Childhood immunization appointment reminders and recalls: strengths, weaknesses and opportunities to increase vaccine coverage.

OBJECTIVES: Childhood immunization coverage has been shown to be greatly impacted by parental forgetfulness regarding immunizations and appointments. Evidence supports the use of reminders and recalls to overcome this barrier, which remind parents about upcoming immunization appointments and inform them once their child is overdue for an immunization. In this study, we sought to identify reminder/recall strategies used throughout a large Canadian province and determine the perceived strengths, weaknesses and areas of improvement of existing strategies. STUDY DESIGN AND METHODS: An environmental scan was performed in 2018 in two phases: (1) interviews with public health leaders from the five zones of Alberta and (2) an online survey of public health centres across the province. Data analysis occurred in 2018 and 2019. RESULTS: Commonly reported strengths of reminders and recalls included their ability to increase appointment attendance and remind parents about immunizations, respectively. A major identified weakness was their time-consuming/resource-intensive nature. Many participants believed reminder/recalls could be improved by modernizing delivery methods. Educational information or strategies to overcome language barriers were rarely incorporated into reminder/recall systems. CONCLUSIONS: There was support for incorporating text messaging and automation into reminder/recall systems while encouraging continued exploration of novel reminder/recall delivery methods. Tailoring reminder/recalls to the needs and preferences of target populations can maximize the effectiveness of these systems. This includes modernizing methods of delivery, addressing language barriers, providing educational information, and allotting some degree of flexibility to local level management of reminder/recalls.

The multi-faceted dynamics of HIV-1 transmission in Northern Alberta: A combined analysis of virus genetic and public health data.

Molecular epidemiology has become a key tool for tracking infectious disease epidemics. Here, the spread of the most prevalent HIV-1 subtypes in Northern Alberta, Canada, was characterized with a Bayesian phylogenetic approach using 1146 HIV-1 pol sequences collected between 2007 and 2013 for routine clinical management purposes. Available patient metadata were qualitatively interpreted and correlated with onwards transmission using Fisher exact tests and logistic regression. Most infections were from subtypes A (n=36), B (n=815) and C (n=211). Africa is the dominant origin location for subtypes A and C while the subtype B epidemic was seeded from the USA and Middle America and, from the early 1990s onwards, mostly by interprovincial spread. Subtypes A (77.8%) and C (74.0%) were usually heterosexually transmitted and circulate predominantly among Blacks (61.1% and 85% respectively). Subtype B was mostly found among Caucasians (48.6%) and First Nations (36.8%), and its modes of transmission were stratified by ethnic origin. Compared to subtypes A (5.6%) and C (3.8-10.0%), a larger portion of subtype B patients were found within putative provincial transmission networks (20.3-29.5%), and this almost doubled when focusing on nationwide transmission clusters (37.9-57.5%). No clear association between cluster membership and particular patient characteristics was found. This study reveals complex and multi-faceted transmission dynamics of the HIV-1 epidemic in this otherwise low HIV prevalence population in Northern Alberta, Canada. These findings can aid public health planning.

Hepatitis A virus infection associated with cannabis use.

We identified a case of acute Hepatitis A virus (HAV) infection linked to cannabis use. The local Public Health department received report of a man in his mid-20s with a classic presentation of hepatitis - jaundice, abdominal pain, vomiting, general malaise, and dark urine - as well as elevated serum aminotransferase levels and a positive anti-HAV IgM. Upon questioning, he reported no contact with ill individuals, or travel outside his metropolitan area. His exclusive source of water was the local municipal supply. He reported consuming mainly pre-packaged lower risk foods from large chain-style supermarket stores and eating at several local restaurants. While administering the questionnaire, the investigator identified that the patient smoked cannabis. Upon request, the patient agreed to provide a sample of cannabis for testing purposes. A viral elution of fresh cannabis leaves was completed. The sequences derived from the patient's serum sample and the eluate from the cannabis leaves were identical, but did not match any other HAV sub-genotype 1B sequences from Canadian isolates within the National Microbiology Laboratory database. Hepatitis A virus can survive >60 days when dried and kept at room temperature and low humidity; HAV can remain infectious in water at room temperature for 300 days. It cannot be concluded with certainty that the cannabis was the source of the hepatitis A; however, as other sources were excluded, or were of lesser probability, the association of cannabis with his disease acquisition remains strong.

Q fever in Alberta, Canada: 1998-2011.

Establishing the diagnosis of Q fever (Coxiella burnetii) is important in directing the application of therapy to prevent severe manifestations of the infection. In Alberta, Canada, the presence of high livestock density creates a significant risk of infection, but to date, there has been no comprehensive analysis of local Q fever epidemiological trends and exposure patterns. Between 1998 and 2011, there were 39 cases and an overall adjusted case rate of 0.087 per 100 000 person-years. Cases were identified most commonly during the May-June season (Figure 2). The median age at date of diagnosis was 49.0 (range: 8.7-71.5) with slightly higher percentage of cases in men (56.4%) than in women (43.6%). There was an apparent geographical clustering of cases. The majority of these cases, with exposure data (n = 31), reported contact with farms and/or livestock, predominantly cattle (6), sheep (5) and goats (5). Cases tended to occur in census divisions with higher density of sheep, goats and cattle. Our findings suggest the need for an increase in targeted messages about Q fever to those in the livestock industry, as more targeted case finding among patients with a high index of suspicion for Q fever. In addition, widespread implementation of a standard questionnaire for cases would enhance surveillance of Q fever in Alberta.

[The tolerability of nasal drugs with special regard to preservatives and physico-chemical parameters]. / Die Verträglichkeit von Nasalia unter besonderer Berücksichtigung des Einflusses von Konservierungsmitteln und physikalisch-chemischen Parametern.

BACKGROUND: Recent technical developments allow preservative-free nasal drug application in multi-dose systems. New pharmaceutical formulations for better tolerable nasal sprays are now possible and consequently reformulations introduced to the market. Therefore, a representative and systematic overview on comparable products is mandatory. METHODS: Marketed nasal products in the indication groups: decongestants, antiallergics, care and wound-healing, hormones and saline solutions were tested for their cytotoxic properties according to DIN EN 30 993 - 5, pH, and osmolality. RESULTS: In all indication groups reformulation to preservative-free application resulted in significant increase of cell growth and reduction of cytotoxicity. Physico-chemical galenic properties are of considerable importance too. With decongestants tolerability is dependant on the concentration of the active compound. CONCLUSIONS: Our data lead to the conclusion that preserved nasal sprays are obsolete, when preservative-free alternatives are available. Attention should be paid to galenic properties and dosage of the active.

Manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) administration protects mice from esophagitis associated with fractionated radiation.

Intraesophageal administration of manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) prior to single fraction radiation has been shown to protect mice from lethal esophagitis. In our study, C3H/HeNsd mice received fractionated radiation in two protocols: (i) 18 Gy daily for four days with MnSOD-PL administration 24 hr prior to the first and third fraction, or (ii) 12 Gy daily for six days with MnSOD-PL 24 hr prior to the first, third, and fifth fraction. Control radiated mice received either no liposomes only or LacZ (bacterial beta-galactosidase gene)-plasmid/liposome (LacZ-PL) by the same schedules. We measured thiol depletion and lipid peroxidation (LP) in whole esophagus and tested the effectiveness of a new plasmid, hemagglutinin (HA) epitope-tagged MnSOD (HA-MnSOD). In fractionation protocols, mice receiving MnSOD-PL, but not LacZ-PL (200 microl of plasmid/liposomes containing 200 microg of plasmid DNA), showed a significant reduction in morbidity, decreased weight loss, and improved survival. Four and seven days after 37 Gy single fraction radiation, the esophagus demonstrated a significant increase in peroxidized lipids and reduction in overall antioxidant levels, reduced thiols, and decreased glutathione (GSH). These reductions were modulated by MnSOD-PL administration. The HA-MnSOD plasmid product was detected in the basal layers of the esophageal epithelium 24 hr after administration and provided significant radiation protection compared to glutathione peroxidase-plasmid/liposome (GPX-PL), or liposomes containing MnSOD protein, vitamin E, co-enzyme Q10, or 21-aminosteroid. Thus, MnSOD-PL administration significantly improved tolerance to fractionated radiation and modulated radiation effects on levels of GSH and lipid peroxidation (LP). These studies provide further support for translation of MnSOD-PL treatment into human esophageal radiation protection.

Modulation of radiation-induced cytokine elevation associated with esophagitis and esophageal stricture by manganese superoxide dismutase-plasmid/liposome (SOD2-PL) gene therapy.

Radiation of the esophagus of C3H/HeNsd mice with 35 or 37 Gy of 6 MV X rays induces significantly increased RNA transcription for interleukin 1 (Il1), tumor necrosis factor alpha (Tnf), interferon gamma inducing factor (Ifngr), and interferon gamma (Ifng). These elevations are associated with DNA damage that is detectable by a comet assay of explanted esophageal cells, apoptosis of the esophageal basal lining layer cells in situ, and micro-ulceration leading to dehydration and death. The histopathology and time sequence of events are comparable to the esophagitis in humans that is associated with chemoradiotherapy of non-small cell lung carcinoma (NSCLC). Intraesophageal injection of clinical-grade manganese superoxide dismutase-plasmid/liposome (SOD2-PL) 24 h prior to irradiation produced an increase in SOD2 biochemical activity in explanted esophagus. An equivalent therapeutic plasmid weight of 10 microgram ALP plasmid in the same 500 microliter of liposomes, correlated to around 52-60% of alkaline phosphatase-positive cells in the squamous layer of the esophagus at 24 h. Administration of SOD2-PL prior to irradiation mediated a significant decrease in induction of cytokine mRNA by radiation and decreased apoptosis of squamous lining cells, micro-ulceration, and esophagitis. Groups of mice receiving 35 or 37 Gy esophageal irradiation by a technique protecting the lungs and treating only the central mediastinal area were followed to assess the long-term effects of radiation. SOD2-PL-treated irradiated mice demonstrated a significant decrease in esophageal wall thickness at day 100 compared to irradiated controls. Mice with orthotopic thoracic tumors composed of 32D-v-abl cells that received intraesophageal SOD2-PL treatment showed transgenic mRNA in the esophagus at 24 h, but no detectable human SOD2 transgene mRNA in explanted tumors by nested RT-PCR. These data provide support for translation of this strategy of SOD2-PL gene therapy to studies leading to a clinical trial in fractionated irradiation to decrease the acute and chronic side effects of radiation-induced damage to the esophagus.

Plasmid/liposome transfer of the human manganese superoxide dismutase transgene prevents ionizing irradiation-induced apoptosis in human esophagus organ explant culture.

Esophagitis is a major limiting factor in the treatment of lung cancer by radiation alone or in combination with chemotherapy. We have previously demonstrated that intraesophageal injection of manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) complex into C3H/HeNsd mice blocks irradiation-induced esophagitis. To determine whether the human esophagus can be similarly transfected, normal human esophageal sections obtained from the margins of esophagectomy specimens from esophageal cancer patients were transfected in vitro with alkaline phosphatase (AlkP)-PL complex and stained for AlkP activity, and the percent of cells expressing AlkP was calculated. At 24 hr after transfection with 20 or 200 microgram of AlkP-PL complex, 55.0% and 85.8% of esophageal epithelial cells expressed detectable AlkP, respectively. Other sections transfected with MnSOD-PL complex showed transgene mRNA by nested reverse transcriptase-polymerase chain reaction (RT-PCR) assay and increased MnSOD biochemical activity for at least 96 hr after transfection. Irradiated MnSOD-PL complex-transfected sections demonstrated a significantly decreased percentage of apoptotic cells when compared to irradiated control sections. Following 1,000 cGy, MnSOD-PL-treated samples showed 7.5 +/- 2.8% and 33.3 +/- 7.3% apoptotic cells at 24 and 48 hr compared to 53.6 +/- 6.9% and 59.0 +/- 13.8% for nontransfected controls (P < 0.0001 and P < 0.1175). After 2,000 cGy, results at 24 and 48 hr were 25.0 +/- 7.6% and 66.9 +/- 4.9% for MnSOD-transfected sections compared to 65.6 +/- 4.3% and 90.0 +/- 4.1% for control sections (P < 0.0001 and P = 0.0353), respectively. Thus, human esophageal sections can be transfected with MnSOD-PL complex in vitro and thereby protected against ionizing irradiation-induced apoptosis. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 128-137 (2000).

Intratracheal injection of manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation.

To determine whether intratracheal (IT) lung protective manganese superoxide-plasmid/liposomes (MnSOD-PL) complex provided 'bystander' protection of thoracic tumors, mice with orthotopic Lewis lung carcinoma-bacterial beta-galactosidase gene (3LL-LacZ) were studied. There was no significant difference in irradiation survival of 3LL-LacZ cells irradiated, then cocultured with MnSOD-PL-treated compared with control lung cells (D0 2.022 and 2.153, respectively), or when irradiation was delivered 24 h after coculture (D0 0.934 and 0.907, respectively). Tumor-bearing control mice showed 50% survival at 18 days and 10% survival at 21 days. Mice receiving liposomes with no insert or LacZ-PL complex plus 18 Gy had 50% survival at 22 days, and a 20% and 30% survival at day 50, respectively. Mice receiving MnSOD-PL complex followed by 18 Gy showed prolonged survival of 45% at 50 days after irradiation (P < 0.001). Nested RT-PCR assay for the human MnSOD transgene demonstrated expression at 24 h in normal lung, but not in orthotopic tumors. Decreased irradiation induction of TGF-beta1, TGF-beta2, TGF-beta3, MIF, TNF-alpha, and IL-1 at 24 h was detected in lungs, but not orthotopic tumors from MnSOD-PL-injected mice (P < 0.001). Thus, pulmonary radioprotective MnSOD-PL therapy does not provide detectable 'bystander' protection to thoracic tumors.

Manganese [correction of Magnesium] superoxide dismutase (MnSOD) plasmid/liposome pulmonary radioprotective gene therapy: modulation of irradiation-induced mRNA for IL-I, TNF-alpha, and TGF-beta correlates with delay of organizing alveolitis/fibrosis.

Radiation pneumonitis remains a critical dose-limiting toxicity of total body irradiation (TBI) for use in bone marrow transplantation. The acute and chronic phases of radiation damage in the mouse lung have been shown to correlate with mouse strain genotype and are dependent on fraction size, total dose, and total lung volume. Our prior studies demonstrated effective prevention of irradiation-induced lung damage and improved survival in C57BL/6J mice by MnSOD plasmid/liposome gene therapy. In the present studies, we investigated the kinetics of irradiation-induced upregulation of mRNA for acute phase cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, and fibrosis-associated transforming growth factor (TGF)-beta and isoforms (TGF-beta1, TGF-beta2 and TGF-beta3) in 2000 cGy whole-lung irradiated C57BL/6J mice, a strain known to develop dose and volume-dependent organizing alveolitis/fibrosis. The results demonstrate increase in mRNA for IL-1 between days 1 and 14 after irradiation with return to baseline levels out to 120 days. TNF-alpha mRNA levels were not initially elevated but increased between 80 and 100 days and then decreased by 120 days. The mRNA levels for TGF-beta1 demonstrated an initial increase within the first 14 days after total lung irradiation with a decrease to baseline levels out to 100 days. Then, in striking contrast to the other two cytokines, an increase in TGF-beta2 mRNA occurred at around 120 days and correlated with the detection of organizing alveolitis/radiation fibrosis and mortality. These results are consistent with a two-phase mechanism in the molecular pathology of irradiation lung injury, in which IL-1 cytokine mRNA levels correlated with the acute pneumonitis phase and delayed elevation of TNF-alpha (80-100 days), TGF-beta1 (100 days), and TGF-beta2 (120 days) were associated with the fibrosis phase. Insight into the cell-specific and tissue-specific molecular mechanisms of ionizing irradiation induction of mRNA for pulmonary cytokines may provide new strategies for treatment of radiation pneumonitis in TBI patients.

A prospective, randomized, controlled evaluation of peripheral nerve stimulation versus standard clinical dosing of neuromuscular blocking agents in critically ill patients.

OBJECTIVES: To determine if vecuronium doses individualized by peripheral nerve stimulation are lower than those doses chosen by standard clinical techniques; and to determine whether patients monitored by peripheral nerve stimulation exhibit shorter recovery times and less prolonged neuromuscular blockade after discontinuation of vecuronium than control patients. DESIGN: A prospective, randomized, controlled, single-blind trial. SETTING: Two ten-bed medical intensive care units of a 937-bed tertiary care, not-for-profit, teaching hospital and health system. PATIENTS: Mechanically ventilated patients requiring continuous neuromuscular blockade as part of their therapy. INTERVENTIONS: After obtaining written, informed consent and baseline neurologic examinations, patients were randomized to treatment, where dosing was individualized by peripheral nerve stimulation or standard clinical assessment. Doses in the peripheral nerve stimulation group were adjusted to 90% blockade (Train-of-Four of 1/4). The standard clinical dosing group received doses individualized to clinical response by the medical team (blinded to Train-of-Four). Differences between groups were evaluated by Wilcoxon matched-pairs signed rank test. MEASUREMENTS AND MAIN RESULTS: A total of 77 patients (35 standard clinical patients vs. 42 peripheral nerve stimulation patients) were enrolled in the study. Despite no difference in initial doses and time to reach 90% blockade or clinical response between groups, the peripheral nerve stimulation group used less drug than the standard clinical group (0.040 +/- 0.028 vs. 0.070 +/- 0.030 mg/kg/hr, respectively, p = .001). The total cumulative amount of vecuronium for the episode of paralysis was greater in the control group (285.8 +/- 246.6 vs. 137.1 +/- 106.4 mg, p = .001). The peripheral nerve stimulation group recovered neuromuscular function (relative risk of 1.85, with 95% confidence interval [CI] of 1.02-3.35, p = .039) and spontaneous ventilation (relative risk of 1.86, 95% CI 1.00-3.45, p = .047) faster than the control group. In patients, adjusting for renal dysfunction, the likelihood of a faster recovery in the peripheral nerve stimulation group increased for neuromuscular function (relative risk of 1.89, 95% CI of 1.07-3.32, p = .018) and spontaneous ventilation (relative risk of 2.27, 95% CI of 1.23-4.21, p = .019). Patients with combined renal and liver failure similarly demonstrated a faster recovery in the peripheral nerve stimulation group. The recovery was affected to a lesser extent by adjusting for concurrent aminoglycoside and corticosteroid administration. CONCLUSIONS: Use of peripheral nerve stimulation for monitoring the degree of blockade and adjusting drug doses in continuously paralyzed critically ill medical patients results in lower doses of vecuronium to maintain a desired depth of paralysis, and allows a faster recovery of neuromuscular function and spontaneous ventilation.

Compensatory growth in fibrotic lung injury.

We induced severe left-sided lung fibrosis by the unilateral endobronchial instillation of paraquat (1.0 mg/kg) into the left lungs of adult Fischer 344 male rats. Growth of the contralateral lung as well as its proliferative activity were measured 6 or 14 days later. Whereas the left lung underwent severe fibrosis and shrinkage with more than 85% reduction in lung volume, the right lung more than doubled in size. In addition, there was a significant increase in total protein content, DNA content, and DNA synthesis. We conclude that unilateral lung injury resulting in ipsilateral fibrosis and loss of parenchyma is associated with compensatory growth of the contralateral lung.