self-renewal and protection against ferroptosis in SIX2-positive renal progenitor cells.

Interpreting permeability as a function of free drug fraction: The case studies of cyclodextrins and liposomes.

In order to solubilize poorly soluble active pharmaceutical ingredients, various strategies have been implemented over the years, including the use of nanocarriers, such as cyclodextrins and liposomes. However, improving a drug's apparent solubility does not always translate to enhanced bioavailability. This work aimed to investigate to which extent complexation with cyclodextrins and incorporation into liposomes influence drug in vitro permeability and to find a mechanistic description of the permeation process. For this purpose, we investigated hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and phosphatidylcholine liposomes formulations of three chemically diverse compounds (atenolol, ketoprofen and hydrocortisone). We studied drug diffusion of the formulations by UV-localized spectroscopy and advanced data fitting to extract parameters such as diffusivity and bound-/free drug fractions. We then correlated this information with in vitro drug permeability obtained with the novel PermeaPadⓇ barrier. The results showed that increased concentration of HP-ß-CD leads to increased solubilization of the poorly soluble unionized ketoprofen, as well as hydrocortisone. However, this net increment of apparent solubility was not proportional to the increased flux measured. On the other hand, normalising the flux over the empirical free drug concentration, i.e., the free fraction, gave a meaningful absolute permeability coefficient. The results achieved for the liposomal formulation were consistent with the finding on cyclodextrins. In conclusion, we proved the adequacy and usefulness of our method for calculating free drug fractions in the examined enabling formulations, supporting the validity of the established drug diffusion/permeation theory that the unbounded drug fraction is the main driver for drug permeation across a membrane.

Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity.

CDK2 is a core cell-cycle kinase that phosphorylates many substrates to drive progression through the cell cycle. CDK2 is hyperactivated in multiple cancers and is therefore an attractive therapeutic target. Here, we use several CDK2 inhibitors in clinical development to interrogate CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. Whereas CDK1 is known to compensate for loss of CDK2 in Cdk2-/- mice, this is not true of acute inhibition of CDK2. Upon CDK2 inhibition, cells exhibit a rapid loss of substrate phosphorylation that rebounds within several hours. CDK4/6 activity backstops inhibition of CDK2 and sustains the proliferative program by maintaining Rb1 hyperphosphorylation, active E2F transcription, and cyclin A2 expression, enabling re-activation of CDK2 in the presence of drug. Our results augment our understanding of CDK plasticity and indicate that co-inhibition of CDK2 and CDK4/6 may be required to suppress adaptation to CDK2 inhibitors currently under clinical assessment.

P-element invasion fuels molecular adaptation in laboratory populations of Drosophila melanogaster.

Transposable elements (TEs) are mobile genetic parasites that frequently invade new host genomes through horizontal transfer. Invading TEs often exhibit a burst of transposition, followed by reduced transposition rates as repression evolves in the host. We recreated the horizontal transfer of P-element DNA transposons into a Drosophila melanogaster host and followed the expansion of TE copies and evolution of host repression in replicate laboratory populations reared at different temperatures. We observed that while populations maintained at high temperatures rapidly go extinct after TE invasion, those maintained at lower temperatures persist, allowing for TE spread and the evolution of host repression. We also surprisingly discovered that invaded populations experienced recurrent insertion of P-elements into a specific long non-coding RNA, lncRNA:CR43651, and that these insertion alleles are segregating at unusually high frequency in experimental populations, indicative of positive selection. We propose that, in addition to driving the evolution of repression, transpositional bursts of invading TEs can drive molecular adaptation.

Benign Acute Childhood Myositis in a Pediatric Patient Post Influenza B Infection.

Benign acute childhood myositis (BACM) is a mild and self-limited sudden onset of lower extremity pain during or following recovery from a viral illness. It is characterized by difficulty walking due to severe bilateral calf pain, which usually resolves in three days. It is typically appreciated during times of large influenza outbreaks and epidemics. The most severe complication can be rhabdomyolysis without proper treatment and can lead to renal damage and potential renal failure. There are limited reported cases of BACM and therefore no clear guidelines in the treatment or management of the condition. This case is unique in the sense that the patient had leg pain the entire month prior to presentation in the absence of trauma or injury, and it is believed that the pre-existing myalgia may have been exacerbated by an upper respiratory infection (URI) that started a few weeks after the leg pain onset. In addition, this patient's creatine kinase peaked at over 13,000 U/L, which is three to five times higher than the average of other reported children with this condition. The patient is a five-year-old male who presented to the emergency department with bilateral leg pain and difficulty ambulating. His guardian reported that the leg pain began one month prior to presentation and worsened to the point where he could no longer ambulate, following a fever and cough that began one week prior to presentation. A respiratory viral panel was positive for influenza B, and initial creatine kinase (CK) levels were greater than 10,000. A diagnosis of BACM was made, and supportive care was initiated. BACM is an infrequent complication following a viral infection that is typically treatable with hydration management and routine CK monitoring. Symptoms of BACM are usually limited to muscle pain and weakness, but it can progress to rhabdomyolysis and renal failure if not managed properly. It is therefore crucial that physicians monitor CK values daily until a downtrend is noticed and symptoms begin to resolve.

Method for noninvasive whole-body stimulation with spinning oscillating magnetic fields and its safety in mice.

We recently reported shrinkage of untreatable recurrent glioblastoma (GBM) in an end-stage patient using noninvasive brain stimulation with a spinning oscillating magnetic field (sOMF)-generating device called the Oncomagnetic device. Our in vitro experiments demonstrated selective cancer cell death while sparing normal cells by sOMF-induced increase in intracellular reactive oxygen species (ROS) levels due to magnetic perturbation of mitochondrial electron transport. Here, we describe the results of an in vivo study assessing the toxicity of chronic sOMF stimulation in mice using a newly constructed apparatus comprised of the sOMF-generating active components of the Oncomagnetic device. We chronically stimulated 10 normal 60-day old female C57BL/6 mice in their housing cages for 2 h 3 times a day, as in the patient treatment protocol, over 4 months. We also studied the effects of 2-h acute sOMF stimulation. Our observations and those of blinded independent veterinary staff observers, indicated no significant adverse effects of chronic or acute sOMF stimulation on the health, behavior, electrocardiographic and electroencephalographic activities, hematologic profile, and brain and other tissue and organ morphology of treated mice compared to age-matched untreated control mice. These findings suggest that short- and long-term therapies with the Oncomagnetic device are safe and well tolerated.

Correction: Nguyen et al. The Nephrotoxin Puromycin Aminonucleoside Induces Injury in Kidney Organoids Differentiated from Induced Pluripotent Stem Cells. Cells 2022, 11, 635.

In the original publication [...].

Modulation of spontaneous motor unit potentials by a new motor cortical magnetic stimulation method in amyotrophic lateral sclerosis.

BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) show altered cortical excitability. In this study, we measure modulation of spontaneous motor unit potentials (sMUPs) in hand muscles by multifocal cortical stimulation with a newly developed wearable transcranial rotating permanent magnet stimulator (TRPMS). METHODS: We conducted cross-sectional and longitudinal electromyographic assessments in 40 and 20 ALS patients, respectively, of the stimulation-induced peak increase in the count of sMUPs in two hand muscles modulated by unilateral TRPMS stimulation of the primary motor cortex. We measured peak sMUP counts during several short sessions consisting of 10 stimuli over 60 s and 30 s post-stimulation periods. The longitudinal component involved an initial assessment at an early stage of the disease and up to five follow-up assessments at least 3 months apart. RESULTS: TRPMS stimulation produced no device-related adverse effects. It showed an inverted V-shaped modulation of the peak sMUP counts as a function of ALS functional rating scale revised scores. The ratios of ALS subjects showing peak sMUP count increases between early and intermediate stages (χ2 = 4.086, df = 1, p = 0.043) and intermediate and late stages (χ2 = 4.29, df = 1, p = 0.038) in cross-sectional data were significantly different. Longitudinal assessment also produced a significant (z = 2.31, p = 0.021) result, with all subjects showing a post-initial visit increase in peak sMUP counts. CONCLUSIONS: These results are consistent with delayed onset of upper motor neuronal dysfunction with respect to onset of clinical features. However, the above results need to be confirmed in a larger sample of patients and with multiple lines of evidence.

The Nephrotoxin Puromycin Aminonucleoside Induces Injury in Kidney Organoids Differentiated from Induced Pluripotent Stem Cells.

Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), which can progress to end stage renal disease (ESRD), are a worldwide health burden. Organ transplantation or kidney dialysis are the only effective available therapeutic tools. Therefore, in vitro models of kidney diseases and the development of prospective therapeutic options are urgently needed. Within the kidney, the glomeruli are involved in blood filtration and waste excretion and are easily affected by changing cellular conditions. Puromycin aminonucleoside (PAN) is a nephrotoxin, which can be employed to induce acute glomerular damage and to model glomerular disease. For this reason, we generated kidney organoids from three iPSC lines and treated these with PAN in order to induce kidney injury. Morphological observations revealed the disruption of glomerular and tubular structures within the kidney organoids upon PAN treatment, which were confirmed by transcriptome analyses. Subsequent analyses revealed an upregulation of immune response as well as inflammatory and cell-death-related processes. We conclude that the treatment of iPSC-derived kidney organoids with PAN induces kidney injury mediated by an intertwined network of inflammation, cytoskeletal re-arrangement, DNA damage, apoptosis and cell death. Furthermore, urine-stem-cell-derived kidney organoids can be used to model kidney-associated diseases and drug discovery.

Virtual Care Access and Health Equity during the COVID-19 Pandemic, a qualitative study of patients with chronic diseases from Canada.

OBJECTIVES: The COVID-19 pandemic has led to the widespread uptake of virtual care in Canada; however, virtual care may also create new barriers to health care. The purpose of this paper was to explore patient perceptions and concerns around virtual care access. METHODS: Between February and April 2020, we conducted semi-structured interviews with participants from four chronic disease clinics (stroke, epilepsy, amyotrophic lateral sclerosis, obstetrics medicine) in a mid-sized academic hospital in Southern Ontario, Canada. Consecutive sampling was done by including the patients receiving virtual care in those months. Caregivers were invited to participate in the event that patients were unable to participate in the interview. Thematic analysis was employed to identify overarching themes, and codes were reviewed and refined using a consensus process. RESULTS: We interviewed 31 participants (27 patients, four caregivers) that had taken part in virtual care. Our findings suggested that the COVID-19 pandemic served to isolate participants and had negatively impacted their access to health care. However, virtual care did provide a safe avenue for patients to receive care and served as a reassuring option during the pandemic. Low technological literacy and access were identified as barriers to virtual care. Greater awareness and patient engagement is needed in future research to improve access. CONCLUSION: Certain populations can be disproportionately affected by differential access to virtual care. Future studies should examine how social determinants intersect to impact virtual health care access in different patient populations.

Immediate impact of bringing a school to the community with a new community-based clinical education program.

OBJECTIVES: To examine the implementation of a community-based clinical education (CBCE) program at the University of California, Los Angeles School of Dentistry (SOD) and the preliminary outcomes on dental students and affiliated clinics. METHODS: A retrospective review was carried out of SOD CBCE program implementation and program data between March 2018 and June 2019 related to patient encounters, pre- and post-rotation student self-assessments, student exit surveys and surveys administered to faculty within affiliate clinics. RESULTS: In five academic quarters, 133 students delivered care for 7556 patients and completed 12,467 procedures in underserved communities. Students reported increased confidence across 14 areas of self-assessment. The percentage of students reporting future plans of working in public health clinics upon graduation increased from 6% to 19%. Affiliate clinic faculty indicated increased care delivery for underserved patients, appointment availability, and job satisfaction. CONCLUSIONS: The newly implemented UCLA SOD CBCE program preliminarily yielded immediate positive outcomes for SOD students and affiliate community clinics.

Practical aspects of oral immunotherapy: The importance of optimal office design and workflow.

Oral immunotherapy (OIT) is an emerging treatment, but it is more than products and protocols. Office setup, including spacing, staffing, and logistics, is critical to assess to fully implement OIT into clinical practice. To provide insights into what needs to be considered in setting up an office to practically implement OIT into clinical practice. Most of the clinical research about OIT focuses on the products and protocols used for OIT. However, to safely and effectively integrate this into clinical practice, there are many practical aspects that need to be considered. Proper staffing, office space, scheduling, and on-call responsibilities all need to be considered because OIT will impact all of these aspects of practice. We provide suggestions and considerations as you think through these vital logistics in your office. These are practical considerations that must be determined to effectively handle OIT in an office setting. OIT products and protocols are one aspect of OIT. Actually delivering the treatment with staff, office space, and handling the patient needs after hours is really when OIT becomes more of a reality for the physician and the patient.

Management of Type 2 Retinopathy of Prematurity or Less in Infants Aged 45 Weeks Postmenstrual Age or Older.

BACKGROUND AND OBJECTIVE: This study aimed to identify the degree of concordance between fluorescein angiograms (FA) and fundus photographs (FP) in assessing the severity and potential need for treatment in infants 45 weeks or older postmenstrual age (PMA) with type 2 or less retinopathy of prematurity (ROP). PATIENTS AND METHODS: An observational retrospective case series performed at Associated Retinal Consultants, William Beaumont Hospital in Royal Oak, Michigan. All infants born between 2006 and 2016 with stage 1 to 3 ROP that did not meet type 1 ROP criteria (type 2 or less) who received ablative laser therapy during or after age 45 weeks PMA. Pretreatment FP and FA images were randomized and sent to nine expert retina specialist graders to assess severity and inter-grader variability. RESULTS: A total of 10 babies (19 eyes) were enrolled in this study, and 53 FAs and 27 FPs of these 19 eyes were selected to be interpreted by the nine graders. The number of eyes deemed to be abnormal and warranted for treatment was higher with FA, whereas more eyes were deemed "normal" with FP. CONCLUSION: Although still controversial, knowledge of these findings may encourage retina specialists to closely examine infants with mild ROP older than age 45 weeks PMA and consider ablative laser therapy under certain conditions (even if not meeting type 1 Early Treatment for ROP criteria). [Ophthalmic Surg Lasers Imaging Retina. 2021;52:636-641.].

Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor.

The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.

Case Report: End-Stage Recurrent Glioblastoma Treated With a New Noninvasive Non-Contact Oncomagnetic Device.

Alternating electric field therapy has been approved for glioblastoma (GBM). We have preclinical evidence for anticancer effects in GBM cell cultures and mouse xenografts with an oscillating magnetic field (OMF) generating device. Here we report OMF treatment of end-stage recurrent glioblastoma in a 53-year-old man who had undergone radical surgical excision and chemoradiotherapy, and experimental gene therapy for a left frontal tumor. He experienced tumor recurrence and progressive enlargement with leptomeningeal involvement. OMF for 5 weeks was well tolerated, with 31% reduction of contrast-enhanced tumor volume and reduction in abnormal T2-weighted Fluid-Attenuated Inversion Recovery volume. Tumor shrinkage appeared to correlate with treatment dose. These findings suggest a powerful new noninvasive therapy for glioblastoma.

Patient perceptions of the benefits and barriers of virtual postnatal care: a qualitative study.

OBJECTIVE: The objective of this study is to understand the perceptions of new mothers using virtual care via video conferencing to gain insight into the benefits and barriers of virtual care for obstetric patients. METHODS: Semi-structured interviews were conducted with 15 patients attending the Kingston Health Sciences Centre. The interviews were 20-25 min in length and recorded through an audio recorder. Thematic analysis was conducted in order to derive the major themes explored in this study. RESULTS: New mothers must often adopt new routines to balance their needs and their child's needs. These routines could impact compliance and motivation to attend follow-up care. In our study, participants expressed high satisfaction with virtual care, emphasizing benefits related to comfort, convenience, communication, socioeconomic factors, and the ease of technology use. Participants also perceived that they could receive emotional support and build trust with their health care providers despite the remote nature of their care. Due to its ease of use and increased accessibility, we argue that virtual care shows promise to facilitate long-term compliance to care in obstetric patients. CONCLUSIONS: Virtual care is a useful modality that could improve compliance to obstetric care. Further research and clinical endeavours should examine how social factors and determinants intersect to determine how they underpin patient perceptions of virtual and in-person care.