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Zuned A Hakim, Syed Ali, R Stephen Bale, Peter J HughesTrauma and Orthopaedic Department, Royal Preston Hospital, Preston, UK Introduction: Rotator cuff pathology is a commonly encountered shoulder complaint, which is routinely investigated with ultrasound scan. Sensitivities and specificities for detecting tears have been reported to be between 79% and 100%. Our aim was to compare the scans performed by a radiographer versus a radiologist with that of surgery. Patients and methods: This study is a retrospective review of 184 cases over a 12-month period who underwent arthroscopy following an ultrasound scan for cuff disease. Single clinician collected data for cuff pathology based on the scan report and compared to intraoperative findings. StatsDirect was used for statistical analysis to determine sensitivities, specificities, and accuracy. Results: The radiologist had better sensitivity for partial-thickness tears by 33% (95% CI 4.4%–59.9%, P=0.018). The radiographer had better specificity by 24% (CI 11.9%–38.8%, P=0.0001). The radiographer had better accuracy at 55% versus radiologist at 23% and was better at quantifying the size of the tear. Intraoperative change in the plan occurred in 15% of cases in each group. Discussion: Our findings for specificity, sensitivity, and accuracy for full-thickness tears are comparable to the existing literature, but lower than most of the quoted papers for partial-thickness tears. Change in intraoperative plan as a result of differing findings at surgery is equal in each group. We found the radiographer to be better at sizing the full-thickness tears. Keywords: rotator cuff, ultrasound, accuracy difference

Objective The objective of this study was to identify differentially expressed salivary proteins in bisphosphonate-related osteonecrosis of the jaw ( BRONJ) patients that could serve as biomarkers for BRONJ diagnosis. Subjects and Methods Whole saliva obtained from 20 BRONJ patients and 20 controls were pooled within groups. The samples were analyzed using i TRAQ-labeled two-dimensional liquid chromatography-tandem mass spectrometry. Results Overall, 1340 proteins were identified. Of these, biomarker candidates were selected based on P-value (<0.001), changes in protein expression (≥1.5-fold increase or decrease), and unique peptides identified (≥2). Three comparisons made between BRONJ and control patients identified 200 proteins to be differentially expressed in BRONJ patients. A majority of these proteins were predicted to have a role in drug metabolism and immunological and dermatological diseases. Of all the differentially expressed proteins, we selected metalloproteinase-9 and desmoplakin for further validation. Immunoassays confirmed increased expression of metalloproteinase-9 in individual saliva ( P = 0.048) and serum samples ( P = 0.05) of BRONJ patients. Desmoplakin was undetectable in saliva. However, desmoplakin levels tended to be lower in BRONJ serum than controls ( P = 0.157). Conclusions Multiple pathological reactions are involved in BRONJ development. One or more proteins identified by this study may prove to be useful biomarkers for BRONJ diagnosis. The role of metalloproteinase-9 and desmoplakin in BRONJ requires further investigation. [ABSTRACT FROM AUTHOR]

Ceramide has been suggested to participate in the neuronal cell death that leads to Alzheimer's disease (AD), but its role is not yet well-understood. We compared the levels of six ceramide subspecies, which differ in the length of their fatty acid moieties, in brains from patients who suffered from AD, other neuropathological disorders, or both. We found elevated levels of Cer16, Cer18, Cer20, and Cer24 in brains from patients with any of the tested neural defects. Moreover, ceramide levels were highest in patients with more than one neuropathologic abnormality. Interestingly, the range of values was higher among brains with neural defects than in controls, suggesting that the regulation of ceramide synthesis is normally under tight control, and that this tight control may be lost during neurodegeneration. These changes, however, did not alter the ratio between the tested ceramide species. To explore the mechanisms underlying this dysregulation, we evaluated the expression of four genes connected to ceramide metabolism: ASMase, NSMase 2, GALC, and UGCG. The patterns of gene expression were complex, but overall, ASMase, NSMase 2, and GALC were upregulated in specimens from patients with neuropathologic abnormalities in comparison with age-matched controls. Such findings suggest these genes as attractive candidates both for diagnostic purposes and for intervening in neurodegenerative processes. [ABSTRACT FROM AUTHOR]

PURPOSE: The use of nitrogen-containing bisphosphonates (n-bis) is associated with necrosis of the jaws, also known as bisphosphonate-related osteonecrosis of the jaws (BRONJ); however, the pathophysiology is unknown. Matrix metalloproteinase-9 (MMP-9) expression is essential for normal bone healing and is also required for angiogenesis. N-bis alters MMP-9 expression in vitro and in vivo; therefore, we hypothesized that n-bis alters MMP-9 expression during oral wound healing after tooth extraction. MATERIALS AND METHODS: A total accumulated dose of 2.25 mg/kg (n = 20) of Zoledronic acid (ZA) Zometa or saline (control, n = 20) was administered to Sprague-Dawley male rats. Next, both groups had maxillary molar teeth extracted. Rats were sacrificed at postoperative day 1, 3, 7, or 21. Western blotting or multiplex ELISA was used to evaluate proteins of interest. Real-time polymerase chain reaction was used to assess the relative quantities of target gene mRNA. MMP-9 enzymatic activity was assessed by zymography. RESULTS: The ZA group showed a statistically significant reduction in bone mineralization rate 21 days after tooth extraction compared with the control group (Student t test, P = .005). Moreover, ZA-treated animals showed a statistically significant increase in MMP-9-specific mRNA at postoperative days 3 (P = .003), 7 (P < .0001), and 21 (P < .0001) and protein on postoperative days 3 (P = .005) and 7 (P < .0001). MMP-9 enzymatic activity was also increased in ZA-treated rats compared with control animals (Student t test, P = .014). We also evaluated the extraction sockets for the presence of tissue inhibitor of MMP-1 (TIMP1), which is an inhibitor of MMP-9 enzymatic activity. TIMP1-specific mRNA and protein were not significantly altered by ZA treatment at the times tested (P > .05). Receptor of NF-[kappa]B ligand (RANKL) is known to regulate the expression of MMP-9; we therefore assessed the RANKL expression in our experimental oral wound-healing model. The ZA-treated animals had significantly increased RANKL mRNA at postoperative days 3 (P = .02) and 21 (P = .004), while the protein expression was significantly increased at postoperative days 1 (P < .0001), 7 (P = .02), and 21 (P = .03) compared with the control group. CONCLUSIONS: ZA reduced bone mineralization within tooth extraction sockets, suggesting aberrant bone healing. ZA increases the amount and enzymatic activity of MMP-9, while apparently not altering the amount of TIMP1 within extraction sockets. RANKL is increased in ZA-treated rats, which suggests that increased MMP-9 expression is due, in part, to augmented RANKL expression. [ABSTRACT FROM AUTHOR]

The limb-girdle muscular dystrophies are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, limb-girdle muscular dystrophy 2L and non-dysferlin Miyoshi muscular dystrophy. We screened a candidate group of 64 patients from 59 British and German kindreds and found the truncating mutation, c.191dupA in exon 5 of ANO5 in 20 patients, homozygously in 15 and in compound heterozygosity with other ANO5 variants in the rest. An intragenic single nucleotide polymorphism and an extragenic microsatellite marker are in linkage disequilibrium with the mutation, suggesting a founder effect in the Northern European population. We have further defined the clinical phenotype of ANO5-associated muscular dystrophy. Patients show adult onset proximal lower limb weakness with highly raised serum creatine kinase values (average 4500 IU/l) and frequent muscle atrophy and asymmetry of muscle involvement. Onset varies from the early 20 s to 50 s and the weakness is generally slowly progressive, with most patients remaining ambulant for several decades. Distal presentation is much less common but a milder degree of distal lower limb weakness is often observed. Upper limb strength is only mildly affected and cardiac and respiratory function is normal. Females appear less frequently affected. In the North of England population we have identified eight patients with ANO5 mutations, suggesting a minimum prevalence of 0.27/100,000, twice as common as dysferlinopathy. We suggest that mutations in ANO5 represent a relatively common cause of adult onset muscular dystrophy with high serum creatine kinase and that mutation screening, particularly of the common mutation c.191dupA, should be an early step in the diagnostic algorithm of adult limb-girdle muscular dystrophy patients. [ABSTRACT FROM AUTHOR]

Background: A recent report has suggested that local injection of botulinum toxin type A is an effective method of treatment for chronic tennis elbow. The toxin is thought to provide temporary paralysis of the painful common extensor origin, thereby allowing a healing response to occur. To test this theory, we performed a double-blind, randomized, controlled, pilot trial comparing injections of botulinum toxin type A with those of a placebo (normal saline solution) in the treatment of chronic tennis elbow.Methods: Forty patients with a history of chronic tennis elbow for which all conservative treatment measures, including steroid injection, had failed were randomized into two groups. Half the patients received 50 units of botulinum toxin type A, and the remainder received normal saline solution. The intramuscular injections were performed 5 cm distal to the maximum point of tenderness at the lateral epicondyle, in line with the middle of the wrist. The two solutions used for the injections were identical in appearance and temperature. The results of a quality-of-life assessment with the Short Form-12 (SF-12), the pain score on a visual analogue scale, and the grip strength measured with a validated Jamar dynamometer were recorded before and three months after the injection.Results: Three months following the injections, there was no significant difference between the two groups with regard to grip strength, pain, or quality of life.Conclusions: With the numbers studied, we failed to find a significant difference between the two groups; thus, we have no evidence of a benefit from botulinum toxin injection in the treatment of chronic tennis elbow. [ABSTRACT FROM AUTHOR]

1 A colonic delivery system is described to deliver orally ingested drugs to the colon and release them at that site by coating with an acrylic based resin (Eudragit S). The technique is validated using X- ray evidence and serum levels of a convenient marker, sulphapyridine. 2 This colonic delivery system is particularly suitable for drugs such as 5-amino salicylic acid or steroids in the management of patients with colitis. [ABSTRACT FROM AUTHOR]

Little is known about how knot-pusher design affects arthroscopic knot tying. In our practice, we observed the knot-pusher riding onto the arthroscopic knot at the point of maximum tightening. This can lead to snagging of the knot, which is undesirable as it may lead to loosening of, or damage to the knot. The aim of this study is to determine the optimum size of a knot-pusher to efficiently push the knot without overriding or snagging it.We used an apparatus to model arthropcopic knot tying. Ten examples each of the Duncan loop were tied under controlled conditions of load using one polydioxanone (PDS) monofilament absorbable suture (Ethicon, Livingston, UK), two Ethibond, two Fibrewire and two Panacryl. The loop of the knot was then secured and a 50 N force applied to tension the knot. The suture diameter was measured. Then the knot diameter was measured in two planes using an analogue micrometer. The internal diameter of a Mitek knot-pusher was measured.The mean maximum diameter for each knot was respectively PDS, 2.061 +/- 0.13 mm; Panacryl, 1.907 +/- 0.14 mm; Ethibond, 1.717 +/- 0.16 mm and Fibrewire, 1.654 +/- 0.14 mm. There were significant differences in size between knots tied with different materials except between Ethibond and Fibrewire where the difference was not significant. For each set of knots the smallest maximum knot diameter observed was identified. This was respectively PDS, 1.92 mm; Ethibond, 1.476 mm; Fibrewire, 1.488 mm and Panacryl, 1.715 mm. The internal diameter of a Mitek knot-pusher was found to be 1.95 mm.The current Mitek knot-pusher appears to be well suited to one PDS and two Panacryl. It appears less ideal for two Ethibond and two Fibrewire. One knot-pusher does not fit all and we suggest that different knot-pushers be used for different suture materials. [ABSTRACT FROM AUTHOR]

Examines the role of litigation risk in initial public offering (IPO) pricing. Linkage between litigation risk and IPO underpricing; Irrelevance of litigation risk under rational expectations and market clearing constraints; Presentation of richer model that permits a litigation-risk-based explanation for IPO underpricing.

Following a 2015 conference on the future of continuing pharmacy education (CPE), the Accreditation Council for Pharmacy Education's Board of Directors ratified recommendations to address two key questions: (1) "What next steps should the profession take to ensure practitioner competence based on marketplace and regulatory changes in the next 10 to 15 years?" and (2) "How can the value of CPE be optimized over the next 10 to 15 years?" In this article, we describe how these recommendations have been addressed since the 2015 conference, highlighting advancements in technology and the adoption of continuing professional development, and describe future directions and additional opportunities to optimize CPE., Competing Interests: Declaration of Competing Interest All study authors are either Accreditation Council for Pharmacy Education (ACPE) staff and employed by ACPE or Continuing Pharmacy Education Commission Members., (Copyright © 2024 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)

Background: Increased patient utilization of cannabidiol (CBD) leads to potential drug interactions with various medications and questions posed to pharmacists. Objective: To quantify the knowledge gap of pharmacists on CBD and CBD-containing products and assess the degree a continuing pharmacy education (CPE) program alters pharmacist confidence and competency on CBD knowledge. Methods: A 1-h CPE activity was offered as a home study from May 9, 2022, through September 30, 2022. Subjects were practicing pharmacy preceptors in Alabama who completed the pre-survey and post-survey for inclusion in matched-pair analyses. The primary outcome measure was participant score improvement between the pre-post surveys. Secondary measures involved pre-post comparisons on self-rated Likert questions concerning participant confidence in counseling, answering drug information questions, and ensuring patient safety regarding CBD. Results: A total of 124 participants completed the course. After matched pairing, 64 and 56 individuals were included in the knowledge-based and confidence ranking analyses, respectively. Participant scoring improved on the knowledge-based questions between the pre-post surveys (50.0% vs 87.8%, P < .001). There was a significant confidence improvement of participants from baseline on counseling patients about prescription or over-the-counter CBD products, answering questions from other healthcare professionals about these products, and ensuring patient safety while using these products (Average 5-level Likert scale increases of 1.75, 1.73, 1.70, respectively; all P < .001). Conclusion: Implementation of a CPE program improved practicing pharmacists' knowledge on information about CBD, which lead to increased competency on counseling patients, answering drug information questions, and promoting patient safety., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: To report on our experience using intravitreal methotrexate (MTX) in patients with retinal detachment associated with proliferative vitreoretinopathy and/or open globe injury., Methods: This study performed a retrospective chart review of a consecutive series of 21 eyes of 21 patients who underwent serial intravitreal MTX injection for treatment and/or prevention of proliferative vitreoretinopathy from December 2021 to January 2024., Results: Twenty-one patients underwent pars plana vitrectomy, membrane peeling, laser photocoagulation, silicone oil infusion, and intravitreal MTX injection. Postoperatively, all eyes received a series of intravitreal MTX (400 μg/0.1 mL) injections. Optimally, injections were administered weekly for 8 weeks and every 2 weeks for four weeks for a total of 13 injections, beginning intraoperatively at the conclusion of retinal reattachment surgery. Mean baseline preoperative and postoperative visual acuity was logarithm of the minimum angle of resolution 3.2 (approximately hand motions vision) and 2.5 (between CF and hand motions vision), respectively, yielding an average improvement in visual acuity of 0.7 logarithm of the minimum angle of resolution units (0 ETDRS lines/letters). These 21 patients received an average of 10.5 injections. With a single operation, detachments in 19 (90%) of 21 eyes were successfully reattached. Corneal epithelial defects were noted in 7 (33%) of 21 patients., Conclusion: Serial intravitreal MTX injection was associated with 90% single operation retinal reattachment rate in the setting of retinal detachment with proliferative vitreoretinopathy or retinal detachment at high risk of proliferative vitreoretinopathy.

Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by an expansion of immature myeloid precursors. Despite therapeutic advances, the prognosis of AML patients remains poor and there is a need for the evaluation of promising therapeutic candidates to treat the disease. The objective of this study was to evaluate the efficacy of duocarmycin Stable A (DSA) in AML cells in vitro. We hypothesized that DSA would induce DNA damage in the form of DNA double-strand breaks (DSBs) and exert cytotoxic effects on AML cells within the picomolar range. Human AML cell lines Molm-14 and HL-60 were used to perform 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), DNA DSBs, cell cycle, 5-ethynyl-2-deoxyuridine (EdU), colony formation unit (CFU), Annexin V, RNA sequencing and other assays described in this study. Our results showed that DSA induced DNA DSBs, induced cell cycle arrest at the G2M phase, reduced proliferation and increased apoptosis in AML cells. Additionally, RNA sequencing results showed that DSA regulates genes that are associated with cellular processes such as DNA repair, G2M checkpoint and apoptosis. These results suggest that DSA is efficacious in AML cells and is therefore a promising potential therapeutic candidate that can be further evaluated for the treatment of AML.

Objective: To investigate 12-month glycemic and psychosocial changes following transition from multiple daily injections (MDI) to advanced hybrid closed-loop (AHCL) therapy in youth (aged 13-25 years) with type 1 diabetes and suboptimal glycemia (glycated hemoglobin [HbA 1c ] ≥8.5% [69 mmol/mol]). Research Design and Methods: Prospective, single arm, dual-center study in 20 participants. Extension phase outcomes reported after 12 months, including HbA 1c , time in glycemic ranges, AHCL system performance, and psychosocial questionnaires assessing quality of life, diabetes treatment, and sleep. Results: After 12 months, 19 out of 20 participants continued to use AHCL. Average time-in-range 70-180 mg/dL (3.9-10.0 mmol/L) improved from 27.6% ± 13.2% to 62.5% ± 11.4%. This translated to an average 2.5 percentage-point (27.1 mmol/mol) improvement in HbA 1c from 10.5% ± 2.1% (91.2 mmol/mol) at baseline to 8.0% ± 0.9% (64.1 mmol/mol) at 12 months. Psychosocial questionnaires and very high HbA 1c at study entry indicated significant diabetes-associated burden for both individuals and parents. After 12 months, improvements were observed in general and diabetes-specific health-related quality of life, as well as in diabetes treatment satisfaction. Safety data were reassuring with a diabetic ketoacidosis rate of 0.15 per participant-year after 12 months of AHCL (compared to 0.25 per participant-year in the 12 months before the study). Conclusions: After 12 months of AHCL usage, this study highlights the potential for substantial and sustained glycemic and psychosocial improvements among individuals experiencing considerable diabetes burden and suboptimal glycemia, following their switch from MDI to AHCL.

Continuing Professional Development (CPD) has received increased attention within the pharmacy profession in the United States and is recognized as a potential pathway for ongoing professional development and practice transformation. Despite potential benefits of CPD, adoption in the United States has remained limited. A CPD program accreditation pathway, including principles, guidance, and a credit system for CPD programs, has recently been approved by the Accreditation Council for Pharmacy Education Board of Directors. This commentary reviews existing literature regarding pharmacy CPD, introduces CPD program principles and guidance for CPD program providers, and describes the model for awarding CPD units., 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 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this quality improvement (QI) initiative was to evaluate the effects of a repositioning intervention bundle on the occurrences and severity of hospital-acquired pressure injuries (HAPIs) of the face in patients with COVID-19-related acute respiratory distress syndrome (ARDS) managed by ventilation and placed in a prone position., Participants and Setting: Eighteen critically ill, ventilated patients were placed in a prone position for extended periods (range, 1-13 days). The study setting was critical care units in a 504-bed nonprofit teaching hospital located in the Northeastern United States., Approach: Standard of care for the prevention of pressure injury (PI) in ventilated patients placed in a prone position at our facility included use of foam dressings over bony prominences on the face and the application of tape to secure the endotracheal (ET) tube as compared to commercial ET tube securement devices. We also placed a fluidized pillow with pillowcase wrapped with an absorbent pad under the head to absorb secretions. We added 2 interventions to our facility's existing HAPI prevention bundle. The first was a repositioning strategy; ventilated and prone patients were lifted by their shoulders by critical care RNs while their ET tube was stabilized by a respiratory therapist every 6 hours. The RNs then repositioned the patient's head and arms to the opposite side into a swimmer's position (head lying to the side with one cheek in contact with the fluidized pillow). The second intervention was micromovement of the head performed by an RN every 4 hours., Outcomes: Prior to implementation of the QI initiative, data collected during the early pandemic demonstrated that multiple patients developed facial PIs secondary to prone positioning; a majority were full-thickness or unstageable PIs, whereas a minority were partial-thickness PIs (stage 2). Following implementation of the QI initiative, data indicated that 5 of 18 (28%) patients placed in a prone position had HAPIs of the face; 4 (22%) of the HAPIs were stage 1 or 2 and 1 was unstageable. Patients were placed in a prone position from 1 to 13 days. All facial HAPIs developed within the first 2 days of placement in a prone position., Implications for Practice: The addition of an RN and a respiratory therapist repositioning intervention and micromovements of the head every 4 hours by the RN to an existing pressure prevention bundle during prone positioning led to a clinically relevant reduction in the severity of facial HAPIs. As a result, care for these patients has been changed to incorporate the repositioning interventions implemented during this QI project., Competing Interests: Conflict of Interest: None declared., (Copyright © 2023 by the Wound, Ostomy and Continence Nurses Society.)

Introduction: Approximately 30% to 50% of hospital discharge antimicrobials are inappropriate. Limited data exist on approaches to improve antimicrobial prescribing practices at the time of discharge from a community hospital. Objective : To assess the impact of a comprehensive pharmacist-led antimicrobial stewardship intervention at discharge., Methods: We conducted a quasi-experimental, pre-post study. A biphasic intervention took place on 2 medicine units from November 2019 to May 2020 at a community hospital. Baseline data were collected, followed by prescriber education on antimicrobial stewardship to both units (education phase). Next, a pharmacist-led intervention took place on one unit (intervention phase). The primary outcome was composite appropriateness of an oral antimicrobial prescribed to an adult at the time of discharge, defined by narrow spectrum of activity, dosing, and duration of therapy. The primary outcome was assessed using Fisher exact test., Results: Baseline composite appropriateness was 30% (n = 12) on the control unit and 30.8% (n = 20) on the intervention unit. From baseline to posteducation, no significant change in composite appropriateness was found on the control (30% to 26.7%, P = 0.256) or intervention (30.8% to 19.4%, P = 0.09) unit. There was no significant difference between the education to intervention phase (26.7% vs 35%, P = 0.254) on the control unit. On the intervention unit, a significant difference in composite appropriateness was found from the education to intervention phase (19.4% vs 47.8%, P = 0.017)., Conclusion and Relevance: A pharmacist-led intervention improved appropriateness of oral antimicrobials prescribed at discharge. One-time education was insufficient for improving antimicrobial stewardship.

Objective: To evaluate glycemic outcomes in youth (aged 13-25 years) with type 1 diabetes and high-risk glycemic control (HbA1c ≥8.5% [69 mmol/mol]) on multiple daily injection (MDI) therapy after transitioning to advanced hybrid closed loop (AHCL) therapy., Research Design and Methods: This prospective, 3-month, single-arm, dual-center study enrolled 20 participants, and all completed the study., Results: HbA1c decreased from 10.5 ± 2.1% (91.2 ± 22.8 mmol/mol) at baseline to 7.6 ± 1.1% (59.7 ± 11.9 mmol/mol), and time spent in target range 70-180 mg/dL (3.9-10.0 mmol/L) increased from 27.6 ± 13.2% at baseline to 66.5 ± 9.8% after 3 months of AHCL. Two episodes of diabetic ketoacidosis attributed to infusion set failure occurred., Conclusions: AHCL has the potential to improve suboptimal glycemia in youth with type 1 diabetes previously on MDI therapy., (© 2023 by the American Diabetes Association.)

Introduction: Treatment-related toxicity following either chemo- or radiotherapy can create significant clinical challenges for HNSCC cancer patients, particularly those with HPV-associated oropharyngeal squamous cell carcinoma. Identifying and characterizing targeted therapy agents that enhance the efficacy of radiation is a reasonable approach for developing de-escalated radiation regimens that result in less radiation-induced sequelae. We evaluated the ability of our recently discovered, novel HPV E6 inhibitor (GA-OH) to radio-sensitize HPV+ and HPV- HNSCC cell lines to photon and proton radiation., Methods: Radiosensitivity to either photon or proton beams was assessed using various assays such as colony formation assay, DNA damage markers, cell cycle and apoptosis, western blotting, and primary cells. Calculations for radiosensitivity indices and relative biological effectiveness (RBE) were based on the linear quadratic model., Results: Our results showed that radiation derived from both X-ray photons and protons is effective in inhibiting colony formation in HNSCC cells, and that GA-OH potentiated radiosensitivity of the cells. This effect was stronger in HPV+ cells as compared to their HPV- counterparts. We also found that GA-OH was more effective than cetuximab but less effective than cisplatin (CDDP) in enhancing radiosensitivity of HSNCC cells. Further tests indicated that the effects of GA-OH on the response to radiation may be mediated through cell cycle arrest, particularly in HPV+ cell lines. Importantly, the results also showed that GA-OH increases the apoptotic induction of radiation as measured by several apoptotic markers, even though radiation alone had little effect on apoptosis., Conclusion: The enhanced combinatorial cytotoxicity found in this study indicates the strong potential of E6 inhibition as a strategy to sensitize cells to radiation. Future research is warranted to further characterize the interaction of GA-OH derivatives and other E6-specific inhibitors with radiation, as well as its potential to improve the safety and effectiveness of radiation treatment for patients with oropharyngeal cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chitsike, Bertucci, Vazquez, Lee, Unternaehrer and Duerksen-Hughes.)

High-risk human papillomaviruses (HPVs) cause virtually all cervical cancer cases and are also associated with other types of anogenital and oropharyngeal cancers. Normally, HPV exists as a circular episomal DNA in the infected cell. However, in some instances, it integrates into the human genome in such a way as to enable increased expression of viral oncogenes, thereby leading to carcinogenesis. Since viral integration requires breaks in both viral and human genomes, DNA damage likely plays a key role in this critical process. One potentially significant source of DNA damage is exposure to elevated doses of ionizing radiation. Natural background radiation is ubiquitous; however, some populations, including radiological workers, radiotherapy patients, and astronauts, are exposed to significantly higher radiation doses, as well as to different types of radiation such as particle radiation. We hypothesize that ionizing radiation-induced DNA damage facilitates the integration of HPV into the human genome, increasing the risk of developing HPV-related cancers in the exposed population. To test this, we first determined the kinetics of DNA damage in keratinocytes exposed to ionizing radiation (protons) by assessing γ-H2AX foci formation using immunofluorescence (direct damage), and also measured ROS and 8-oxoG levels via DCFDA and Avidin-FITC (indirect damage).As anticipated, direct DNA damage was observed promptly, within 30 min, whereas indirect DNA damage was delayed due to the time required for ROS to accumulate and cause oxidative damage. Although radiation was lethal at high doses, we were able to establish an experimental system where radiation exposure (protons and X-rays) induced DNA damage dose-dependently without causing major cytotoxic effects as assessed by several cytotoxicity assays. Most importantly, we explored the impact of radiation exposure on integration frequency using a clonogenic assay and demonstrated that as predicted, proton-induced DNA damage promotes the integration of HPV-like foreign DNA in oral keratinocytes. Overall, the insights gained from this work enable us to better understand the contribution of radiation exposure and DNA damage to HPV-mediated carcinogenesis and direct us toward strategies aimed at preventing malignancies in HPV-infected individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Katerji, Bertucci, Filippov, Vazquez, Chen and Duerksen-Hughes.)

Purpose: Access and affordability of hearing health care varies depending on residency and individual financial means. Those living in rural areas have limited health care resources and experience higher levels of poverty compared to those living in urban regions. The purpose of this study was to determine the feasibility of interprofessional collaboration among physicians and audiologists and pharmacists and audiologists to improve access and affordability of hearing health care in rural communities., Method: Sixteen family physicians and medicine residents and 15 community pharmacists participated in the study. Physicians and residents completed an online survey to assess education regarding hearing health care and their understanding of hearing loss intervention. They also participated in small virtual focus group discussions. Pharmacists participated in virtual discussions based on guided questions., Results: The discussions with both physicians and pharmacists highlighted the need for more education, resources, and awareness of the negative impact of hearing loss on overall quality of life. Comments from these discussions were placed within the socio-ecological model of health behavior to increase understanding of hearing health behavior., Conclusions: Increased collaboration among medical professionals has the potential to improve access to hearing health care for those living in audiologically underserved regions of the country. Further research will identify how to increase effective and sustainable hearing health care resources in rural communities.

Background: High-titer convalescent plasma given early for COVID-19 may decrease progression into a severe infection. Here, we reported a study of serial antibody measurements in patients who received CP at our center and performed a systematic review of randomized trials on CP. Methods: Our center participated in the Mayo Clinic Expanded Access Program for COVID-19 Convalescent Plasma. Patients diagnosed with COVID-19 by nasopharyngeal polymerase chain reaction at our center between April and August 2020 were included in the study if staffing was available for specimen collection. Through a colloidal gold immunochromatography assay, these patients’ IgM and IgG antibody responses were measured at baseline (Day 0) and after transfusion (Day 1, 2, etc.). Donor CP antibody levels were measured as well. Results: 110 serum specimens were obtained from 21 COVID-19 patients, 16 of whom received CP. The median time from developing symptoms to receiving CP was 11 days (range 4−21). In 9 of 14 (64%) cases where both recipient and donor CP antibody levels were tested, donor COVID-19 IgG was lower than that of the recipient. Higher donor antibody levels compared with the recipient (R = 0.71, p < 0.01) and low patient IgG before CP transfusion (p = 0.0108) correlated with increasing patient IgG levels from baseline to Day 1. Among all patients, an increased COVID-19 IgG in the short-term and longitudinally was positively correlated with improved clinical outcomes (ρ = 0.69, p = 0.003 and ρ = 0.58, p < 0.006, respectively). Conclusions: In a real-world setting where donor CP was not screened for the presence of antibodies, CP in donors might have less COVID-19 IgG than in recipients. An increase in patient antibody levels in the short term and longitudinally was associated with improved clinical outcomes.

Background: Penicillin allergy is one of the most frequent self-reported allergies; however, only about 10% of reported allergies are accurate. Objectives: Through the creation of a continuing pharmacy education (CPE) activity, we sought to assess knowledge gaps and comfort levels in the management of penicillin allergies. Methods: A 1-hour enduring-content CPE activity was offered as an interactive course from September 20, 2019, to September 20, 2020. Participants completed 3 surveys (pre-survey, post-survey, and follow-up survey). Participants were pharmacists and pharmacy technicians who completed, at a minimum, the activity and both pre- and post-surveys. The primary outcome was the percentage of participants scoring >80% on knowledge-based questions on the post-survey compared with the pre-survey. Secondary outcomes included pre-post comparisons on knowledge-based questions, participants' self-report of an allergy, and comfort levels dispensing cephalosporins in a patient with a self-reported penicillin allergy. Results: A total of 389 participants completed the CPE activity, with 176 included for analysis. Significantly more participants scored >80% on knowledge-based questions on the post-survey compared with the pre-survey (71.6% vs 22.7%, P < .001). There was no significant difference between the percentage of participants scoring >80% on the post-survey and the follow-up survey (71.6% vs 65%, P = .119). The majority of participants (74%) felt comfortable dispensing a cephalosporin in a patient with a penicillin allergy on the pre-survey, with similar percentages on the post- and follow-up surveys (77% and 90%, respectively). Conclusion: A targeted continuing education program improved overall knowledge, which was sustained for up to 2 months., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SHD: has served on the advisory boards for Shionogi Pharmaceuticals and Theratechnologies.CMB: Advisory Board: Merck Pharmaceuticals; Speaker’s Bureau: Merck Pharmaceuticals; Grant Funding: ALK Abello, Inc, and Merck Pharmaceuticals.PBB: receives consultation fees from Kedrion Biopharma; content developer and CE provider for programs funded by Eli Lilly.EBC: serves on the advisory board for Theratechnologies and on the speakers’ bureau of Paratek Pharmaceuticals.JCC: serves on the speaker’s bureau for Allergan and has served on the advisory board for AcelRx Pharmaceuticals.BMJ: serves on the speaker’s bureau or has consulted for Allergan/Abbvie, Tetraphase/La Jolla, Merck, Melinta, and Paratek, and has received grant funding from Merck and ALK Abello.PJH: serves on the Continuing Pharmacy Education Commission for the Accreditation Council for Pharmacy Education (ACPE). The views expressed in this work only represent the authors’ views and do not necessarily represent the views of ACPE.EWC, FD, JAK, KRS, and JLW: have nothing to disclose., (© The Author(s) 2021.)

The COVID-19 pandemic that began in late 2019 continues with new challenges arising due to antigenic drift as well as individuals who cannot or choose not to take the vaccine. There is therefore an urgent need for additional therapies that complement vaccines and approved therapies such as antibodies in the fight to end or slow down the pandemic. SARS-CoV-2 initiates invasion of the human target cell through direct contact between the receptor-binding domain of its Spike protein and its cellular receptor, angiotensin-converting enzyme-2 (ACE2). The ACE2 and S1 RBD interaction, therefore, represents an attractive therapeutic intervention to prevent viral entry and spread. In this study, we developed a proximity-based AlphaScreen™ assay that can be utilized to quickly and efficiently screen for inhibitors that perturb the ACE2 : S1 RBD interaction. We then designed several peptides candidates from motifs in ACE2 and S1 RBD that play critical roles in the interaction, with and without modifications to the native sequences. We also assessed the possibility of reprofiling of candidate small molecules that previously have been shown to interfere with the viral entry of SARS-CoV. Using our optimized AlphaScreen™ assay, we evaluated the activity and specificity of these peptides and small molecules in inhibiting the binding of ACE2 : S1 RBD. This screen identified cepharanthine as a promising candidate for development as a SARS-CoV-2 entry inhibitor., Competing Interests: The authors in this study declare that they have no conflicts of interest., (Copyright © 2021 Lennox Chitsike et al.)

The author explores gender issues related to oral and maxillofacial training programs and the role that accreditation should have to ensure gender equity, antidiscrimination, and support of women in the profession of oral and maxillofacial surgery., Competing Interests: Disclosure The author has nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The treatment landscape of locally advanced HPV-oropharyngeal squamous cell carcinoma (OPSCC) is undergoing transformation. This is because the high cures rates observed in OPSCC are paired with severe treatment-related, long-term toxicities. These significant adverse effects have led some to conclude that the current standard of care is over-treating patients, and that de-intensifying the regimens may achieve comparable survival outcomes with lower toxicities. Consequently, several de-escalation approaches involving locally advanced OPSCC are underway. These include the reduction of dosage and volume of intensive cytotoxic regimens, as well as elimination of invasive surgical procedures. Such de-intensifying treatments have the potential to achieve efficacy and concurrently alleviate morbidity. Targeted therapies, given their overall safer toxicity profiles, also make excellent candidates for de-escalation, either alone or alongside standard treatments. However, their role in these endeavors is currently limited, because few targeted therapies are currently in clinical use for head and neck cancers. Unfortunately, cetuximab, the only FDA-approved targeted therapy, has shown inferior outcomes when paired with radiation as compared to cisplatin, the standard radio-sensitizer, in recent de-escalation trials. These findings indicate the need for a better understanding of OPSCC biology in the design of rational therapeutic strategies and the development of novel, OPSCC-targeted therapies that are safe and can improve the therapeutic index of standard therapies. In this review, we summarize ongoing research on mechanism-based inhibitors in OPSCC, beginning with the salient molecular features that modulate tumorigenic processes and response, then exploring pharmacological inhibition and pre-clinical validation studies of candidate targeted agents, and finally, summarizing the progression of those candidates in the clinic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chitsike and Duerksen-Hughes.)

DNA lesions arise from a combination of physiological/metabolic sources and exogenous environmental influences. When left unrepaired, these alterations accumulate in the cells and can give rise to mutations that change the function of important proteins (i.e. tumor suppressors, oncoproteins), or cause chromosomal rearrangements (i.e. gene fusions) that also result in the deregulation of key cellular molecules. Progressive acquisition of such genetic changes promotes uncontrolled cell proliferation and evasion of cell death, and hence plays a key role in carcinogenesis. Another less-studied consequence of DNA damage accumulating in the host genome is the integration of oncogenic DNA viruses such as Human papillomavirus, Merkel cell polyomavirus, and Hepatitis B virus. This critical step of viral-induced carcinogenesis is thought to be particularly facilitated by DNA breaks in both viral and host genomes. Therefore, the impact of DNA damage on carcinogenesis is magnified in the case of such oncoviruses via the additional effect of increasing integration frequency. In this review, we briefly present the various endogenous and exogenous factors that cause different types of DNA damage. Next, we discuss the contribution of these lesions in cancer development. Finally, we examine the amplified effect of DNA damage in viral-induced oncogenesis and summarize the limited data existing in the literature related to DNA damage-induced viral integration. To conclude, additional research is needed to assess the DNA damage pathways involved in the transition from viral infection to cancer. Discovering that a certain DNA damaging agent increases the likelihood of viral integration will enable the development of prophylactic and therapeutic strategies designed specifically to prevent such integration, with an ultimate goal of reducing or eliminating these viral-induced malignancies., Competing Interests: None., (AJCR Copyright © 2021.)

Advanced cervical cancer is primarily managed using cytotoxic therapies, despite evidence of limited efficacy and known toxicity. There is a current lack of alternative therapeutics to treat the disease more effectively. As such, there have been more research endeavors to develop targeted therapies directed at oncogenic host cellular targets over the past 4 decades, but thus far, only marginal gains in survival have been realized. The E6 oncoprotein, a protein of human papillomavirus origin that functionally inactivates various cellular antitumor proteins through protein-protein interactions (PPIs), represents an alternative target and intriguing opportunity to identify novel and potentially effective therapies to treat cervical cancer. Published research has reported a number of peptide and small-molecule modulators targeting the PPIs of E6 in various cell-based models. However, the reported compounds have rarely been well characterized in animal or human subjects. This indicates that while notable progress has been made in targeting E6, more extensive research is needed to accelerate the optimization of leads. In this review, we summarize the current knowledge and understanding of specific E6 PPI inhibition, the progress and challenges being faced, and potential approaches that can be utilized to identify novel and potent PPI inhibitors for cervical cancer treatment.

The incidence of human papillomavirus-positive head and neck squamous cell carcinoma (HPV + -HNSCC) has increased dramatically over the past decades due to an increase in infection of the oral mucosa by HPV. The etiology of HPV + -HNSCC is linked to expression of the HPV oncoprotein, E6, which influences tumor formation, growth and survival. E6 effects this oncogenic phenotype in part through inhibitory protein-protein interactions (PPIs) and accelerated degradation of proteins with tumor suppressor properties, such as p53 and caspase 8. Interfering with the binding between E6 and its cellular partners may therefore represent a reasonable pharmacological intervention in HPV + tumors. In this study, we probed a small-molecule library using AlphaScreen™ technology to discover novel E6 inhibitors. Following a cascade of screens we identified and prioritized one hit compound. Structure activity relationship (SAR) studies of this lead uncovered an analog, 30-hydroxygambogic acid (GA-OH), that displayed improved activity. Further testing of this analog in a panel of HPV + and HPV - cell lines showed good potency and a large window of selectivity as demonstrated by apoptosis induction and significant inhibition of cell growth, cell survival in HPV + cells. In summary, GA-OH may serve as a starting point for the development of potent E6-specific inhibitors., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2021 Chitsike et al.)

Epigenetic studies in animal models have demonstrated that diet affects gene regulation by altering methylation patterns. We interrogated methylomes in humans who have different sources of protein in their diet. We compared methylation of DNA isolated from buffy coat in 38 vegans, 41 pescatarians and 68 nonvegetarians. Methylation data were obtained using Infinium HumanMethylation450 arrays and analyzed using the Partek Genomic software. Differences in differentially methylated sites were small, though with the use of relaxed statistical tests we did identify diet-associated differences. To further test the validity of these observations, we performed separate and independent comparisons of the methylation differences between vegans and nonvegetarians, and between vegans and pescatarians. The detected differences were then examined to determine if they were enriched in specific pathways. Pathway analysis revealed enrichment of several specific processes, including homeobox transcription and glutamate transport. The detected differences in DNA methylation patterns between vegans, pescatarians, and nonvegetarians enabled us to identify 77 CpG sites that may be sensitive to diet and/or lifestyle, though high levels of individual-specific differences were also noted., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

High-risk human papillomaviruses (HPV) are the causative agents of cervical cancer. However, not all infected women develop cervical cancer. Cervical tumorigenesis is characterized by a multifactorial etiology, with oxidative stress (OS) likely playing a major role. In addition to exogenous sources, metabolic processes also contribute to OS. In principle, variability in levels of cervical OS has the potential to influence the likelihood of conversion to cervical cancer. To ask whether such variability indeed existed, we assessed the levels of ROS and the oxidative DNA damage biomarker 8-oxodG in normal non-cancerous cervical tissues and cells obtained from women with uterovaginal pelvic organ prolapse following vaginal hysterectomy. We demonstrated five and ten-fold variability between tissues isolated from the transformation zone (TZ) and ectocervix (EC) of different women, respectively. Despite the greater variability (likely due to differences in tissue composition), the overall pattern of ROS levels in EC tissues mirrored those obtained in their corresponding TZ tissues. Our results also show that the levels of ROS in TZ tissues were always higher than or equal to those found in the respective EC tissues, providing a possible explanation for TZ tissue being the primary target for HPV infection and cervical carcinogenesis. Interestingly, primary keratinocytes isolated and cultured from these cervical specimens also displayed high variability in ROS levels, with some strongly mirroring the levels of ROS observed in their corresponding tissues, while others were less closely associated. Finally, we demonstrated that the levels of DNA damage mirrored the levels of ROS in the cultured primary cells. Understanding the factors and mechanisms that dispose certain individuals to develop cervical cancer has the potential to enable the development of approaches that make the conversion of HPV infection to cancer development even more rare.

Objective: To evaluate the effectiveness of a Continuing Professional Development (CPD) plan template used in Fall of 2017 on quality of SMART goal development and student quiz scores., Innovation: The gap in time from when pharmacology is taught and when it is applied has contributed to poor student retention and performance in the diabetes pharmacotherapy course. To address this gap, the diabetes pharmacotherapy learning sequence was redesigned and included a self-assessment (pre-test), and the completion of a "CPD plan template", which involved writing 1-3 SMART goals for each question missed on the pre-test. Following sequence completion, students took an identical post-quiz. Pre- and post-quiz scores were compared. Quality of CPD plan SMART goals was evaluated., Key Findings: The CPD plan template was completed by 98% of students. The majority, 62.5% of students, wrote SMART goals at the intermediate or good level, while 37.5% were evaluated as needs improvement. The average pre-quiz score was 7.4 points and average post-quiz score was 17.1 points with an average improvement of 9.8 points (p<0.0001). There was a statistically significant improvement for top 25% post-quiz scoring students who wrote "good" SMART goals compared to those who wrote goals needing improvement (p= 0.002). For students scoring in the lowest 25%, students with goals needing improvement scored higher than those with intermediate quality goals (p< 0.04)., Next Steps: It may be beneficial to introduce CPD to students sooner, as well as teach students more intentionally how to create and use SMART goals to improve learning. Finally, instructor follow up with students regarding use of their plan during a learning sequence may have additional benefit., Competing Interests: Conflicts of interest: None, (© Individual authors.)

Background: In the USA, opioid overdose accounted for more than 60% of drug overdose deaths in 2015. Of these deaths, 40% were due to use of prescription opioids., Objectives: The aims of the study were to (i) study family medicine physician opioid-prescribing rate and duration of prescription, (ii) study the distribution of prescription by medication potency, (iii) study opioid-prescribing trends in health care shortage areas and (iv) study the association between extreme high prescribing rates and medical board discipline., Methods: This is a retrospective cross-sectional study of the 2015 Medicare Part D claim data., Results: Family practitioners have opioid prescription rates (5.6%) similar to medical subspecialists (6.0%), but lower than pain specialists (53.2%) and surgical specialists (36.6%). Family practitioners have an average opioid prescription duration (21.5 days) similar to medical subspecialists (23.1 days) and pain specialists (27.1 days), but longer than surgical specialists (8.9 days). Family practitioners tend to prescribe lower potency opioids. Family practitioners in rural health care shortage areas have a higher opioid prescription rate than other family practitioners (6.5% versus 5.6%). Among the 52 family practitioners who prescribed opioids as frequently as pain specialists, 26 of the 52 (50%) were certified in pain management or worked with a partner certified in pain management. Of the other 26 family practitioners, 3 (12%) had medical board disciplinary actions regarding opioid prescription., Conclusions: While monitoring extreme prescribers is important and needs to be continued, the next step in policies to reduce prescription opioids will require systemic change, especially providing support for family practitioners in rural health care shortage areas., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A three-credit, simulation-based, emergency medicine elective course was designed and offered to doctor of pharmacy students for two years. The primary objective was to determine if there was a difference in exam performance stratified by student simulation experience, namely either as an active observer or as part of bedside clinical care. The secondary objective was to report student satisfaction. Examination performance for simulation-based questions was compared based on the student role (evaluator versus clinical) using the Student&rsquo;s t -test. Summary responses from Likert scale-based student satisfaction responses were collected. A total of 24 students took the course: 12 in each offering. Performance was similar whether the student was assigned to the evaluation team or the clinical team for all of the comparisons (mid-term and final 2015 and 2016, all p -values > 0.05). Students were very satisfied with the course. Of the 19 questions assessing the qualitative aspects of the course, all of the students agreed or strongly agreed to 17 statements, and all of the students were neutral, agreed, or strongly agreed to the remaining two statements. Direct participation and active observation in simulation-based experiences appear to be equally valuable in the learning process, as evidenced by examination performance.

Background: Acromioclavicular joint dislocations are common shoulder girdle injuries. The treatment of grade III acromioclavicular joint dislocations is controversial. Furthermore, the literature on the use of the Sur-giligTM synthetic ligament for reconstruction of dislocations is sparse., Materials and Methods: This retrospective review aimed to establish whether operative treatment was superior to non-operative treatment in grade III acromioclavicular joint dislocations treated at our institute over a 5-year period. We also reviewed the effectiveness of reconstruction with SurgiligTM after acute and chronic dislocations across all grades of acromioclavicular joint dislocations., Results: Twenty-five patients completed full follow-up with grade III dislocations. The mean follow-up in the operated group was 3.56 years and in the non-operated group this was 3.29 years. The mean Oxford Shoul-der Score (OSS) in the operated group was 39.8, whereas the mean OSS in the non-operated group was 45.9 (p=0.01). The mean pain score in the operated group was 2.2, and in the non-operated group this was 1.6. The mean satisfaction score in the operated group was 8.2 and that in the non-operated group was 7.8. There was no statistically significant difference in pain or satisfaction scores. In respect to the cohort treated with Surg-iligTM synthetic ligament, 22 patients across all grades of dislocations had this procedure performed. The mean post-operative Oxford Shoulder Score (OSS) was 40., Conclusions: 1. Non-operative treatment is not inferior to operative treatment for grade III acromioclavicular joint dislocations. The data from this study demonstrat-ed that the non-operated group had superior Ox-ford Shoul-der Scores that were statistically significant. 2. Additionally, the use of the SurgiligTM ligament appears to be effective in treating both chronic and acute acromioclavicular joint dislocations.