The adoption of the HPV vaccine school-entry requirement in Puerto Rico: How practical lessons can inform future vaccine policies.

Vaccine requirements are policy-level strategies used to improve population health outcomes; however, discourse politicization of vaccines may hinder adoption and implementation. An example of the complexities related to adoption of vaccine policies in the United States (US) is the human papillomavirus (HPV) vaccine school-entry requirement. In 2018, Puerto Rico's (PR) Department of Health adopted this policy. This study assessed stakeholders' recommendations for adoption of the HPV vaccine school-entry requirement that could inform future vaccine policies. Stakeholders (e.g., researchers, members of medical and non-profit organizations) were interviewed from May to August 2018. Participants (n = 20) discussed recommendations for public health professionals interested in adopting such policy. Data were analyzed using applied thematic techniques. Participants emphasized the importance of raising HPV vaccine awareness and providing education prior to the requirement. They recommended using real stories and making the problem relevant by using local data. Participants recommended considering the local culture and government bureaucracies, and promoting multisectoral collaborations to combine limited resources. The combination of education efforts, local data, and multisectoral collaborations facilitated the adoption of the HPV vaccine school-entry requirement in PR. Findings highlight the need to understand the contextual distinctions of the communities where vaccination requirements may be adopted and implemented to anticipate barriers and leverage existing resources. Consideration of the politico-cultural context may be important as political beliefs have become entrenched with vaccine policy. These practical lessons can inform public health professionals and policymakers who are seeking to adopt and implement vaccine policies in other settings to ensure equitable vaccine access.

Carboxyhemoglobinemia in a pediatric cardiopulmonary bypass patient derived from a contaminated unit of allogenic blood.

A 4.3 kg, three-month-old patient, diagnosed with a perimembranous ventricular septal defect, presented for cardiac surgery. Upon initiation of cardiopulmonary bypass (CPB), the patient developed carboxyhemoglobinemia (11.1%). Potential sources for the unexpected acquired carboxyhemoglobinemia were sought quickly. Testing of residual blood from the unit of packed red blood cells (PRBCs) used to prime the CPB circuit revealed a carboxyhemoglobin (COHb) of 15.1 %. A decrease in cerebral oximetry (rSO(2)) on CPB was initially felt to be a result of the elevated COHb levels. When ventilation of the oxygenator with 100% oxygen (O(2)) failed to decrease COHb levels, a partial exchange transfusion was performed with reduction in COHb to 7.1%. The operation was completed successfully and the patient's COHb levels returned to normal within 75 minutes. Post case analysis of events and data collected during the case revealed a broader differential for explaining the compromised patient's O(2) delivery than the transient acquired carboxyhemoglobinemia. A partial obstruction of the superior vena cava could have triggered the drop in rSO(2) on CPB. Follow-up of the donor blood confirmed the donor had previously undiagnosed carboxyhemoglobinemia as a result of chronic carbon monoxide exposure from a faulty vehicle exhaust system.

Emergency department visits and unplanned hospitalizations in the treatment period for head and neck cancer patients treated with curative intent: A population-based analysis.

BACKGROUND: Mucosal head and neck squamous cell cancers are often managed with multimodality treatment which can be associated with significant toxicity. The objective of this study was to assess emergency department visits and unplanned hospitalizations for these patients during and immediately after their treatment. METHODS: A cohort of patients treated for head and neck squamous cell carcinoma was developed using administrative data. Emergency department visits and hospitalizations in the 90-day post-treatment period was determined. If a second treatment was initiated prior to the completion of 90 days, the attributable risk period was changed to the second treatment. RESULTS: Cohort of 3898 patients (1312 larynx/hypopharynx; 2586 oral cavity/oropharynx) from 2008 to 2012. The number of unplanned hospitalizations or ED visits (per 100 patient days) were 0.69 for surgery, 0.78 for surgery followed by concurrent chemoradiotherapy (CCRT), 0.55 for surgery followed by radiotherapy, 0.86 for CCRT, and 0.50 for radiation. Patients receiving CCRT had a statistically higher likelihood of treatment period events. The larynx/hypopharynx cancer subsite, higher comorbidity and more advanced stage of disease were all independent predictors of events. CONCLUSIONS: Patients undergoing treatment for head and neck cancer have significant unplanned hospitalizations and visits to the emergency department in the treatment period. Rates are higher in patients receiving CCRT. Quality improvement interventions should be used to improve these rates.

Micropuncture studies of sodium transport in the remnant kidney of the dog. The effect of graded volume expansion.

Proximal and distal tubule micropuncture studies were performed to examine the response to graded extracellular volume (ECV) expansion in 10 normal dogs (stage I), 11 dogs with a unilateral remnant kidney (stage II), and 7 dogs with a remnant kidney after removal of the contralateral kidney (stage III). Before ECV expansion in stage III, there was a suggestive reduction in proximal tubule as well as loop fractional reabsorption of sodium. After ECV expansion to 3% body weight proximal tubule reabsorption was depressed in all groups of animals, while little further inhibition was observed in this segment with additional expansion to 10% body weight. In contrast, the fraction of filtered sodium remaining in the distal tubule rose progressively in all three groups after graded ECV expansion, suggesting that the graded natriuretic response found in the final urine was largely due to a similar response in the loop of Henle rather than that in the proximal tubule. The distal tubule response of the remnant kidney in both stages II and III was greater than that in stage I. These data indicate that although enhanced sodium excretion per nephron in chronic renal failure may be related to uremia, its exaggerated response to ECV expansion is due, at least in part, to certain as yet unidentified intrarenal factors consequent to reduction in functioning renal mass.

Best Practice Recommendations for the Retention of Radiotherapy Records.

This paper offers best practice recommendations for the maintenance and retention of radiotherapy health records and technical information for cancer programmes. The recommendations are based on a review of the published and grey literature, feedback from key informants from seven countries and expert consensus. Ideally, complete health records should be retained for 5 years beyond the patient's lifetime, regardless of where they are created and maintained. Technical information constituting the radiotherapy plan should also be retained beyond the patient's lifetime for 5 years, including the primary images, contours of delineated targets and critical organs, dose distributions and other radiotherapy plan objects. There have been increased data storage and access requirements to support modern image-guided radiotherapy. Therefore, the proposed recommendations represent an ideal state of radiotherapy record retention to facilitate ongoing safe and effective care for patients as well as meaningful and informed retrospective research and policy development.

Using antifibrinolytics in the peripartum period - concern for a hypercoagulable effect?

INTRODUCTION: Although antifibrinolytic agents are used to prevent and treat hemorrhage, there are concerns about a potential increased risk for peripartum venous thromboembolism. We sought to determine the impact of tranexamic acid and ɛ-aminocaproic acid on in vitro clotting properties in pregnancy. METHODS: Blood samples were obtained from healthy pregnant, obese, and preeclamptic pregnant women (n = 10 in each group) prior to delivery as well as from healthy non-pregnant controls (n = 10). Maximum clot firmness (MCF) and clotting time (CT) were measured using rotation thromboelastometry in the presence of tranexamic acid (3, 30, or 300 µg/mL) or ɛ-aminocaproic acid (30, 300, or 3000 µg/mL). ANOVA and regression analyses were performed. RESULTS: Mean whole blood MCF was significantly higher in healthy pregnant vs. non-pregnant women (66.5 vs. 57.5 mm, p < 0.001). Among healthy pregnant women, there was no significant difference between mean MCF (whole blood alone, and with increasing tranexamic acid doses = 66.5, 66.1, 66.4, 66.3 mm, respectively; p = 0.25) or mean CT (409, 412, 420, 424 sec; p = 0.30) after addition of tranexamic acid. Similar results were found using ɛ-aminocaproic acid. Preeclamptic women had a higher mean MCF after the addition of ɛ-aminocaproic acid and tranexamic acid (p = 0.05 and p = 0.04, respectively) compared to whole blood alone. CONCLUSIONS: Pregnancy is a hypercoagulable state, as reflected by an increased MCF compared to non-pregnant women. Addition of antifibrinolytic therapy in vitro does not appear to increase MCF or CT for non-pregnant, pregnant, and obese women. Whether antifibrinolytics are safe in preeclampsia may require further study.

Targeting early events in T cell activation to construct improved vaccines.

Live, attenuated vaccines currently offer the best protection against virulent pathogens. Recent advances in Immunology and Molecular Biology provide an opportunity to design vaccines that will be more effective and safer than existing ones. Immunologists are rapidly developing the capacity to identify and construct the minimal immunogenic units from pathogens. The molecular signals required to fully activate antigen presenting cells (APCs) and responder T cells are becoming apparent. Improved vaccine delivery systems are being designed which will mimic the actions of pathogens in vivo. These vaccines will incorporate protective epitopes fused to immunoregulatory cytokines in chimeric proteins. They will be encapsulated in formulations which allow for the slow release of these chimeric proteins thereby inducing the memory T cells required for long-lived immunity. These vaccine formulations will target receptors present on the most active APCs. Here we discuss how these advances will allow us to rationally construct "virtual pathogens" which will provide improved protection against new and old microbial foes.

Brompheniramine, loratadine, and placebo in allergic rhinitis: a placebo-controlled comparative clinical trial.

A double-blind, randomized, placebo-controlled, parallel-group, multicenter study was conducted to compare the effectiveness of an extended-release formulation of a classical antihistamine, brompheniramine, and a second-generation compound, loratadine, in the treatment of allergic rhinitis. Subjects with symptoms of allergic rhinitis received brompheniramine 12 mg twice daily (n = 112), loratadine 10 mg once daily (n = 112), or placebo twice daily (n = 114) for 7 days. Study medications were blinded using a double-dummy technique. Subjects completed an overall evaluation of symptom relief on a daily basis and returned on treatment days 3 and 7, at which times the investigator assessed symptom severity. The investigator and subject each completed a global efficacy evaluation, and subjects were interviewed regarding adverse experiences. The primary efficacy variable was the physicians' global efficacy evaluation on day 3. Symptoms also were analyzed as summed severity scores for all symptoms and for the nasal symptom cluster of rhinorrhea, sneezing, and nasal blockage. At all post-baseline evaluations (days 3, 7, and averaged over the two days), brompheniramine was significantly better than loratadine and placebo for both sets of summed symptom scores and all three global assessments. Loratadine was significantly better than placebo for physician ratings of total symptom severity averaged over the two days and for the physician and subject ratings of the nasal cluster on day 3. Central nervous system-related symptoms were the most frequently reported adverse experiences; somnolence was reported most frequently by patients taking brompheniramine, and its occurrence was less frequent as treatment continued. A nonprescription, extended-release formulation of brompheniramine 12 mg twice daily provided significantly better relief of symptomatic allergic rhinitis than loratadine 10 mg once daily.

The characterisation of a cervine immunoregulatory cytokine, interleukin 12.

The cloning, sequencing, and production of cervine interleukin-12 is described. The cervine IL-12 p35 subunit coding sequence is 666 bp long and has highest homology to bovine p35 (94%), followed by human (79%), then murine (57%). The cDNA codes for a 221 aa long protein with predicted molecular weight of 24,902 Da. The cervine p40 subunit has a coding sequence of 984 bp and shows 96% homology to bovine, 85% homology to human, and 65% homology to murine p40 respectively. Cervine p40 cDNA codes for a 327 aa long protein with a predicted molecular weight of 37,461. Both subunits were inserted into a recombinant baculovirus that was then used to produce cervine IL-12 in Trichoplusia ni cells. Interleukin-12 was secreted into the culture medium and was biologically active as measured by proliferation of mitogen sensitised peripheral blood lymphocytes and the induction of interferon-gamma transcription in peripheral blood lymphocytes.

The cloning and sequencing of cervine interleukin 10.

We report the cloning and sequencing of the cervine interleukin-10 gene. Specific cDNA was amplified by PCR using primers based on the bovine sequence. This was cloned into pGEM 5Zf and several clones were sequenced. The 762 nucleotide product coded for a 179 amino acid protein which was 86% homologous with its bovine and 77% homologous with its human counterparts. There is a strongly hydrophobic signal sequence consisting of the first 20 amino acids and a potential glycosylation site at amino acids 134-136. There are three regions, comprising 34% of the protein, which show complete homology between the cervine, bovine and human sequences. The transcription of the gene was shown by Northern Blotting where a single, 1.8kb, mRNA transcript was detected 4-8 hours after activation of peripheral blood mononuclear cells with mitogen.

Adenoviral-mediated, intratumor gene transfer of interleukin 23 induces a therapeutic antitumor response.

Interleukin 23 (IL-23) is a member of the IL-12 family of heterodimeric cytokines, composed of p19 and p40 subunits, which exhibits immunostimulatory properties similar to IL-12. IL-23 has been shown to possess potent antitumor activities in several establishment models of cancer and a few therapeutic models, but the efficacy of local, adenoviral-mediated expression of IL-23 in established tumors has yet to be investigated. Here we have examined the antitumor activity of adenovirally delivered IL-23 in a day-7 MCA205 murine fibrosarcoma tumor model. Three intratumoral injections of adenovirus expressing IL-23 (Ad.IL-23) significantly increased animal survival and resulted in complete rejection of 40% of tumors, with subsequent generation of protective immunity and MCA205-specific cytotoxic T lymphocytes. In addition, we have shown that the antitumor activity of IL-23 is independent of IL-17, perforin and Fas ligand, but dependent on interferon-gamma, CD4(+) and CD8(+) T cells. These results demonstrate that direct intratumoral injection of adenovirus expressing IL-23 results in enhanced survival, tumor eradication and generation of protective immunity by generation of a Th1-type immune response.

Epidural analgesia in parturients with previous spinal irradiation.

PURPOSE: To present two successful cases of labour analgesia in patients who had been treated with radiation to the lumbar spine for neuroblastomas and to discuss the considerations when planning the anaesthetic management of these patients. CLINICAL FEATURES: We recently encountered two primigravidas requesting labour analgesia, both of whom were noted to have very thin backs with prominent spinous processes and obvious scoliosis. In both patients, the epidural space was easily identified and very shallow. Successful labour analgesia was achieved in both patients, one with a combined spinal epidural technique and the other with an epidural catheter. CONCLUSION: Craniospinal irradiation is known to have long-term effects on exposed nervous tissue, bone, and blood vessels. While a larger experience is necessary to demonstrate safety of regional anaesthesia in parturients following previous spinal irradiation, we provide reports of two successful cases.

Cardiac electrophysiologic effects of intravenous ketanserin in humans.

The hypotensive effects of ketanserin, a selective blocker of 5-hydroxytryptamine2, are well defined, but its electrophysiologic effects in humans are not. Intravenous ketanserin (0.15 mg/kg) was therefore given to 10 patients undergoing electrophysiologic evaluation, and data were obtained before and after drug administration. The mean ketanserin plasma level was 389 +/- 211 ng/ml. Ketanserin decreased systolic and diastolic blood pressure, but the change did not reach statistical significance. Ketanserin increased the QTc interval by 3% (p less than 0.01), without effect on QRS or the HV intervals. Ketanserin exerted no effect on ventricular effective refractory period (ERP) but decreased the atrial ERP by 6% (p less than 0.01); the decrease in atrioventricular (AV) nodal ERP and in the AV nodal Wenkebach cycle length did not reach statistical significance. The sinus node recovery time and intranodal conduction time were shortened significantly by ketanserin. The data indicate that ketanserin has a modest effect in prolonging ventricular repolarization without influencing the fast sodium channel. Its effect on atrial refractoriness and on sinus and AV-nodal function suggests a complex interaction with the autonomic nervous system in producing its net cardiac electrophysiologic actions.

The production and biological assessment of cervine interferon gamma.

Cervine interferon gamma (IFN-gamma) was cloned and expressed using an Escherichia coli expression system pET-32. The expressed protein contained a 6 histidine purification tag and an 11 kDa thioredoxin fusion partner 5' to the IFN-gamma molecule. The ability of IFN-gamma to inhibit the killing of Madin-Darby bovine kidney cells by Semliki forest virus was used as a measure of the bioactivity of the recombinant cervine IFN-gamma (rIFN-gamma). It was shown that the presence of the thioredoxin fusion partner 5' to the IFN-gamma molecule did not affect its biological activity. As in the mouse model, it was shown that cervine rIFN-gamma was able to down-regulate the transcription of interleukin 10 mRNA while up-regulating the transcription of interleukin 12 mRNA in lipopolysaccharide-sensitized, peripheral blood mononuclear cells. A prototype ELISA was tested for its ability to detect both recombinant and native IFN-gamma. The ELISA was able to detect rIFN-gamma at concentrations greater than 100 pg/ml. It was also used to detect native IFN-gamma produced by peripheral blood lymphocytes from Mycobacterium bovis infected or vaccinated deer after in vitro restimulation with antigen. The rIFN-gamma and the cervine IFN-gamma specific ELISA provide valuable tools with which to study important zoonotic infections in farmed and wild deer.

Influenza hemagglutinin peptides fused to interferon gamma and encapsulated in liposomes protects mice against influenza infection.

The immunogenicity of a peptide vaccine may be improved by fusing antigen to a cytokine and administering this chimeric protein in a particulate delivery system. We have investigated this using a vaccine comprising an immunodominant T cell epitope and a B cell epitope from influenza haemagglutinin (HATB) fused to interferon gamma and encapsulated in liposomes (HATB/IFN-gamma/lipo). Controls comprised groups receiving HATB/IFN-gamma mixed with liposomes, HATB incorporated in liposomes or heat inactivated PR8 influenza virus (HI PR8). IFN-gamma production in mice treated with HATB/IFN-gamma/lipo was significantly higher than in mice inoculated with either HATB/IFN-gamma mixed with liposomes or HATB incorporated in liposomes but less than HI PR8. Lung viral titres were significantly lower in mice treated with HATB/IFN-gamma/lipo compared with those treated with HATB/IFN-gamma mixed with liposomes. HI PR8-treated mice recorded a nil viral titre. There was no correlation between the level of antibody production and clearance of virus from the lungs. These data suggest that particulate delivery systems may be useful adjuncts to improve immune responses to chimeric proteins and to induce protection against disease.

Factors affecting proximal tubular reabsorption during development.

Studies performed in several animal species have demonstrated that glomerulotubular balance is maintained throughout development despite the many changes that occur in the factors known to control it. In an attempt to understand the nature of this phenomenon we quantified the magnitude and described the profile of these changes in guinea pigs. The changes in physical forces were assessed from measurements of hydrostatic and oncotic pressures, whereas those in the permeability characteristics of the proximal tubule epithelium were estimated from permeance to macromolecules of graded radii, histologic measurements of the intercellular channels, and measurements of end-proximal ratio of tubular fluid-to-plasma osmolality (TF/Posm). Between 1 and 50 days of age the net pressure for reabsorption increased from 15.0 to 30.9 mmHg (P less than 0.01, n = 15) with the major change occurring during the first 2-3 wk of postnatal life. The urinary recovery of inulin, sucrose, and creatinine, injected in the early segment of proximal tubules did not vary with age. The urinary recovery of mannitol (MW 180 daltons, Stokes-Einstein radius 4.0 X 10(-10) m) increased from 92% at birth to 100% at 49 days of age (P less than 0.001, n = 24), consistent with a decrease of approximately 0.5 X 10(-10) m in the luminal openings of the paracellular channels. The length of the zonulae occludens and the width of the intercellular channels did not change during this period; however, the length of the channels increased from 5.0 +/- 0.17 to 8.9 +/- 0.48 micron (P less than 0.01, n = 16). These changes should result in an increase in resistance across the intercellular channels. Consistent with this assertion is the observation that the mean TF/Posm of the fluid collected toward the end of the proximal convoluted tubule decreased as a function of age from 1.05 at day 2 to 0.98 at day 80 (P less than 0.001, n = 24). The findings support the hypothesis that during early postnatal life glomerulotubular balance is made possible by a high permeability of the proximal tubule, which compensates for the low net reabsorptive pressure. As the animal matures and the proximal tubule epithelium becomes tighter, for glomerulotubular balance to be maintained, an increase in the number of intercellular channels and in the active transport of sodium need to be postulated.

The cloning, expression and purification of cervine interleukin 2.

The cloning, sequencing and expression of cervine interleukin 2 (IL-2) is described. Cervine IL-2 cDNA is 489 base pairs long and shows high homology to bovine and ovine IL-2 (approximately 94%) with lower homologies to human (50%) and mouse (53%). The predicted protein sequence is 162 amino acids long with a signal sequence containing 20 amino acids. A molecular weight of 16273 Da was predicted for the mature protein. The expression plasmid pTRXFUS was redesigned to allow recombinant proteins to be expressed at high levels in a soluble form and subsequently affinity purified. This new plasmid, pTRXHIS, has been used to express the first cervine cytokine, IL-2. The fusion of the cervine IL-2 gene to the thioredoxin gene (TRX) stabilizes the recombinant product allowing the high expression of soluble IL-2. A polyHis (6 x Histidines) tag has been inserted between the two fusion partners which allows the fusion product to be affinity purified on a nickel-nitrilo-tri-acetic acid (Ni-NTA) column. The purified cervine IL-2 fusion protein was shown to be biologically active despite the presence of the TRX at the amino terminus. The TRX can be removed enzymatically with enterokinase releasing the biologically active IL-2 molecule. This expression system has several features that are useful in producing and purifying large quantities of biologically active cytokines.

Brompheniramine, terfenadine, and placebo in allergic rhinitis.

BACKGROUND: Second-generation antihistamines, reported to lack central nervous system depressant activity, may be considered to have a clinical advantage over traditional antihistamines. OBJECTIVE: To compare the effectiveness, at recommended doses, of an extended-release formulation of nonprescription brompheniramine and prescription terfenadine in the treatment of allergic rhinitis. METHODS: This was a double-blind, randomized, placebo-controlled, multicenter, parallel study. Subjects with symptoms of allergic rhinitis received brompheniramine 12 mg (n = 96), terfenadine 60 mg (n = 96), or placebo (n = 95) twice daily for 14 days. Subjects returned on treatment days 3, 7, and 14; at which times, the investigator assessed symptom severity (i.e., rhinorrhea; sneezing; nasal blockage; pruritus of the eyes, nose, or pharynx; watery eyes; and postnasal drip). The investigator and the subject each completed a global efficacy evaluation, and subjects were interviewed regarding the occurrence of adverse experiences. Symptoms were analyzed as summed severity scores for (1) all symptoms and (2) for the symptom cluster of rhinorrhea, sneezing, and nasal blockage. RESULTS: At all post-baseline evaluations (days 3, 7, and 14), brompheniramine was significantly better (P < or = .05) than terfenadine and placebo for both sets of summed symptom scores and for both global assessments. Terfenadine was significantly better (P < or = .05) than placebo on the physician's global at day 14. Central nervous system-related complaints were the most frequently reported adverse experiences among all three groups; somnolence was reported most frequently by brompheniramine-treated subjects. CONCLUSION: A nonprescription, extended-release formulation of brompheniramine, 12 mg bid, provided significantly better relief of symptomatic allergic rhinitis than terfenadine, 60 mg bid.