The Osteogenic Peptide P-15 for Bone Regeneration: A Narrative Review of the Evidence for a Mechanism of Action.

Bone regeneration is a complex multicellular process involving the recruitment and attachment of osteoprogenitors and their subsequent differentiation into osteoblasts that deposit extracellular matrixes. There is a growing demand for synthetic bone graft materials that can be used to augment these processes to enhance the healing of bone defects resulting from trauma, disease or surgery. P-15 is a small synthetic peptide that is identical in sequence to the cell-binding domain of type I collagen and has been extensively demonstrated in vitro and in vivo to enhance the adhesion, differentiation and proliferation of stem cells involved in bone formation. These events can be categorized into three phases: attachment, activation and amplification. This narrative review summarizes the large body of preclinical research on P-15 in terms of these phases to describe the mechanism of action by which P-15 improves bone formation. Knowledge of this mechanism of action will help to inform the use of P-15 in clinical practice as well as the development of methods of delivering P-15 that optimize clinical outcomes.

Intracranial arachnoid cyst in pregnancy: case report, literature review and evaluation of neuraxial anaesthesia risk.

Choosing the type of intrapartum anaesthesia for pregnant women with intracranial arachnoid cysts can be challenging due to a lack of research. We report the intrapartum anaesthetic management of a 25-year-old woman with a known 10 cm arachnoid cyst. By means of a literature review and discussion of safety surrounding neuraxial techniques, this report will help to inform obstetric anaesthesia practice. Overall, in the absence of raised intracranial pressure, neuraxial analgesia and anaesthesia during the intrapartum period appears to be a safe option.

The role of pandemic planning in the management of COVID-19 in England from an infection prevention and control perspective: results of a national survey.

OBJECTIVES: This national survey aimed to explore how existing pandemic preparedness plans (PPP) accounted for the demands placed on infection prevention and control (IPC) services in acute and community settings in England during the first wave of the COVID-19 pandemic. STUDY DESIGN: This was a cross-sectional survey of IPC leaders working within National Health Service Trusts or clinical commissioning groups/integrated care systems in England. METHODS: The survey questions related to organisational COVID-19 preparedness pre-pandemic and the response provided during the first wave of the pandemic (January to July 2020). The survey ran from September to November 2021, and participation was voluntary. RESULTS: In total, 50 organisations responded. Seventy-one percent (n = 34/48) reported having a current PPP in December 2019, with 81% (n = 21/26) indicating their plan was updated within the previous 3 years. Around half of IPC teams were involved in previous testing of these plans via internal and multi-agency tabletop exercises. Successful aspects of pandemic planning were identified as command structures, clear channels of communication, COVID-19 testing, and patient pathways. Key deficiencies were lack of personal protective equipment, difficulties with fit testing, keeping up to date with guidance, and insufficient staffing. CONCLUSIONS: Pandemic plans need to consider the capability and capacity of IPC services to ensure they can contribute their critical knowledge and expertise to the pandemic response. This survey provides a detailed evaluation of how IPC services were impacted during the first wave of the pandemic and identifies key areas, which need to be included in future PPP to better manage the impact on IPC services.

Repeat single-fraction stereotactic radiosurgery for recurrent vestibular schwannoma.

Background: Data are scarce on the efficacy of a second radiosurgery (SRS) treatment of vestibular schwannoma that has progressed following initial treatment with SRS. We sought to report the outcome of our repeat SRS series with long-term imaging follow-up. Materials and methods: We retrospectively analyzed 6 patients who met the following criteria: Repeat SRS at our institution between 1995 and 2018; solitary unilateral tumor; no evidence of neurofibromatosis; and magnetic resonance (MR) planning for both SRS treatments. All treatments were delivered with a linear accelerator-based system using head frame immobilization. The prescribed dose to the periphery of the tumor was 12.5 Gy in all initial and repeat SRS treatments, except for one repeat treatment to 10 Gy. Results: Follow-up with MR scan following the second SRS treatment was a median 8.4 years. The tumor control rate (lack of progression) following the second SRS treatment was 83% (5/6). Actuarial 10-year outcomes following repeat SRS were: tumor control, 80%; absolute survival, 80%; and cause-specific survival, 100%. Of the patients with at least minimal hearing retention before initial SRS, none had ipsilateral hearing preservation after initial radiation treatment. Improvement in any pretreatment cranial nerve deficits was not seen. The only permanent grade ≥ 3 toxicity from repeat SRS was a case of infraorbital nerve deficit. No patient developed a stroke, malignant transformation, induced second tumor, or facial nerve deficit. Conclusion: There was excellent overall survival, tumor control, and low morbidity in our series for recurrent vestibular schwannoma submitted to repeat single-fraction SRS, supporting additional studies of this treatment strategy.

Dose-escalated proton therapy with elective nodal irradiation and concomitant chemotherapy for unresectable, borderline resectable, or medically inoperable pancreatic cancer: a phase II trial.

Background: To report outcomes of a phase II single-institution trial of dose-escalated proton radiotherapy with elective nodal irradiation (ENI) and concomitant chemotherapy for patients with unresectable, borderline resectable, or medically inoperable pancreatic adenocarcinoma. Methods: Patients received 40.5 GyRBE in 18 fractions to the gross disease and elective nodal volumes followed by 22.5 GyRBE as a 10-fraction boost to the gross disease for a cumulative dose of 63 GyRBE over 28 fractions. Oral capecitabine (1,000 mg taken orally twice daily) was given on radiation treatment days. The primary objective of this study was to improve the proportion surviving to at least 1 year from the historical rate of 50% to 75%. Secondary objectives included assessing gastrointestinal (GI) toxicity and weight loss during treatment, and evaluating the safety of subsequent surgical resection. This single-institution study was closed to accrual early after the opening of the multicenter PAN009-18 trial by the Proton Collaborative Group (PCG), which follows a similar protocol. Results: At enrollment, 10 (67%) patients had unresectable disease, 3 (20%) had borderline-resectable disease, and 2 (13%) refused surgery. All 15 patients successfully completed radiation therapy as prescribed. With regard to toxicity, a single patient experienced grade 3 nausea requiring cessation of capecitabine, which ultimately resolved by treatment completion. The median percentage weight loss during treatment was -3.0% (range, -9.6% to +12.0%). Two (13%) initially borderline patients ultimately underwent R0 resection: their total operating room times were 267 and 410 minutes, and blood loss was 700 and 400 mL, respectively. Neither patient experienced intraoperative or postoperative complications. Both were discharged on postoperative day 6. The median follow-up was 0.93 years (range, 0.21 to 2.14 years). The 1-year overall survival (OS) rate was 47%. Three enrolled patients are currently alive: 2 with no evidence of disease and 1 with stable disease. Conclusions: The primary objective of 1-year OS of 75% was not reached. Proton therapy was well-tolerated. Patients undergoing surgery did not experience operative or perioperative complications, suggesting that patients with borderline resectable or even resectable disease may benefit from neoadjuvant proton therapy. The PCG will test this premise as patients accrue to the multicenter PAN009-18 trial. Trial Registration: NCT02598349.

Potential Financial Implications of Substituting Cognitive Medicine for Technical Radiation Oncology Billing Services.

Respected authors recommend broadening the radiation oncology (RO) scope-of-practice by taking more responsibility for the general medical care of our patients, directing the delivery of systemic cancer treatments that avoid the high toxicity of cytotoxic chemotherapy, managing palliative care, and supervising inpatient services for brachytherapy cases and problems related to radiation toxicity. The purpose of these changes is to increase RO involvement in clinical decision making and to avoiding becoming pigeon-holed as technicians instead of oncologists. There are no data estimating the financial implications of substituting traditional radiation oncology practice with that of an expanded clinical role. We sought to fill this void with a general proof-of-principle analysis based on current benchmark data. To determine the relative value units (RVU) of a blended radiation oncology practice, we selected the specialties of general internal medicine, hospital medicine, and palliative care as these fields most closely match the scope of the broadened clinical roles, which supporters of a more diversified radiation oncology practice typically advocate. To estimate the financial implications of a blended radiation oncology practice, we retrieved salary data by specialty and academic rank from the Clinical Practice Solutions Center report of annual RVU generation and the American Association of Medical Colleges annual faculty salary survey. For an assistant professor, this simulation estimates an 11% to 15% decrease in RVU generation for the median assistant professor operating with a 20% blended practice which, in turn, translates to a 7% to 9% decrease in total salary. The calculations for full professor demonstrate a similar decrease in total salary of approximately 8% to 9%.

Aberrantly low STAT3 and STAT5 responses are associated with poor outcome and an inflammatory gene expression signature in pediatric acute myeloid leukemia.

The relapse rate for children with acute myeloid leukemia is nearly 40% despite aggressive chemotherapy and often stem cell transplant. We sought to understand how environment-induced signaling responses are associated with clinical response to treatment. We previously reported that patients whose AML cells showed low G-CSF-induced STAT3 activation had inferior event-free survival compared to patients with stronger STAT3 responses. Here, we expanded the paradigm to evaluate multiple signaling parameters induced by a more physiological stimulus. We measured STAT3, STAT5 and ERK1/2 responses to G-CSF and to stromal cell-conditioned medium for 113 patients enrolled on COG trials AAML03P1 and AAML0531. Low inducible STAT3 activity was independently associated with inferior event-free survival in multivariate analyses. For inducible STAT5 activity, those with the lowest and highest responses had inferior event-free survival, compared to patients with intermediate STAT5 responses. Using existing RNA-sequencing data, we compared gene expression profiles for patients with low inducible STAT3/5 activation with those for patients with higher inducible STAT3/5 signaling. Genes encoding hematopoietic factors and mitochondrial respiratory chain subunits were overexpressed in the low STAT3/5 response groups, implicating inflammatory and metabolic pathways as potential mechanisms of chemotherapy resistance. We validated the prognostic relevance of individual genes from the low STAT3/5 response signature in a large independent cohort of pediatric AML patients. These findings provide novel insights into interactions between AML cells and the microenvironment that are associated with treatment failure and could be targeted for therapeutic interventions.

Geospatial Analysis of Rurality and Food Banks in Appalachian Ohio.

Introduction: Food insecurity is a problem for individuals across Ohio, including those living in Appalachia. Adequate access to resources that help combat food insecurity is important for these populations. Purpose: To examine how rurality relates to food insecurity and need for food resources, as well as availability of those resources including food pantries and soup kitchens, in 15 northern Ohio Appalachian counties. Methods: A cross-sectional study with a geographical analysis was conducted using data from the American Community Survey census data, County Health Rankings data, and regional foodbank websites. Results: Rural counties had a higher ratio of potential clients per service for food insecurity than did non-rural counties. They also had slightly more children eligible for free or reduced-price lunches than non-rural counties. However, the non-rural counties had slightly higher percentages of residents classified as food insecure and with limited access to healthy food. Implications: There are more potential clients per service for food insecurity in rural counties compared to non-rural counties. To promote greater access, additional food pantries should be opened in rural counties.

Age, sex, and regional differences in scavenger receptor CD36 in the mouse brain: Potential relevance to cerebral amyloid angiopathy and Alzheimer's disease.

Scavenger receptor CD36 contributes significantly to lipid homeostasis, inflammation, and amyloid deposition, while CD36 deficiency is associated with restored cerebrovascular function in an Alzheimer's disease (AD) mouse model. Yet the distribution of CD36 has not been examined in the brain. Here, we characterized CD36 gene and protein expression in the brains of young, middle aged, aged, and elderly male and female C57BL/6J mice. Age-related increases in CD36 mRNA expression were observed in the male hippocampus and female midbrain. Additionally, male mice had greater CD36 mRNA expression than females in the striatum, hippocampus, and midbrain. CD36 protein was primarily expressed intravascularly, and this expression differed by region, age, and sex in the mouse brain. Although male mice brains demonstrated an increase in CD36 protein with age in several cortices, basal ganglia, hippocampus, and midbrain, a decrease with age was observed in female mice in the same regions. These data suggest that distinctive age, region, and sex expression of CD36 in the brain may contribute to Aß deposition and neuroinflammation in AD.

Oral and Maxillofacial Surgery and Oral Surgery - what's the difference? A Western Australian dental student survey.

Confusion exists around the terms 'Oral Surgeon' and 'Oral and Maxillofacial Surgeon'. Historical terms and international differences have added to this confusion. Recently, the University of Sydney has begun to offer a Doctor of Clinical Dentistry in Oral Surgery to graduate dentists. With this new dental specialty entering the Australian workforce, distinction must be made between their role and the role of Oral and Maxillofacial Surgeons to facilitate effective referral pathways. A cross sectional survey of 3rd and 4th year dental students was distributed in June 2019. Students were queried with regards to their perception of the scope of practice of Oral Surgeons and Oral and Maxillofacial Surgeons as well as their knowledge of the training pathways and level of interest in pursuing either pathway. A total of 85% of students responded. Responses indicated a general awareness of the increased scope of practice of Oral and Maxillofacial Surgeons with some exceptions. No significant difference was seen between third and fourth year responses. Knowledge of both training pathways was lacking. Further education is required with regards to the scope of practice of both specialties. A lack of exposure to Oral and Maxillofacial Surgery during the undergraduate years may be partly to blame. Consideration should be given to the renaming of Oral Surgery to Surgical Dentistry.

Coronavirus disease 2019 (COVID-19) outcomes in HIV/AIDS patients: a systematic review.

OBJECTIVES: The aim of the study was to systematically review current studies reporting on clinical outcomes in people living with HIV (PLHIV) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. A comprehensive literature search was conducted in Global Health, SCOPUS, Medline and EMBASE using pertinent key words and Medical Subject Headings (MeSH) terms relating to coronavirus disease 2019 (COVID-19) and HIV. A narrative synthesis was undertaken. Articles are summarized in relevant sections. RESULTS: Two hundred and eighty-five articles were identified after duplicates had been removed. After screening, eight studies were analysed, totalling 70 HIV-infected patients (57 without AIDS and 13 with AIDS). Three themes were identified: (1) controlled HIV infection does not appear to result in poorer COVID-19 outcomes, (2) more data are needed to determine COVID-19 outcomes in patients with AIDS and (3) HIV-infected patients presenting with COVID-19 symptoms should be investigated for superinfections. CONCLUSIONS: Our findings suggest that PLHIV with well-controlled disease are not at risk of poorer COVID-19 disease outcomes than the general population. It is not clear whether those with poorly controlled HIV disease and AIDS have poorer outcomes. Superimposed bacterial pneumonia may be a risk factor for more severe COVID-19 but further research is urgently needed to elucidate whether PLHIV are more at risk than the general population.

The relationship between an electronic mental health stigma campaign and suicidal thoughts and behaviours: a two-arm randomized controlled trial in the Australian construction industry.

Males employed in the construction industry are at greater risk of suicide than other employed males. It is plausible that a high level of stigma against mental health problems explains the elevated rates of suicide among this group. This study sought to test the effectiveness of an electronic mental health stigma intervention on suicide ideation, communication about suicide and attempts. Participants were randomly assigned to receive either a series of brief contact interventions over a 6-week period or a wait list control. Suicidal ideation, communication about suicide and suicide attempts were assessed using the Suicidal Behaviors Questionnaire-Revised at post-intervention. We used linear regression to assess effectiveness at post-intervention, adjusting for relevant covariates using both conventional methods and a propensity score approach. Results indicate that the intervention had no significant impact on suicidal thoughts, communication or suicide attempts. There was some indication that individuals in the intervention group reported a slight increase in attempts and communication about suicide. These observations underscore an urgent need for more research to understand the complex and nuanced relationship between stigma and suicide in non-clinical populations.

Magnetic resonance imaging for three-dimensional printing of the bony orbit: is clinical use imminent?

The aim of this study was to examine the accuracy of three dimensionally (3D) printed models of the bony orbit derived from magnetic resonance imaging (MRI) for the purpose of preoperative plate bending in the setting of orbital blowout fracture. Retrospective computed tomography (CT) and MRI data from patients with suspected orbital fractures were used. Virtual models were manually generated and analysed for spatial accuracy of the fracture margins. 3D-printed models were produced and orbital fan plates bent by a single operator. The plates were then digitized and analysed for spatial discrepancy using reverse engineering software. Seven orbital blowout fractures were evident in six orbits. Analysis of the virtual models revealed high congruence between blowout fracture margins on CT and MRI (n=7, average deviation 0.85mm). Three zygomaticomaxillary complex fractures were seen, for which MRI did not demonstrate the same accuracy. For plates bent to the 3D-printed models of blowout fractures (n=6), no significant difference was found between those bent to CT versus those bent to MRI when compared for average surface and average border deviation (Wilcoxon signed rank test). Orbital blowout fractures can be defined on MRI with clinically acceptable accuracy. 3D printing of orbital biomodels from MRI for bending reconstructive plates is an acceptable and accurate technique.

Radiation treatment of soft palate squamous cell carcinoma.

BACKGROUND: To report our institution's experience treating soft palate squamous cell carcinoma with radiotherapy alone or combined with adjuvant chemotherapy and/or neck dissection for residual disease. METHODS: We analyzed 159 patients treated curatively between 1963 and 2016. Median follow-up was 4 years. RESULTS: The 5-year local control rates were T1, 90%; T2, 90%; T3, 70%; and T4, 59%. The 5-year cause-specific survival (CSS) rate was nearly identical for patients with stage I-III disease (88%, 86%, and 88%, respectively) compared to stage IVA/B (58%). Five-year overall survival was similar between patients with stage I-III disease (50%, 57%, and 54%, respectively) and approximately double that of patients with stage IVA/B disease (26%). Thirteen patients (8%) had severe complications related to radiotherapy. CONCLUSIONS: The likelihood of cure after definitive radiotherapy is relatively high in patients with stage I-III disease with soft palate carcinoma. Patients with stage IVA/B disease have a lower cure rate but with a 5-year CSS exceeding 50%.

Dosimetric Predictors of Cardiotoxicity in Thoracic Radiotherapy for Lung Cancer.

BACKGROUND: Higher cardiac radiotherapy (RT) doses when treating lung cancer are associated with worse overall survival (OS), although the direct association between cardiac dose and early cardiotoxicity is poorly understood. We hypothesized that RT doses to the heart and cardiac substructures are associated with under-reported early cardiotoxicity and worse OS. PATIENTS AND METHODS: We conducted an institutional retrospective review of lung cancer patients treated with conventionally fractionated RT from 2010 to 2015. Collected data included pre-RT cardiac risk factors, post-RT cardiotoxicities, and dose-volume parameters for cardiac substructures. Univariate and multivariate analyses were performed to identify predictors of cardiotoxicity and OS. RESULTS: Seventy-six cases were evaluated with 1.2 years median follow-up. Cardiotoxicities included atrial arrhythmia (n = 5), pericardial effusion (n = 16), and valvular disease (n = 1). In univariate analysis, significant dose-volume predictors for cardiotoxicity included mean RT dose to structure of interest, volume of structure of interest receiving ≥30 Gy RT dose, and volume of structure of interest receiving ≥45 Gy RT dose (V45) to the atria, ventricles, and pericardium. Higher ventricular V45 was associated with post-RT cardiotoxicity in multivariate analysis (hazard ratio [HR], 1.50; P = .027). Cardiotoxicity occurrence was a highly significant predictor of OS in multivariate analysis (HR, 12.7; P < .001), but higher ventricular V45 alone was not (HR, 0.78; P = .450). CONCLUSION: Early cardiac events were relatively common after lung cancer RT and associated with multiple cardiac dose-volume parameters. Occurrence of early cardiotoxicity was strongly associated with worse OS. In practice, early cardiotoxicity is under-reported, supporting the need for more detailed cardiac evaluations in high-risk patients to detect and address early cardiotoxicity.

Suzuki coupling-based synthesis of VATPase inhibitor archazolid natural product derived fragments.

An archazolid natural product fragment that displays dose-dependent inhibition of the vacuolar-type ATPase (VATPase) has been synthesized by a high-yielding Suzuki coupling of two complex subunits. Similarly, a further simplified fragment was prepared and evaluated for VATPase inhibitory activity. This compound did inhibit the VATPase, as evidenced by growth inhibition of etiolated Arabidopsis seedlings, however at approximately 10× lower potency than the more complex fragment. Cyclooxygenase (COX) enzyme inhibition was not observed for either fragment.

Infants with esophageal atresia and right aortic arch: Characteristics and outcomes from the Midwest Pediatric Surgery Consortium.

PURPOSE: Right sided aortic arch (RAA) is a rare anatomic finding in infants with esophageal atresia with or without tracheoesophageal fistula (EA/TEF). In the presence of RAA, significant controversy exists regarding optimal side for thoracotomy in repair of the EA/TEF. The purpose of this study was to characterize the incidence, demographics, surgical approach, and outcomes of patients with RAA and EA/TEF. METHODS: A multi-institutional, IRB approved, retrospective cohort study of infants with EA/TEF treated at 11 children's hospitals in the United States over a 5-year period (2009 to 2014) was performed. All patients had a minimum of one-year follow-up. RESULTS: In a cohort of 396 infants with esophageal atresia, 20 (5%) had RAA, with 18 having EA with a distal TEF and 2 with pure EA. Compared to infants with left sided arch (LAA), RAA infants had a lower median birth weight, (1.96 kg (IQR 1.54-2.65) vs. 2.57 kg (2.00-3.03), p = 0.01), earlier gestational age (34.5 weeks (IQR 32-37) vs. 37 weeks (35-39), p = 0.01), and a higher incidence of congenital heart disease (90% vs. 32%, p < 0.0001). The most common cardiac lesions in the RAA group were ventricular septal defect (7), tetralogy of Fallot (7) and vascular ring (5). Seventeen infants with RAA underwent successful EA repair, 12 (71%) via right thoracotomy and 5 (29%) through left thoracotomy. Anastomotic strictures trended toward a difference in RAA patients undergoing right thoracotomy for primary repair of their EA/TEF compared to left thoracotomy (50% vs. 0%, p = 0.1). Side of thoracotomy in RAA patients undergoing EA/TEF repair was not significantly associated with mortality, anastomotic leak, recurrent laryngeal nerve injury, recurrent fistula, or esophageal dehiscence (all p > 0.29). CONCLUSION: RAA in infants with EA/TEF is rare with an incidence of 5%. Compared to infants with EA/TEF and LAA, infants with EA/TEF and RAA are more severely ill with lower birth weight and higher rates of prematurity and complex congenital heart disease. In neonates with RAA, surgical repair of the EA/TEF is technically feasible via thoracotomy from either chest. A higher incidence of anastomotic strictures may occur with a right-sided approach. LEVEL OF EVIDENCE: Level III.

A smart-phone intervention to address mental health stigma in the construction industry: A two-arm randomised controlled trial.

BACKGROUND: High levels of self-stigma are associated with a range of adverse mental health, treatment, and functional outcomes. This prospective study examined the effects of an electronic mental health stigma reduction intervention on self-stigma (self-blame, shame, and help-seeking inhibition) among male construction workers in Australia. METHOD: Male construction workers (N = 682) were randomly assigned to receive either the intervention condition or the wait list control over a six-week period. Self-stigma was assessed using the Self-Stigma of Depression Scale at post-intervention. We conducted linear regression to assess the effectiveness of the intervention on self-stigma, adjusting for relevant covariates. RESULTS: Self-stigma was relatively low in the sample. The intervention had no significant effect on self-stigma, after adjusting for confounders. There were reductions in stigma in both the intervention and control groups at 6-week follow-up. Process evaluation indicated that participants generally enjoyed the program and felt that it was beneficial to their mental health. CONCLUSIONS: These observations underscore the need for further research to elucidate understanding of the experience of self-stigma among employed males.