Nirmatrelvir-ritonavir treatment of COVID-19 in a high-risk patient population: A retrospective observational study.

Background: Coronavirus disease 2019 (COVID-19) is a highly contagious, airborne viral infection that can infect anyone. Those with certain underlying conditions may be at higher risk for infection to develop into a severe disease requiring hospitalization. This report summarizes use of nirmatrelvir-ritonavir for the treatment of COVID-19 in high-risk patients at a single academic medical center through a pharmacist delegation protocol and demonstrates real-world efficacy and safety of treatment. Methods: This retrospective, single-center, observational study analyzed all patients who received nirmatrelvir-ritonavir ordered by a clinical pharmacist for treatment of COVID-19 infection. The primary outcomes were safety and efficacy of nirmatrelvir-ritonavir. Safety was evaluated by analyzing drug interaction management and adverse events. Efficacy was evaluated through hospitalization and death within 28 days of nirmatrelvir-ritonavir use. Results: Sixty patients were eligible for inclusion. No patients were hospitalized or died within 28 days after initiation of nirmatrelvir-ritonavir. Pharmacists identified 101 drug interactions with 60% considered clinically significant, requiring modification of home medications. Adverse outcomes associated with the use of nirmatrelvir-ritonavir were reported in 13 patients (21.7%). Conclusions: A comprehensive program to mitigate drug interactions and prescribe nirmatrelvir-ritonavir ensured timely access to COVID-19 therapy, which may be associated with the prevention of hospitalization and death.

Acute multidrug delivery via a wearable bioreactor facilitates long-term limb regeneration and functional recovery in adult Xenopus laevis.

Limb regeneration is a frontier in biomedical science. Identifying triggers of innate morphogenetic responses in vivo to induce the growth of healthy patterned tissue would address the needs of millions of patients, from diabetics to victims of trauma. Organisms such as Xenopus laevis-whose limited regenerative capacities in adulthood mirror those of humans-are important models with which to test interventions that can restore form and function. Here, we demonstrate long-term (18 months) regrowth, marked tissue repatterning, and functional restoration of an amputated X. laevis hindlimb following a 24-hour exposure to a multidrug, pro-regenerative treatment delivered by a wearable bioreactor. Regenerated tissues composed of skin, bone, vasculature, and nerves significantly exceeded the complexity and sensorimotor capacities of untreated and control animals' hypomorphic spikes. RNA sequencing of early tissue buds revealed activation of developmental pathways such as Wnt/ß-catenin, TGF-ß, hedgehog, and Notch. These data demonstrate the successful "kickstarting" of endogenous regenerative pathways in a vertebrate model.

A Meta-Analysis of Bioelectric Data in Cancer, Embryogenesis, and Regeneration.

Developmental bioelectricity is the study of the endogenous role of bioelectrical signaling in all cell types. Resting potentials and other aspects of ionic cell physiology are known to be important regulatory parameters in embryogenesis, regeneration, and cancer. However, relevant quantitative measurement and genetic phenotyping data are distributed throughout wide-ranging literature, hampering experimental design and hypothesis generation. Here, we analyze published studies on bioelectrics and transcriptomic and genomic/phenotypic databases to provide a novel synthesis of what is known in three important aspects of bioelectrics research. First, we provide a comprehensive list of channelopathies-ion channel and pump gene mutations-in a range of important model systems with developmental patterning phenotypes, illustrating the breadth of channel types, tissues, and phyla (including man) in which bioelectric signaling is a critical endogenous aspect of embryogenesis. Second, we perform a novel bioinformatic analysis of transcriptomic data during regeneration in diverse taxa that reveals an electrogenic protein to be the one common factor specifically expressed in regeneration blastemas across Kingdoms. Finally, we analyze data on distinct Vmem signatures in normal and cancer cells, revealing a specific bioelectrical signature corresponding to some types of malignancies. These analyses shed light on fundamental questions in developmental bioelectricity and suggest new avenues for research in this exciting field.

Mechanosensation Mediates Long-Range Spatial Decision-Making in an Aneural Organism.

The unicellular protist Physarum polycephalum is an important emerging model for understanding how aneural organisms process information toward adaptive behavior. Here, it is revealed that Physarum can use mechanosensation to reliably make decisions about distant objects in its environment, preferentially growing in the direction of heavier, substrate-deforming, but chemically inert masses. This long-range sensing is abolished by gentle rhythmic mechanical disruption, changing substrate stiffness, or the addition of an inhibitor of mechanosensitive transient receptor potential channels. Additionally, it is demonstrated that Physarum does not respond to the absolute magnitude of strain. Computational modeling reveales that Physarum may perform this calculation by sensing the fraction of its perimeter that is distorted above a threshold substrate strain-a fundamentally novel method of mechanosensation. Using its body as both a distributed sensor array and computational substrate, this aneural organism leverages its unique morphology to make long-range decisions. Together, these data identify a surprising behavioral preference relying on biomechanical features and quantitatively characterize how the Physarum exploits physics to adaptively regulate its growth and shape.

Regenerative Adaptation to Electrochemical Perturbation in Planaria: A Molecular Analysis of Physiological Plasticity.

Anatomical homeostasis results from dynamic interactions between gene expression, physiology, and the external environment. Owing to its complexity, this cellular and organism-level phenotypic plasticity is still poorly understood. We establish planarian regeneration as a model for acquired tolerance to environments that alter endogenous physiology. Exposure to barium chloride (BaCl2) results in a rapid degeneration of anterior tissue in Dugesia japonica. Remarkably, continued exposure to fresh solution of BaCl2 results in regeneration of heads that are insensitive to BaCl2. RNA-seq revealed transcriptional changes in BaCl2-adapted heads that suggests a model of adaptation to excitotoxicity. Loss-of-function experiments confirmed several predictions: blockage of chloride and calcium channels allowed heads to survive initial BaCl2 exposure, inducing adaptation without prior exposure, whereas blockade of TRPM channels reversed adaptation. Such highly adaptive plasticity may represent an attractive target for biomedical strategies in a wide range of applications beyond its immediate relevance to excitotoxicity preconditioning.

Tamoxifen Acceptance and Adherence among Patients with Ductal Carcinoma In Situ (DCIS) Treated in a Multidisciplinary Setting.

Tamoxifen and other endocrine agents have proven benefits for women with ductal carcinoma in situ (DCIS), but low patient acceptance is widely reported. We examined factors associated with tamoxifen acceptance and adherence among DCIS patients who received a recommendation for therapy in a multidisciplinary setting. Using our institutional database, we identified women diagnosed with DCIS, 1998 to 2009, who were offered tamoxifen. We recorded data on demographics, tumor and therapy variables, tamoxifen acceptance, and adherence to therapy for ≥4 years. Univariable and multivariable analyses were conducted using logistic regression to identify factors specific to each group that were related to acceptance and adherence. A total of 555 eligible women identified, of whom 369 were offered tamoxifen; 298 (81%) accepted, among whom 214 (72%) were adherent, 59 of 298 (20%) were nonadherent, and for 25 (8%), adherence was undetermined. After stepwise elimination in adjusted logistic regression models, acceptance of breast radiotherapy was associated with acceptance of tamoxifen [OR, 2.22; 95% confidence interval (CI), 1.26-3.90; P < 0.01], as was a medical oncology consultation (OR, 1.76; 95% CI, 0.99-3.15; P = 0.05). Insured patients were more likely to adhere to tamoxifen (OR, 6.03; 95% CI, 2.60-13.98; P < 0.01). The majority of nonadherent women (n = 38/56, 68%) discontinued the drug during the first year of treatment with 48 (86%) citing adverse effect(s) as the reason. In a multidisciplinary, tertiary care setting, we observed relatively high rates of acceptance and adherence of tamoxifen. Acceptance of tamoxifen and radiotherapy were associated, and adherence was influenced by insurance status.Key Message: Tamoxifen acceptance and adherence following resection of DCIS of the breast is related to acceptance of radiotherapy and may be improved by confirmation of the recommendation by a medical oncologist. Despite the low cost of tamoxifen, adherence to therapy is significantly impacted by lack of insurance; those who discontinue therapy report adverse effects as a major reason. Cancer Prev Res; 10(7); 389-97. ©2017 AACR.

Malignant meningitis secondary to oesophageal adenocarcinoma presenting with sensorineural hearing loss: a series of three cases and discussion of the literature.

Malignant meningitis may rarely present to the otolaryngologist. We report our experience with 3 patients presenting with sudden, progressive bilateral sensorineural hearing loss secondary to malignant meningitis. The primary tumour in all 3 cases was oesophageal adenocarcinoma. All 3 cases were notable for the rapidity of the patients' clinical deterioration; the interval from presentation to death ranged from 21 to 28 days. We suggest that otolaryngologists should remain vigilant to the possibility of this devastating diagnosis and have a low threshold for further investigation in patients with suspicious features. It is important to note that initial MRI and lumbar puncture may be negative and repeat testing should be undertaken if there is clinical suspicion.

Gli3 repressor controls cell fates and cell adhesion for proper establishment of neurogenic niche.

Neural stem cells (NSCs) in the subventricular zone (SVZ) rely on environmental signals provided by the neurogenic niche for their proper function. However, little is known about the initial steps of niche establishment, as embryonic radial glia transition to postnatal NSCs. Here, we identify Gli3 repressor (Gli3R), a component of the Sonic hedgehog (Shh) pathway, as a critical factor controlling both cell-type specification and structural organization of the developing SVZ. We demonstrate that Gli3R expressed in radial glia temporally regulates gp130/STAT3 signaling at the transcriptional level to suppress glial characteristics in differentiating ependymal cells. In addition, Gli3R maintains the proper level of Numb in ependymal cells to allow localization of cell adhesion molecules such as vascular cell adhesion molecule (VCAM) and E-cadherin. Thus, our findings reveal a role for Gli3R as a mediator of niche establishment and provide insights into the conditions required for proper SVZ neurogenic niche formation.

Pneumoparotitis: a case report.

BACKGROUND: Pneumoparotid is a rare cause of parotid enlargement. Pneumatic enlargement of the gland is caused by retrograde insufflation via Stensen's duct. Most reported cases have been managed conservatively, thus running a short course. METHODS AND RESULTS: We report on a case of a 48-year-old man with a chronic painful right facial swelling and symptoms of repeated infection. Clinical examination found a parotid swelling with surgical emphysema and a dilated Stensen's duct. Pneumoparotitis with cystic changes and dilated intraparotid ducts was confirmed by CT. The patient proceeded to undergo excision of the gland, with subsequent resolution of symptoms. CONCLUSION: Repeated retrograde movement of air and contaminated saliva leads to chronic infection and sialectasis. Management is aimed at preventing these sequelae by identifying and addressing the insult early; however, repeated pneumoparotid leads to chronic pneumoparotitis, the management of which is excision of the gland.

Inflammatory fibroid polyp of the ileum causing recurrent intussusception and chronic ischaemia: a case report.

INTRODUCTION: Inflammatory fibroid polyp is a rare condition of the gastrointestinal tract which can lead to intestinal obstruction. CASE PRESENTATION: We present a case of a 65-year-old woman presenting with a 1-month history of intermittent generalised abdominal pain. Computerised tomography imaging demonstrated intussusception of the small bowel. Histology of the resected small bowel revealed an inflammatory fibroid polyp with evidence of chronic ischaemia related to repeated intussusception. This rare complication of inflammatory fibroid polyps is reviewed. CONCLUSION: Although computed tomography is useful in confirming an anatomical abnormality, final diagnosis requires histopathological analysis. Operative resection of the affected segment is recommended.

Sequence analysis of P21-activated kinase 3 (PAK3) in chronic schizophrenia with cognitive impairment.

The P21-activated kinase PAK3 is critical for cognitive development and truncating mutations cause non-syndromic mental retardation (MR). Missense mutations are also associated with psychotic disorders, most commonly with schizophrenia involving premorbid MR, namely "pfropfschizophrenie". We set out to measure the frequency of sequence variants in PAK3 in schizophrenia without premorbid MR. We conducted complete gene reseqeuncing of all coding exons and exon-intron boundaries in patients with schizophrenia with cognitive impairment but without premorbid MR. Deleterious variants in schizophrenia alone were rare (<1/159 or 0.6%). Thereby, while PAK3 remains a strong biological candidate in psychosis, evidence from human genetics provides strongest support for a link to pfropfschizophrenie and not to schizophrenia without premorbid intellectual disability.

Small cell carcinoma of the appendix.

BACKGROUND: An extrapulmonary small cell carcinoma is a rare condition. It has similar histological features to pulmonary small cell carcinoma and is equally aggressive. CASE PRESENTATION: We present the case of a 60-year-old woman who presented with right upper quadrant pain. Computerised tomography revealed an appendiceal lesion and multiple liver metastases. Exploratory laparotomy and right hemicolectomy was performed with histopathological analysis confirming a primary small cell carcinoma of her appendix. CONCLUSION: This is the first reported case of a pure extrapulmonary carcinoma arising from the appendix.