Imported rickettsial infections to the United Kingdom, 2015-2020.

OBJECTIVE: The burden of imported rickettsial infection in the UK is not previously described. This retrospective review identifies rickettsial cases diagnosed at the national reference laboratory between 2015 and 2022. METHODS: Samples testing positive for spotted fever group, typhus group, and scrub typhus IgG/IgM on acute and convalescent blood samples, and/or PCR on tissue/blood were categorized as suspected, confirmed or past infection. RESULTS: 220 patients had rickettsioses, and the commonest import was acute spotted fever group infection (61%, 125/205), 54% (62/114) from South Africa. In acute typhus group cases, 60% (40/67) were from Southeast Asia. One patient with Rickettsia typhi bacteremia died. Scrub typhus group infections (5%, 10/205) were exclusively from Asia and the Western Pacific regions. Overall, 43% of confirmed cases (39/91) had not received doxycycline prior to results. CONCLUSIONS: Rickettsial infections are important and under-recognized causes of imported fever in the UK. Thorough history, examination, and timely treatment with doxycycline should be considered if there is suspicion of Rickettsia infection before testing.

Infections in travellers returning to the UK: a retrospective analysis (2015-2020).

BACKGROUND: Every year, many thousands of travellers return to the United Kingdom (UK) from visits to other countries and some will become unwell due to infections acquired abroad. Many imported infections have similar clinical presentations, such as fever and myalgia, so diagnostic testing is an important tool to improve patient management and outcomes. The aim of this study was to examine the demographics, travel history, presenting symptoms and diagnostic outcomes of referrals to the UK's specialist diagnostic Rare & Imported Pathogens Laboratory (RIPL) for the period 2015-2020. METHODS: Anonymised clinical and laboratory data were extracted from RIPL's Laboratory Information Management System and cleaned prior to descriptive analysis of the data. Travel history data were mapped to one of eight world regions, whereas symptom data were categorised into presenting syndromes. Diagnostic data were categorised as either positive, equivocal or negative. RESULTS: During the period 2015-2020, RIPL received 73 951 samples from 53 432 patients suspected of having infections that are rare in the UK. The most common age group for unwell returning travellers was 30-39 years and the most commonly reported travel destination was Southern and SE Asia. Dengue virus was the most diagnosed infection overall, followed by chikungunya, Zika, leptospirosis and spotted fever group Rickettsia. Dengue virus was among the top three most frequent diagnoses for all world regions except Europe and represented 62.5% of all confirmed/probable diagnoses. CONCLUSIONS: None of the top five infections diagnosed by RIPL in travellers are vaccine-preventable, therefore understanding traveller demographics, destination-specific risk factors and encouraging preventative behaviours is the best available strategy to reduce the number of returning travellers who become infected. Prompt referral of acute samples with a detailed travel history, including purpose of travel and activities undertaken as well as dates and destinations can be a valuable tool in designing public health interventions and diagnostic algorithms.

The impact of COVID-19 on burn referrals received via telemedicine.

BACKGROUND: Burn referrals make up a significant proportion of the referrals received by the on-call Plastics surgery team at University Hospital Plymouth (UHP). UHP is a burns facility that takes referrals that are< 10% total body surface area (TBSA) in adults and< 5% in children. Since switching to a telemedicine service in 2018, this has had the benefit of not needing to see the patient face-to-face. It allows for direct advice given over the phone enabling immediate treatment to be administered. In addition it prevents unnecessary referrals. The COVID-19 pandemic has meant that more people are spending time at home and this study aims to see if this has had an impact on the number of referrals received. METHODS: Data was collected retrospectively over 2 years 2019 and 2020 from MDSAS telemedicine service. The outcome of each referral was recorded as advice given, seen in outpatients or patient admitted. The total for each year was calculated and compared. Also recorded was the age of the patient, the referring unit, the type of burn and the TBSA. RESULTS: A 19.3% increase in referrals received during the year of 2020. The most common age group for a burn referral was the 0-5 years age group; the number of referrals increased by 8.4% in this age group in the year of lockdown. Scalds and contact burns remained the highest mechanism of injury. TBSA of 0.5% was the most common TBSA over both years. Over 47% of referrals travelled from over 30 miles away. The majority of referrals were either seen in outpatients or given advice only. Burn referrals were most commonly over-estimated, 23.2% of burn referrals in 2019 and 20.9% in 2020 were over estimated by> 1% TBSA. 5.5% of referrals were under-estimated. CONCLUSION: There was an increase in the number of referrals during COVID-19. Overall there were a very low number of inappropriate referrals. The telemedicine system has impacted positively in time efficiency especially during COVID-19. It has meant that advice can be given without seeing the patient directly leading to both benefits for the patient and the department.

Viable-but-Nonculturable Listeria monocytogenes and Salmonella enterica Serovar Thompson Induced by Chlorine Stress Remain Infectious.

The microbiological safety of fresh produce is monitored almost exclusively by culture-based detection methods. However, bacterial food-borne pathogens are known to enter a viable-but-nonculturable (VBNC) state in response to environmental stresses such as chlorine, which is commonly used for fresh produce decontamination. Here, complete VBNC induction of green fluorescent protein-tagged Listeria monocytogenes and Salmonella enterica serovar Thompson was achieved by exposure to 12 and 3 ppm chlorine, respectively. The pathogens were subjected to chlorine washing following incubation on spinach leaves. Culture data revealed that total viable L. monocytogenes and Salmonella Thompson populations became VBNC by 50 and 100 ppm chlorine, respectively, while enumeration by direct viable counting found that chlorine caused a <1-log reduction in viability. The pathogenicity of chlorine-induced VBNC L. monocytogenes and Salmonella Thompson was assessed by using Caenorhabditis elegans Ingestion of VBNC pathogens by C. elegans resulted in a significant life span reduction (P = 0.0064 and P < 0.0001), and no significant difference between the life span reductions caused by the VBNC and culturable L. monocytogenes treatments was observed. L. monocytogenes was visualized beyond the nematode intestinal lumen, indicating resuscitation and cell invasion. These data emphasize the risk that VBNC food-borne pathogens could pose to public health should they continue to go undetected.IMPORTANCE Many bacteria are known to enter a viable-but-nonculturable (VBNC) state in response to environmental stresses. VBNC cells cannot be detected by standard laboratory culture techniques, presenting a problem for the food industry, which uses these techniques to detect pathogen contaminants. This study found that chlorine, a sanitizer commonly used for fresh produce, induces a VBNC state in the food-borne pathogens Listeria monocytogenes and Salmonella enterica It was also found that chlorine is ineffective at killing total populations of the pathogens. A life span reduction was observed in Caenorhabditis elegans that ingested these VBNC pathogens, with VBNC L. monocytogenes as infectious as its culturable counterpart. These data show that VBNC food-borne pathogens can both be generated and avoid detection by industrial practices while potentially retaining the ability to cause disease.

A simulator-based analysis of engineering treatments for right-hook bicycle crashes at signalized intersections.

A right-hook crash is a crash between a right-turning motor vehicle and an adjacent through-moving bicycle. At signalized intersections, these crashes can occur during any portion of the green interval when conflicting bicycles and vehicles are moving concurrently. The objective of this research was to evaluate the effectiveness of four types of engineering countermeasures - regulatory signage, intersection pavement marking, smaller curb radius, and protected intersection design - at modifying driver behaviors that are known contributing factors in these crashes. This research focused on right-hook crashes that occur during the latter stage of the circular green indication at signalized intersections with a shared right-turn and through lane. Changes in driver performance in response to treatments were measured in a high-fidelity driving simulator. Twenty-eight participants each completed 22 right-turn maneuvers. A partially counterbalanced experimental design exposed drivers to critical scenarios, which had been determined in a previous experiment. For each turn, driver performance measures, including visual attention, crash avoidance, and potential crash severity, were collected. A total of 75 incidents (47 near-collisions and 28 collisions) were observed during the 616 right turns. All treatments had some positive effect on measured driver performance with respect to the right-turn vehicle conflicts. Further work is required to map the magnitude of these changes in driver performance to crash-based outcomes.

Risk Factors of Epstein-Barr Virus Infection Among United States Children: Data From the National Health and Nutrition Examination Survey (NHANES), 2009-2010.

BACKGROUND: Epstein-Barr virus (EBV) has become a common medical condition in adolescents and young children. The objective of this study was to examine the association of low dietary intake and food insecurity with EBV infection. METHODS: Cross-sectional data were analyzed using the National Health and Nutrition Examination Survey 2009-2010 sample population (n = 1550) aged 6 to 15 years. Self-report data on dietary intake and food security were abstracted from data files. The outcome variable was measured using EBV index from the laboratory data. Multivariable logistic regression analysis was used to determine the association between exposure and outcome variables. RESULTS: The prevalence of EBV in this population was 56.4%. In the unadjusted analyses, adolescents who consumed 100% fruit juice (OR = 1.49, 95% CI = 1.09-2.05), beans (OR = 2.35, 95% CI = 1.12-4.94), and red meat (OR = 1.57, 95% CI = 1.09-2.24) daily had statistically significant elevated odds of EBV as compared to adolescents who consumed them monthly. Furthermore, adolescents who sometimes did not get fed a balanced meal and had to rely on low-cost food had statistically significant increased odds of EBV. However, after adjusting for potential confounders the results for both dietary factors and food insecurity were no longer statistically significant. CONCLUSIONS: Certain dietary factors and food insecurity may predispose children to EBV infection.

Fast vaccine design and development based on correlates of protection (COPs).

New and reemerging infectious diseases call for innovative and efficient control strategies of which fast vaccine design and development represent an important element. In emergency situations, when time is limited, identification and use of correlates of protection (COPs) may play a key role as a strategic tool for accelerated vaccine design, testing, and licensure. We propose that general rules for COP-based vaccine design can be extracted from the existing knowledge of protective immune responses against a large spectrum of relevant viral and bacterial pathogens. Herein, we focus on the applicability of this approach by reviewing the established and up-coming COPs for influenza in the context of traditional and a wide array of new vaccine concepts. The lessons learnt from this field may be applied more generally to COP-based accelerated vaccine design for emerging infections.

Comparative effectiveness of telaprevir-based triple therapy in patients with chronic hepatitis C.

OBJECTIVE: To examine the effectiveness and tolerability of triple therapy with pegylated interferon (p-IFN), ribavirin (RBV), and telaprevir in patients with chronic hepatitis C receiving treatment in an academic practice setting and in a more clinically diverse population compared with patients receiving treatment in phase 3 trials. PATIENTS AND METHODS: A prospective database of all patients with viral hepatitis undergoing antiviral therapy from January 1, 2006, to July 1, 2012, was queried to identify treatment-naive and -experienced patients with chronic hepatitis C receiving dual and triple therapies. On-treatment response categories included rapid virologic response, extended rapid virologic response, early virologic response, and sustained virologic response. These patients were compared with matched controls, namely, patients who underwent dual therapy with p-IFN and RBV. Matching was performed for age, cirrhosis status, and prior treatment. RESULTS: There were 55 patients who received triple therapy and met the eligibility criteria, consisting of treatment-naive (n=35) and -experienced patients (n=20: those with relapse, 9; those with nonresponse, 9; and those who terminated the treatment early, 2). Rapid virologic response was achieved in 41% of the patients, extended rapid virologic response in 41%, and early virologic response in 75%. Sustained virologic response was observed in 51% (18/35) of treatment-naive patients, 67% (6/9) of the patients with prior nonresponse, and 56% (5/9) of those with prior relapse. Corresponding results after dual therapy were 37% (23/62), 11% (2/18), and 27% (3/11), respectively. The mean decrease in the hemoglobin level at weeks 4, 8, and 24 of triple therapy was 2.8, 3.8, and 3.2 mg/dL compared with 2.4, 2.6, and 2.4 mg/dL with dual therapy (to convert mg/dL to mmol/L, multiply values by 0.0259). CONCLUSION: Telaprevir-based triple therapy in clinical practice is considerably more effective than dual therapy with p-IFN and RBV despite the significant degree of anemia that complicated therapy, requiring RBV dose reduction and erythropoietin support.

Visualizing form and function in organotypic slices of the adult mouse parotid gland.

An organotypic slice preparation of the adult mouse parotid salivary gland amenable to a variety of optical assessments of fluid and protein secretion dynamics is described. The semi-intact preparation rendered without the use of enzymatic treatment permitted live-cell imaging and multiphoton analysis of cellular and supracellular signals. Toward this end we demonstrated that the parotid slice is a significant addition to the repertoire of tools available to investigators to probe exocrine structure and function since there is currently no cell culture system that fully recapitulates parotid acinar cell biology. Importantly, we show that a subpopulation of the acinar cells of parotid slices can be maintained in short-term culture and retain their morphology and function for up to 2 days. This in vitro model system is a significant step forward compared with enzymatically dispersed acini that rapidly lose their morphological and functional characteristics over several hours, and it was shown to be long enough for the expression and trafficking of exogenous protein following adenoviral infection. This system is compatible with a variety of genetic and physiological approaches used to study secretory function.

Mucocutaneous ulcerations secondary to methotrexate.

Although methotrexate (MTX) is used in several medical specialties including dermatology, rheumatology, and oncology, drug-induced mucocutaneous ulcerations rarely are reported. We present a 36-year-old woman with plaque psoriasis and psoriatic arthritis being treated with oral MTX (12.5 mg weekly) and oral methoxsalen plus UVA. Following an increase in MTX dose, she developed erosions and ulcerations on her oral mucosa and within her psoriatic plaques. All erosions and ulcerations healed within 2 weeks upon discontinuation of MTX.

Grenz ray therapy in the new millennium: still a valid treatment option?

Grenz ray therapy has declined in the United States during the past several decades with respect to availability, use, and resident training. However, it remains a simple, affordable, and effective option for managing several refractory dermatoses, especially psoriasis, hand eczema, and allergic contact dermatitis. Though high-dose grenz irradiation has been associated with the development of nonmelanoma skin cancers, grenz ray therapy is considered a safe treatment modality when administered according to the guidelines recommended herein. We review the value of grenz irradiation in contemporary dermatology.

Postoperative gait velocity and mean knee flexion in stance of ambulatory children with spastic diplegia four years or more after multilevel surgery.

Factors associated with longer-term outcomes of multilevel orthopaedic surgery in ambulatory children with cerebral palsy using a multivariate approach were evaluated using a retrospective pretest-posttest design. The population included 20 ambulatory children with spastic diplegia who had undergone multilevel orthopaedic surgery with a minimum of 4-year interval between a preoperative and a postoperative gait assessment. Multiple regression analysis was used to identify factors associated with postoperative velocity and mean knee flexion in stance. Independent variables included in the regression models were velocity, mean knee flexion in stance, age at preoperative evaluation, Gross Motor Function Classification System level, use of ankle-foot orthoses, leg length, age-adjusted body mass index, number of surgical procedures, and range of motion of hip and knee. Children who demonstrated faster postoperative gait velocity 4 years or more after surgery were younger at the time of initial evaluation, had undergone fewer surgical procedures, had faster preoperative gait velocity, used ankle-foot orthoses postoperatively, and had increased hip extension range of motion postoperatively (R = 0.55). Children who demonstrated greater knee flexion in stance 4 years or more after surgery had undergone more surgical procedures, greater postoperative popliteal angle, and less knee extension range of motion (R = 0.73). This study demonstrates the usefulness of a multivariate approach toward understanding and predicting outcomes. The results of this study will provide clinicians and researchers more information about those factors associated with maintained improvements in the longer term and may be useful for treatment planning.

Synergism of rheolytic thrombectomy and embolic distal protection using the percusurge guard wire for fresh thrombus removal: an in vitro study.

OBJECTIVES: To test the effectiveness of Rheolytic Thrombectomy (RT) and distal protection balloon wires when used synergistically in an in vitro model. BACKGROUND: Although effective, currently available technologies may not be individually ideal for fresh clots removal. METHODS: Fourteen, fresh blood samples were placed in 14 plastic tubes and left to clot for 6 h. A Percusurge Guardwire balloon was inflated distal to the clot and aspiration was performed using RT in seven tubes and manual aspiration (MA) with the Export catheter in seven tubes. The residual clot in each tube was dried and weighed. Both aspiration systems were advanced over the Guardwire. RESULTS: During RT, none of the protection balloons ruptured and no retrograde clot embolization were observed. MA was most effective when the Export catheter tip was not in direct contact with the clot. The residual clot mass post RT was significantly less than post MA (9.7+/-2.2 versus 59.2+/-45.9, P = 0.01). CONCLUSION: RT is compatible with Distal Protection Balloon Wires and results in more complete clot removal than manual aspiration with the export catheter. Although manual aspiration results in a large variation in extraction efficacy, it is most effective when direct catheter-clot contact is kept to a minimum.

Spatiotemporal analysis of exocytosis in mouse parotid acinar cells.

Exocrine cells of the digestive system are specialized to secrete protein and fluid in response to neuronal and/or hormonal input. Although morphologically similar, parotid and pancreatic acinar cells exhibit important functional divergence in Ca(2+) signaling properties. To address whether there are fundamental differences in exocytotic release of digestive enzyme from exocrine cells of salivary gland versus pancreas, we applied electrophysiological and optical methods to investigate spatial and temporal characteristics of zymogen-containing secretory granule fusion at the single-acinar cell level by direct or agonist-induced Ca(2+) and cAMP elevation. Temporally resolved membrane capacitance measurements revealed that two apparent phases of exocytosis were induced by Ca(2+) elevation: a rapidly activated initial phase that could not be resolved as individual fusion events and a second phase that was activated after a delay, increased in a staircaselike fashion, was augmented by cAMP elevation, and likely reflected both sequential compound and multivesicular fusion of zymogen-containing granules. Optical measurements of exocytosis with time-differential imaging analysis revealed that zymogen granule fusion was induced after a minimum delay of approximately 200 ms, occurred initially at apical and basolateral borders of acinar cells, and under strong stimulation proceeded from apical pole to deeper regions of the cell interior. Zymogen granule fusions appeared to coordinate subsequent fusions and produced persistent structures that generally lasted several minutes. In addition, parotid gland slices were used to assess secretory dynamics in a more physiological context. Parotid acinar cells were shown to exhibit both similar and divergent properties compared with the better-studied pancreatic acinar cell regarding spatial organization and kinetics of exocytotic fusion of zymogen granules.

Concepts of human leukemic development.

Two fundamental problems in cancer research are identification of the normal cell within which cancer initiates and identification of the cell type capable of sustaining the growth of the neoplastic clone. There is overwhelming evidence that virtually all cancers are clonal and represent the progeny of a single cell. What is less clear for most cancers is which cells within the tumor clone possess tumorigenic or 'cancer stem cell' (CSC) properties and are capable of maintaining tumor growth. The concept that only a subpopulation of rare CSC is responsible for maintenance of the neoplasm emerged nearly 50 years ago. Testing of this hypothesis is most advanced for the hematopoietic system due to the establishment of functional in vitro and in vivo assays for stem and progenitor cells at all stages of development. This body of work led to conclusive proof for CSC with the identification and purification of leukemic stem cells capable of repopulating NOD/SCID mice. This review will focus on the historical development of the CSC hypothesis, the mechanisms necessary to subvert normal developmental programs, and the identification of the cell in which these leukemogenic events first occur.

A pilot open-label trial of citalopram for restless activity and aberrant motor behaviors in Alzheimer disease.

OBJECTIVE: In a prospective, open-label pilot study in probable-Alzheimer disease (AD) outpatients, the authors investigated the efficacy of citalopram to reduce restless activity and aberrant motor behaviors. METHODS: Nineteen subjects were evaluated with Neuropsychiatric Inventory subscale and total scores. RESULTS: There was a significant decline in aberrant motor behaviors and overall behavior problems at 4, 8, and 12 weeks. CONCLUSION: This study provides initial evidence that citalopram may be effective in reducing aberrant motor behaviors in AD. However, because of the potential biases of an open-label study, these findings need to be confirmed in a larger, controlled trial.