The predictability of expansion with Invisalign: A retrospective cohort study.

INTRODUCTION: Few studies have evaluated the predictability of expansion with Invisalign for the current SmartTrack material. METHODS: Pretreatment, predicted, and posttreatment digital models from Invisalign's ClinCheck software were obtained for 57 adult patients with a planned arch expansion of at least 3 mm. Arch width measurements were collected using a software measuring tool (MeshLab), Invisalign's arch width table, and the centroid of the clinical crown. Data for 30 patients were remeasured for each method to assess intrarater reliability. Predictability of expansion was calculated by comparing the amount of achieved expansion to predicted expansion. RESULTS: The predictability of expansion across centroids for the maxillary teeth was: 72.2% canines, 78.9% first premolars, 81.1% second premolars, 63.5% first molars, and 41.5% second molars. The predictability of expansion across centroids for the mandibular teeth was: 82.3% canines, 93.0% first premolars, 87.7% second premolars, 79.8% first molars, and 42.9% second molars. The average expansion was significantly different from that predicted for each type of tooth in both the maxilla and mandible. Both underexpansion and overexpansion were observed. Arch width measurement reliability for each employed method was as follows: MeshLab (average error 0.197 mm); calculated centroids (0.002 mm); ClinCheck arch width table (0.000 mm). CONCLUSIONS: On average, the amount of predicted expansion is not achieved with the Invisalign system and varies according to tooth type and arch. Discretion is required when overcorrecting to compensate for expansion inaccuracy. Both underexpansion and overexpansion were observed; further investigation into factors influencing underexpansion and overexpansion is required.

Improving Safety by Evaluating the Impact of the Supply Chain and Drug Shortages on Health-Systems.

Background: The COVID-19 pandemic has shown how fragile our healthcare supply chain is with product delays, drug shortages, and labor shortages being exacerbated in recent years. Objective: This article reviews current threats to the healthcare supply chain that impact patient safety and highlights potential solutions for the future. Method: A review of the literature was conducted, and important up-to-date resources associated with drug shortages and supply chain were analyzed to build foundational knowledge. Potential supply chain threats and solutions were then explored through further literature analyses. Conclusions: The information provided in this article helps to brief pharmacy leaders on current supply chain issues and solutions that can be integrated throughout the healthcare supply chain in the future.

A systematic review of acute telogen effluvium, a harrowing post-COVID-19 manifestation.

This systematic review focuses on the clinical features, physical examination findings, outcomes, and underlying pathology of acute telogen effluvium (TE), a type of diffuse hair loss, occurring in coronavirus disease 2019 (COVID-19) recovered patients. MEDLINE/PubMed and Embase databases were queried till October 2021 to identify studies reporting acute TE occurring after COVID-19 recovery. Data were obtained from 19 studies, which included 465 patients who were diagnosed with acute TE. The median age of these patients was 44 years and 67.5% were females. The most common trichoscopic findings were decreased hair density, the presence of empty follicles, or short regrowing hair. The mean duration from COVID-19 symptom onset to the appearance of acute TE was 74 days, which is earlier than classic acute TE. Most patients recovered from hair loss, while a few patients had persistent hair fall. Our results highlight the need to consider the possibility of post-COVID-19 acute TE in patients presenting with hair fall, with a history of COVID-19 infection, in the context of COVID-19 pandemic. Despite being a self-limiting condition, hair loss post-COVID-19 is a stressful manifestation. Identifying COVID-19 infection as a potential cause of acute TE will help the clinicians counsel the patients, relieving them from undue stress.

Low Intensity Focused Ultrasound Increases Duration of Anti-Nociceptive Responses in Female Common Peroneal Nerve Injury Rats.

OBJECTIVE: Chronic pain affects 7%-10% of Americans, occurs more frequently and severely in females, and available treatments have been shown to have less efficacy in female patients. Preclinical models addressing sex-specific treatment differences in the treatment of chronic pain have been limited. Here we examine the sex-specific effects of low intensity focused ultrasound (liFUS) in a modified sciatic nerve injury (SNI) model. MATERIALS AND METHODS: A modified SNI performed by ligating the common peroneal nerve (CPN) was used to measure sensory, behavioral pain responses, and nerve conduction studies in female and male rats, following liFUS of the L5 dorsal root ganglion. RESULTS: Using the same dose of liFUS in females and males of the same weight, CPN latency immediately after treatment was increased for 50 min in females compared to 25 min in males (p < 0.001). Improvements in mechanical pain thresholds after liFUS lasted significantly longer in females (seven days; p < 0.05) compared to males (three days; p < 0.05). In females, there was a significant improvement in depression-like behavior as a result of liFUS (N = 5; p < 0.01); however, because males never developed depression-like behavior there was no change after liFUS treatment. CONCLUSIONS: Neuromodulation with liFUS has a greater effect in female rats on CPN latency, mechanical allodynia duration, and depression-like behavior. In order to customize neuromodulatory techniques for different patient phenotypes, it is essential to understand how they may alter sex-specific pathophysiologies.

Electrocardiographic changes in Takotsubo cardiomyopathy.

Takotsubo Cardiomyopathy (TC) is a syndrome characterized by reversible left ventricular dysfunction in the presence of possible emotional or physical triggers but without evidence of obstructive coronary artery disease. It has become increasingly reported worldwide and is associated with significant morbidity and mortality. TC may present with an array of electrocardiographic (ECG) findings. These ECG findings, if accurately interpreted, can play an important role in the diagnosis and risk stratification of this syndrome. In the last three decades since the disease was first described, multiple diagnostic criteria have been established. The key diagnostic tools for TC include clinical symptomatology, cardiac biomarkers, non-invasive cardiac imaging, and coronary angiography. The ECG findings in TC can be variable, however, some ECG scores have been proposed in association with TC with reasonably good diagnostic sensitivity and specificity. This article aims to provide a succinct review of important electrocardiographic findings associated with TC and its impact on clinical outcomes.

Inhibition of Human Cytomegalovirus Entry into Host Cells Through a Pleiotropic Small Molecule.

Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one or more limitations, which emphasizes the critical need to develop new approaches and new molecules. We reasoned that a 'poly-pharmacy' approach relying on simultaneous binding to multiple receptors involved in HCMV entry into host cells could pave the way to a more effective therapeutic outcome. This work presents the study of a synthetic, small molecule displaying pleiotropicity of interactions as a competitive antagonist of viral or cell surface receptors including heparan sulfate proteoglycans and heparan sulfate-binding proteins, which play important roles in HCMV entry and spread. Sulfated pentagalloylglucoside (SPGG), a functional mimetic of heparan sulfate, inhibits HCMV entry into human foreskin fibroblasts and neuroepithelioma cells with high potency. At the same time, SPGG exhibits no toxicity at levels as high as 50-fold more than its inhibition potency. Interestingly, cell-ELISA assays showed downregulation in HCMV immediate-early gene 1 and 2 (IE 1&2) expression in presence of SPGG further supporting inhibition of viral entry. Finally, HCMV foci were observed to decrease significantly in the presence of SPGG suggesting impact on viral spread too. Overall, this work offers the first evidence that pleiotropicity, such as demonstrated by SPGG, may offer a new poly-therapeutic approach toward effective inhibition of HCMV.

Ethanol Exposure Regulates Gabra1 Expression via Histone Deacetylation at the Promoter in Cultured Cortical Neurons.

γ-Aminobutyric acid A receptors (GABAA-Rs) mediate the majority of inhibitory neurotransmission in the adult brain. The α1-containing GABAA-Rs are the most prominent subtype in the adult brain and are important in both homeostatic function and several disease pathologies including alcohol dependence, epilepsy, and stress. Ethanol exposure causes a decrease of α1 transcription and peptide expression both in vivo and in vitro, but the mechanism that controls the transcriptional regulation is unknown. Because ethanol is known to activate epigenetic regulation of gene expression, we tested the hypothesis that ethanol regulates α1 expression through histone modifications in cerebral cortical cultured neurons. We found that class I histone deacetylases (HDACs) regulate ethanol-induced changes in α1 gene and protein expression as pharmacologic inhibition or knockdown of HDAC1-3 prevents the effects of ethanol exposure. Targeted histone acetylation associated with the Gabra1 promoter using CRISPR (clustered regularly interspaced palindromic repeat) dCas9-P300 (a nuclease-null Cas9 fused with a histone acetyltransferase) increases histone acetylation and prevents the decrease of Gabra1 expression. In contrast, there was no effect of a mutant histone acetyltransferase or generic transcriptional activator or targeting P300 to a distant exon. Conversely, using a dCas9-KRAB construct that increases repressive methylation (H3K9me3) does not interfere with ethanol-induced histone deacetylation. Overall our results indicate that ethanol deacetylates histones associated with the Gabra1 promoter through class I HDACs and that pharmacologic, genetic, or epigenetic intervention prevents decreases in α1 expression in cultured cortical neurons.

Regulation of Extrasynaptic GABAA α4 Receptors by Ethanol-Induced Protein Kinase A, but Not Protein Kinase C Activation in Cultured Rat Cerebral Cortical Neurons.

Ethanol produces changes in GABAA receptor trafficking and function that contribute to ethanol dependence symptomatology. Extrasynaptic γ-aminobutyric acid A receptors (GABAA-R) mediate inhibitory tonic current and are of particular interest because they are potentiated by physiologically relevant doses of ethanol. Here, we isolate GABAA α4δ receptors by western blotting in subsynaptic fractions to investigate protein kinase A (PKA) and protein kinase C (PKC) modulation of ethanol-induced receptor trafficking, while extrasynaptic receptor function is determined by measurement of tonic inhibition and responses evoked by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). Rat cerebral cortical neurons were grown for 18 days in vitro and exposed to ethanol and/or PKA/PKC modulators. Ethanol exposure (1 hour) did not alter GABAA α4 receptor abundance, but it increased tonic current amplitude, an effect that was prevented by inhibiting PKA, but not PKC. Direct activation of PKA, but not PKC, increased the abundance and tonic current of extrasynaptic α4δ receptors. In contrast, prolonged ethanol exposure (4 hours) reduced α4δ receptor abundance as well as tonic current, and this effect was also PKA dependent. Finally, PKC activation by ethanol or phorbol-12,13-dibutyrate (PdBu) had no effect on extrasynaptic α4δ subunit abundance or activity. We conclude that ethanol alters extrasynaptic α4δ receptor function and expression in cortical neurons in a PKA-dependent manner, but ethanol activation of PKC does not influence these receptors. These results could have clinical relevance for therapeutic strategies to restore normal GABAergic functioning for the treatment of alcohol use disorders.

Metastatic Non-Small-Cell Lung Cancer Presenting as Renal Failure From IgA Nephropathy.

Studies have highlighted a potential link between malignancies and immunoglobulin A nephropathy (IgAN). In such studies, the treatment of malignancy improved the symptoms of IgAN. Here, we report a patient case involving a history of hypertension, tobacco use disorder, and chronic kidney disease (CKD) presenting with hematuria with acute renal failure secondary to IgAN per renal biopsy. Prompted by this association, a malignancy workup was performed including computed tomography (CT) body imaging and biopsies of mediastinal and cervical lymph nodes which revealed a metastatic adenocarcinoma. Current knowledge includes a general mechanism behind the development of IgAN that points toward glomerular deposition of tumor-specific immunoglobulin A (IgA) immunoglobulins. However, the association of IgAN and malignancy has no definitive management guidelines. This clinical case serves as an important contribution in the hopes of future development of guidelines regarding the surveillance and management of IgAN in the setting of malignancy.

The Role of Fatty Acid Synthase in the Vascular Smooth Muscle Cell to Foam Cell Transition.

Vascular smooth muscle cells (VSMCs), in their contractile and differentiated state, are fundamental for maintaining vascular function. Upon exposure to cholesterol (CHO), VSMCs undergo dedifferentiation, adopting characteristics of foam cells-lipid-laden, macrophage-like cells pivotal in atherosclerotic plaque formation. CHO uptake by VSMCs leads to two primary pathways: ABCA1-mediated efflux or storage in lipid droplets as cholesterol esters (CEs). CE formation, involving the condensation of free CHO and fatty acids, is catalyzed by sterol O-acyltransferase 1 (SOAT1). The necessary fatty acids are synthesized by the lipogenic enzyme fatty acid synthase (FASN), which we found to be upregulated in atherosclerotic human coronary arteries. This observation led us to hypothesize that FASN-mediated fatty acid biosynthesis is crucial in the transformation of VSMCs into foam cells. Our study reveals that CHO treatment upregulates FASN in human aortic SMCs, concurrent with increased expression of CD68 and upregulation of KLF4, markers associated with the foam cell transition. Crucially, downregulation of FASN inhibits the CHO-induced upregulation of CD68 and KLF4 in VSMCs. Additionally, FASN-deficient VSMCs exhibit hindered lipid accumulation and an impaired transition to the foam cell phenotype following CHO exposure, while the addition of the fatty acid palmitate, the main FASN product, exacerbates this transition. FASN-deficient cells also show decreased SOAT1 expression and elevated ABCA1. Notably, similar effects are observed in KLF4-deficient cells. Our findings demonstrate that FASN plays an essential role in the CHO-induced upregulation of KLF4 and the VSMC to foam cell transition and suggest that targeting FASN could be a novel therapeutic strategy to regulate VSMC phenotypic modulation.

Blood DNA methylation in post-acute sequelae of COVID-19 (PASC): a prospective cohort study.

BACKGROUND: DNA methylation integrates environmental signals with transcriptional programs. COVID-19 infection induces changes in the host methylome. While post-acute sequelae of COVID-19 (PASC) is a long-term complication of acute illness, its association with DNA methylation is unknown. No universal blood marker of PASC, superseding single organ dysfunctions, has yet been identified. METHODS: In this single centre prospective cohort study, PASC, post-COVID without PASC, and healthy participants were enrolled to investigate their symptoms association with peripheral blood DNA methylation data generated with state-of-the-art whole genome sequencing. PASC-induced quality-of-life deterioration was scored with a validated instrument, SF-36. Analyses were conducted to identify potential functional roles of differentially methylated loci, and machine learning algorithms were used to resolve PASC severity. FINDINGS: 103 patients with PASC (22.3% male, 77.7% female), 15 patients with previous COVID-19 infection but no PASC (40.0% male, 60.0% female), and 27 healthy volunteers (48.1% male, 51.9% female) were enrolled. Whole genome methylation sequencing revealed 39 differentially methylated regions (DMRs) specific to PASC, each harbouring an average of 15 consecutive positions, that differentiate patients with PASC from the two control groups. Motif analyses of PASC-regulated DMRs identify binding domains for transcription factors regulating circadian rhythm and others. Some DMRs annotated to protein coding genes were associated with changes of RNA expression. Machine learning support vector algorithm and random forest hierarchical clustering reveal 28 unique differentially methylated positions (DMPs) in the genome discriminating patients with better and worse quality of life. INTERPRETATION: Blood DNA methylation levels identify PASC, stratify PASC severity, and suggest that DNA motifs are targeted by circadian rhythm-regulating pathways in PASC. FUNDING: This project has been funded by the following agencies: NIH-AI173035 (A. Jaitovich and R. Alisch); and NIH-AG066179 (R. Alisch).

Adverse Social Determinants of Health Elevate Uncontrolled Hypertension Risk: A Cardio-Oncology Prospective Cohort Study.

The role of social determinants of health (SDOH) in controlling hypertension (HTN) in cancer patients is unknown. We hypothesize that high SDOH scores correlate with uncontrolled HTN in hypertensive cancer patients. In our prospective study patients completed the PRAPARE questionnaire. After integrating home and clinic blood pressure readings, uncontrolled HTN was defined as SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg. Using Cox regression, we analyzed the impact of SDOH on HTN control, adjusting for relevant factors. The study involved 318 participants (median age 66.4, median follow-up 166 days, SDOH score 6.5 ± 3.2), with stress, educational insecurity, and social isolation as prevalent adverse SDOH. High SDOH scores led to 77% increased risk of uncontrolled HTN (aHR 1.77; 95% CI 1.10-2.83, p = .018). Urban residents with high SDOH scores were at an even greater risk. Identifying SDOH and mitigating underlying factors may help control HTN, the most typical disease process treated in all cardio-oncology clinics.

Assessing Trustworthiness of Internet Pharmacies with an Internet Browser Extension.

Background: Many people are turning to online pharmacies for medication purchases leading to a growing number of legal and illegal online pharmacies (IOPs). With a growing number of IOPs, consumers are more likely to receive substandard or falsified medications when purchasing medications online. Objectives: This study aims to identify the number of verified, not recommended, and not verified pharmacy websites consumers see using different keywords and medications on an Internet browser based off the National Association Boards of Pharmacy's (NABP) list of verified and not recommended websites. It also aims to compare which keywords result in more not recommended pharmacy websites compared with verified pharmacy websites for consumers over time. Design and Methods: We created an Internet browser extension compatible with different Internet browsers to quickly identify which search results are verified, not recommended, and not verified based on NABP lists. We then utilized an application programming interface to automatically search different key terms and classify the search results as verified, not recommended, and not verified over a 4-week data collection period for analysis. Results: A total of 131 key terms were used for the search. There was an average signal determining the number of verified and not recommended search results compared with not verified results of 4.3% over the 4-week data collection period. There was about a 3:1 ratio of not recommended to verified search results noted. Top signal and not recommended search result producing keywords contained words such as "shipped" and "cheap." Conclusion: The Internet browser extension will aid in making it easier to identify which search results are safe and which are not safe when searching to purchase medications online. This study has set the premise on expanding how to use an Internet pharmacy extension to combat IOPs, improve patient safety, and increase safe access to medications.

A Comparison of Instructions for Use Documents and Manufacturer Produced Administration Videos for Biological Products.

OBJECTIVES: To compare Instructions for Use (IFU) and Manufacturer Produced Administration Videos (MPAV) for biological products to describe if they are highly similar or different. To identify differences between the two that may lead to medication errors and to point out possible solutions to optimize safety. METHODS: We screened 139 biological products having both an IFU and a MPAV. Differences between the IFU and MPAV of each biological product were noted and categorized by importance and how likely it would cause harm to patients. Strategies were discussed based on differences observed. RESULTS: Of the products screened, 51 had an IFU and a MPAV available for evaluation. They were primarily made to support the use of auto-injectors (n = 25) and pre-filled syringes (n = 19). Of this group, we found that 11 had no differences between the IFU and MPAV, while the other 40 had at least one or more identifiable differences. Differences were stratified into the following sub-categories from most to least prevalent: word choice differences, supplementary information, missing information, and unaligned directions. We looked at the distribution of differences per biological product and found an average of two differences per MPAV (IQR 1-3). CONCLUSION: We suggest that when sponsors create or update MPAVs, to focus on aligning critical content between the respective IFU and MPAV. We believe that it is possible for MPAVs to potentially reduce medication errors as a non-text-based media form and that care should be taken to avoid substantial differences in critical content between the IFU and MPAV.

Amoxicillin-Clavulanate Induced Liver Injury in a Young Female.

Amoxicillin-clavulanate (AC) is an antibiotic widely used for various infections. It has rarely been associated with drug-induced liver injury (DILI), mainly in males 55 or older with associated alcohol consumption or medications causing liver injury. Here we present an atypical case of a 22-year-old female with a past medical history of celiac disease and alopecia areata who was prescribed AC in urgent care for bilateral cervical lymphadenopathy, nausea, and chills. Her nausea and vomiting worsened after taking AC for three days, and she developed jaundice. On workup, she was found to have deranged liver functions, and pan-lobular hepatitis was confirmed on liver biopsy. She started to improve symptomatically after withdrawing AC, and her transaminases started showing a decreasing trend.

Pulmonary Adenocarcinoma Mimicking Pneumonia in a Young Adult.

Lung cancer is the third most common cancer in the United States. Lung adenocarcinoma is a subtype of non-small cell lung cancer. On computed tomography (CT) it can appear as ground glass nodules, consolidative opacity, or solid mass lesions located in the periphery. Because it can appear as a consolidation, it can sometimes be confused with an infectious process such as pneumonia. We present a case of a 27-year-old male initially diagnosed with pneumonia; however, three months later, when he presented to the hospital with worsening pleuritic chest pain, fever, and dyspnea after a bronchoscopy a week before admission, pathology was positive for adenocarcinoma.

Chronic Steroid Use Causing Spinal Epidural Lipomatosis.

Chronic steroid use causes aberrant fat deposition in the epidural space, which may in rare cases result in spinal epidural lipomatosis (SEL). We discuss the case of a 79-year-old female who had been on steroids for a long time, initially for polymyalgia rheumatica (PMR), then for adrenal insufficiency. Her dose was raised with a few steroid stress doses to control the flare of adrenal insufficiency. The patient presented with complaints of intractable lumbosacral pain and was subsequently diagnosed with SEL and foraminal and spinal canal stenosis based on magnetic resonance imaging of the lumbar spine. She successfully underwent laminectomy.

A Case Report of Severe Posterior Reversible Encephalopathy Syndrome Due to Accelerated Hypertension in a Young Patient.

Posterior reversible encephalopathy syndrome (PRES) refers to white matter vasogenic edema primarily affecting the brain's posterior occipital and parietal lobes, causing acute neurological symptoms like headaches, visual symptoms, seizures, and altered mental status. We present the case of a 32-year-old male with uncontrolled hypertension, altered mental status, and left-sided weakness. He had a rapid neurological decline, and a computed tomography (CT) head showed blurring of gray-white matter interfaces in the right posterior parietal lobe, suggesting infarction or PRES. Magnetic resonance imaging (MRI) of the brain suggested worsening with acute-early subacute infarction involving the right temporal, parietal, and occipital lobes and diffuse cerebral edema causing compression of the right ventricle with diffuse sulcal effacement and central downward herniation. There were flair hyperintensities in the bifrontal, pons, and cerebellum. Given the history of uncontrolled hypertension, the right hemispheric infarction and edema were thought to be due to secondary complications of severe PRES. He underwent urgent bilateral craniectomies with dural augmentation and external ventricular drain placement to control the intracranial pressure the next day. His mental status, as well as neurologic function, showed gradual improvement in the next few months. A high index of suspicion and rapid treatment can pave the way for a quick recovery and help reduce morbidity and death.

Rare Adverse Events Related to Nivolumab, an Immune Checkpoint Inhibitor: A Case Series.

Immune checkpoint inhibitors are a novel class of immunotherapy drugs that have improved the prognosis of melanoma, renal cell carcinoma, non-small cell lung cancer, urothelial carcinoma, and various other solid tumors. Nivolumab is an immune checkpoint inhibitor that acts by inhibiting programmed death. Its use is associated with significant immune-related adverse events, such as pneumonitis, thyroiditis, hepatitis, pruritus, vitiligo, and diarrhea. However, adrenal insufficiency and checkpoint inhibitor-related autoimmune diabetes mellitus are extremely rare adverse events related to nivolumab treatment. Here, we are highlighting cases of adrenal insufficiency and diabetes inspidus as a result of nivolumab. These rare adverse events in our case series are to raise awareness that this medication also may be the cause for this illness among oncologists, endocrinologists, internists, and other clinicians.

Necrotizing Fasciitis: A Life-Threatening Infection Due to Clostridium Species.

Necrotizing fasciitis (NF), soft tissue infections, are rare but rapidly progressive and life-threatening infections with high morbidity and mortality rates. Early detection and intervention by physicians are paramount in mortality prevention. We present a case report of a 77-year-old female who presented with extensive NF due to a Clostridium septicum infection.