Ageing-associated changes in transcriptional elongation influence longevity.

Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1-4. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions, dietary restriction and lowered insulin-IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms5 and flies6 increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures.

Digital phantom versus patient-specific radiation dosimetry in adult routine thorax CT examinations.

PURPOSE: The aim of this study was to compare the organ doses assessed through a digital phantom-based and a patient specific-based dosimetric tool in adult routine thorax computed tomography (CT) examinations with reference to physical dose measurements performed in anthropomorphic phantoms. METHODS: Two Monte Carlo based dose calculation tools were used to assess organ doses in routine adult thorax CT examinations. These were a digital phantom-based dosimetry tool (NCICT, National Cancer Institute, USA) and a patient-specific individualized dosimetry tool (ImpactMC, CT Imaging GmbH, Germany). Digital phantoms and patients were classified in four groups according to their water equivalent diameter (Dw). Normalized to volume computed tomography dose index (CTDIvol), organ dose was assessed for lungs, esophagus, heart, breast, active bone marrow, and skin. Organ doses were compared to measurements performed using thermoluminescent detectors (TLDs) in two physical anthropomorphic phantoms that simulate the average adult individual as a male (Alderson Research Labs, USA) and as a female (ATOM Phantoms, USA). RESULTS: The average percent difference of NCICT to TLD and ImpactMC to TLD dose measurements across all organs in both sexes was 13% and 6%, respectively. The average ± 1 standard deviation in dose values across all organs with NCICT, ImpactMC, and TLDs was ± 0.06 (mGy/mGy), ± 0.19 (mGy/mGy), and ± 0.13 (mGy/mGy), respectively. Organ doses decreased with increasing Dw in both NCICT and ImpactMC. CONCLUSION: Organ doses estimated with ImpactMC were in closer agreement to TLDs compared to NCICT. This may be attributed to the inherent property of ImpactMC methodology to generate phantoms that resemble the realistic anatomy of the examined patient as opposed to NCICT methodology that incorporates an anatomical discrepancy between phantoms and patients.

A Multi-Modal Egocentric Activity Recognition Approach towards Video Domain Generalization.

Egocentric activity recognition is a prominent computer vision task that is based on the use of wearable cameras. Since egocentric videos are captured through the perspective of the person wearing the camera, her/his body motions severely complicate the video content, imposing several challenges. In this work we propose a novel approach for domain-generalized egocentric human activity recognition. Typical approaches use a large amount of training data, aiming to cover all possible variants of each action. Moreover, several recent approaches have attempted to handle discrepancies between domains with a variety of costly and mostly unsupervised domain adaptation methods. In our approach we show that through simple manipulation of available source domain data and with minor involvement from the target domain, we are able to produce robust models, able to adequately predict human activity in egocentric video sequences. To this end, we introduce a novel three-stream deep neural network architecture combining elements of vision transformers and residual neural networks which are trained using multi-modal data. We evaluate the proposed approach using a challenging, egocentric video dataset and demonstrate its superiority over recent, state-of-the-art research works.

The effect of added filtration on radiation dose and image quality in digital radiography of newborns.

BACKGROUND: Repeated chest and/or abdomen radiographs are needed on mobile digital radiography (DR) units to assess infants' health status. Optimization of DR tube peak kilovoltage (kVp) and tube current time product (mAs) to derive images of diagnostic quality at as low as reasonably achievable radiation dose has been a challenging task. OBJECTIVE: To investigate the effect of exposure parameters and additional filtration on entrance skin dose and image quality in newborn DR imaging. MATERIALS AND METHODS: A physical anthropomorphic phantom that simulates the average full-term neonate was used. Chest and chest/abdomen DR images were acquired at the manufacturer's recommended kVp/mAs exposure parameters followed by a series of image acquisitions at different kVp/mAs and beam filtration combinations. Entrance skin dose (ESD) and signal difference to noise ratio (SdNR) for soft tissue, bone and feeding gastric tube were estimated in raw unprocessed images. A figure of merit (FOM) analysis provided the kVp/mAs and filtration that generated images of adequate quality at the lowest ESD. RESULTS: Signal difference increased with kVp and progressively decreased with increasing filtration. Compared to the manufacturer's recommended 53 kVp/1.6 mAs exposure parameters, ESD was reduced by 76% (47.61 µGy versus 11.3 µGy) in the chest and 66% (47.61 µGy versus 16.14 µGy) in the chest/abdomen when the exposure parameters and additional beam filtration provided by the FOM analysis were used. CONCLUSION: The results derived from this phantom study suggest that additional beam filtration along with the appropriate leverage of exposure parameters can lower ESD while maintaining image quality in full-term newborns.

Implementation and evaluation of the AAPM TG 111 for radiation dosimetry in a state-of-the-art C-arm cone beam CT system.

The aim of this study was to assess the dosimetric characteristics of a state-of-the-art C-arm cone beam computed tomography (CBCT) system using the methodology proposed by the American Association of Physicists in Medicine (AAPM) Task Group (TG) 111. The dose measurement methodology described in AAPM TG 111 for wide cone beam acquisitions without table translation was employed to estimate equilibrium beam length (αeq‾) and equilibrium dose (feq‾) in various interventional task-specific protocols with different tube arc projection geometries. Dose profiles were derived from point dose measurements in the centre and peripheral locations of the ICRU/AAPM and standard polymethyl methacrylate (PMMA) body phantom. Dose measurements were performed in phantom and free-in-air using a solid-state point detector. Monte Carlo (MC) based simulation dosimetry was performed to quantify the inhomogeneous dose patterns imparted in the phantoms. Estimatedαeq‾andfeq‾on the ICRU/AAPM phantom was up to 49.4 cm and 6.17 mGy/100 mAs, respectively. Corresponding values determined on the PMMA phantom were 139 cm and 8.8 mGy/100 mAs, respectively. Free-in-air dose measurement ranged from 1.43 mGy/100 mAs to 5.93 mGy/100 mAs. Per cent difference inαeq‾andfeq‾between MC simulation and solid-state point detector measurement methods in the ICRU/AAPM phantom were within 16% and 18%, respectively. Manufacturers can use the presented methodology to characterize the dosimetric properties of C-arm CBCT systems. Clinical medical physicists may follow this methodology to verify corresponding data provided by the manufacturer and check for C-arm CBCT system performance dosimetric consistency.

Organ doses and normalized organ doses for various age groups in ultralow dose pediatric C-arm cone-beam CT.

OBJECTIVES: To estimate organ dose to major radiosensitive organs during pediatric body C-arm CBCT and determine normalized organ doses using a state-of-the-art equipment. METHODS: This is a study performed utilizing physical anthropomorphic phantoms. Four anthropomorphic phantoms that simulate the average individual as a neonate, 1-year-old, 5-year-old, and 10-year-old child were used. Personalized Monte Carlo (MC)-based dosimetry was performed to estimate organ doses in children referred to thorax and abdomen C-arm CBCT acquisitions on a recently released latest generation C-arm CBCT system. Age-specific normalized organ doses were generated and organ dose was estimated for skin, bone, breast, lungs, esophagus, thymus, and heart, in the thorax, and liver, adrenals, kidneys, pancreas, stomach, gall bladder, and spleen in the abdomen. Estimated doses were compared to corresponding values obtained with physical measurements performed using thermoluminescent dosimeters (TLD). RESULTS: The results consist of organ doses for thorax and abdomen acquisition protocols. The majority of organs received a dose below 1 mSv. For all ages, the normalized organ doses decreased from neonate to 10-year-old. The difference between the organ doses obtained with MC and TLDs was less than 8%. CONCLUSIONS: Normalized organ doses in pediatric C-arm CBCT varied with age. Pediatric C-arm CBCT with latest-generation systems may be performed with sub mGy dose for most organs. KEY POINTS: • The dose to the majority of organs from pediatric C-arm CBCT is in the sub mSv level. • The normalized organ doses decreased from neonate to 10-year-old. • Reported normalized organ doses may be used to estimate organ dose in pediatric C-arm cone-beam CT on modern equipment.

Dual-Energy Computed Tomography as an Adjunct in the Evaluation of Peripheral Chronic Total Occlusions: A Feasibility Study.

This study investigated the role of dual-energy computed tomography (CT) for lesion characterization in patients with peripheral arterial disease manifesting with chronic total occlusions (CTOs). Forty-one symptomatic patients with CTOs underwent dual-energy CT angiography before endovascular treatment. The lesions were subsequently analyzed in a dedicated workstation, and 2 indexes-dual-energy index (DEI) and effective Z (Zeff)-were calculated, ranging from 0.0027 to 0.321 and from 6.89 to 13.02, respectively. Statistical analysis showed a significant correlation between the DEI and Zeff values (P < .001). The interobserver intraclass correlation coefficient was 0.91 for the mean Zeff values and 0.86 for the mean DEI values. This technique could potentially provide useful information regarding the composition of a CTO.

Discrimination of High-Risk Type-2 Endoleak after Endovascular Aneurysm Repair through CT Perfusion: A Feasibility Study.

A type-2 endoleak after an endovascular aneurysm repair is the most prevalent type of endoleak, but as the clinical consequence of its diagnosis is uncertain, at present, management decisions are solely based on aneurysm sac growth. The aim of this study was to investigate the potential of various computed tomography perfusion parameters for their ability to distinguish high-risk type-2 endoleaks from low-risk type-2 endoleaks after an endovascular aneurysm repair.

Evaluation of an organ-based tube current modulation tool in pediatric CT examinations.

OBJECTIVES: To investigate the effect of an organ-based tube current modulation (OTCM) technique on organ absorbed dose and assess image quality in pediatric CT examinations. METHODS: Four physical anthropomorphic phantoms that represent the average individual as neonate, 1-year-old, 5-year-old, and 10-year-old were used. Standard head and thorax acquisitions were performed with automatic tube current modulation (ATCM) and ATCM+OTCM. Dose calculations were performed by means of Monte Carlo simulations. Radiation dose was measured for superficial and centrally located radiosensitive organs. The angular range of the OTCM exposure window was determined for different tube rotation times (t) by means of a solid-state detector. Image noise was measured as the standard deviation of the Hounsfield unit value in regions of interest drawn at selected anatomical sites. RESULTS: ATCM+OTCM resulted in a reduction of radiation dose to all radiosensitive organs. In head, eye lens dose was reduced by up to 13% in ATCM+OTCM compared with ATCM. In thorax, the corresponding reduction for breast dose was up to 10%. The angular range of the OTCM exposure window decreased with t. For t = 0.4 s, the angular range was limited to 74° in head and 135° for thorax. Image noise was significantly increased in ATCM+OTCM acquisitions across most examined phantoms (p < 0.05). CONCLUSIONS: OTCM reduces radiation dose to exposed radiosensitive organs with the eye lens and breast buds exhibiting the highest dose reduction. The OTCM exposure window is narrowed at short t. An increase in noise is inevitable in images located within the OTCM-activated imaged volume. KEY POINTS: • In pediatric CT, organ-based tube current modulation reduces radiation dose to all major primarily exposed radiosensitive organs. • Image noise increases within the organ-based tube current modulation enabled imaged volume. • The angular range of the organ-based tube current modulation low exposure window is reduced with tube rotation time.

CT Foot Perfusion Examination for Evaluation of Percutaneous Transluminal Angioplasty Outcome in Patients with Critical Limb Ischemia: A Feasibility Study.

PURPOSE: To evaluate foot perfusion in patients with critical limb ischemia (CLI) using quantitative perfusion multi-detector-row CT and estimate perfusion parameter changes before and after percutaneous transluminal angioplasty (PTA). MATERIALS AND METHODS: This prospective study investigated 13 patients (10 men; median age, 72 y; range, 51-84 y) with CLI who underwent CT foot perfusion examinations with a 128-slice dual-energy CT scanner 1 day before and 1 week after PTA. Key parameters such as permeability surface (PS), blood volume (BV), and blood flow (BF) were analyzed and compared statistically. The studies were also examined by a second observer to determine interobserver reproducibility. RESULTS: Revascularization was technically successful in all patients, and mean ankle-brachial index increased from 0.36 ± 0.16 to 0.75 ± 0.22. After revascularization, mean BV increased from 1.55 mL/100 g ± 0.83 to 4.51 mL/100 g ± 1.53, BF increased from 16.28 mL/100 g/min ± 4.97 to 31.49 mL/100 g/min ± 6.86, and PS increased from 3.1 mL/min/100 g ± 1.95 to 8.67 mL/min/100 g ± 3.85 (P < .05). Patients with poor response to revascularization who finally underwent amputation presented lower post-PTA perfusion parameters values than patients with significant clinical improvement (P < .05). All measurements demonstrated very good interobserver reproducibility, and intraclass correlation coefficients were 0.91 for BV, 0.94 for BF, and 0.95 for PS. The mean effective dose of the examination was estimated at 0.29 mSv. CONCLUSIONS: CT foot perfusion is a reproducible technique that may be a useful modality for the estimation of PTA outcome. Significant restitution of perfusion parameters was observed after successful revascularization.

The effect of iodine uptake on radiation dose absorbed by patient tissues in contrast enhanced CT imaging: Implications for CT dosimetry.

OBJECTIVES: To investigate the effect of iodine uptake on tissue/organ absorbed doses from CT exposure and its implications in CT dosimetry. METHODS: The contrast-induced CT number increase of several radiosensitive tissues was retrospectively determined in 120 CT examinations involving both non-enhanced and contrast-enhanced CT imaging. CT images of a phantom containing aqueous solutions of varying iodine concentration were obtained. Plots of the CT number increase against iodine concentration were produced. The clinically occurring iodine tissue uptake was quantified by attributing recorded CT number increase to a certain concentration of aqueous iodine solution. Clinically occurring iodine uptake was represented in mathematical anthropomorphic phantoms. Standard 120 kV CT exposures were simulated using Monte Carlo methods and resulting organ doses were derived for non-enhanced and iodine contrast-enhanced CT imaging. RESULTS: The mean iodine uptake range during contrast-enhanced CT imaging was found to be 0.02-0.46% w/w for the investigated tissues, while the maximum value recorded was 0.82% w/w. For the same CT exposure, iodinated tissues were found to receive higher radiation dose than non-iodinated tissues, with dose increase exceeding 100% for tissues with high iodine uptake. CONCLUSIONS: Administration of iodinated contrast medium considerably increases radiation dose to tissues from CT exposure. KEY-POINTS: • Radiation absorption ability of organs/tissues is considerably affected by iodine uptake • Iodinated organ/tissues may absorb up to 100 % higher radiation dose • Compared to non-enhanced, contrast-enhanced CT may deliver higher dose to patient tissues • CT dosimetry of contrast-enhanced CT imaging should encounter tissue iodine uptake.

Automatic exposure control in CT: the effect of patient size, anatomical region and prescribed modulation strength on tube current and image quality.

OBJECTIVES: To study the effect of patient size, body region and modulation strength on tube current and image quality on CT examinations that use automatic tube current modulation (ATCM). METHODS: Ten physical anthropomorphic phantoms that simulate an individual as neonate, 1-, 5-, 10-year-old and adult at various body habitus were employed. CT acquisition of head, neck, thorax and abdomen/pelvis was performed with ATCM activated at weak, average and strong modulation strength. The mean modulated mAs (mAsmod) values were recorded. Image noise was measured at selected anatomical sites. RESULTS: The mAsmod recorded for neonate compared to 10-year-old increased by 30 %, 14 %, 6 % and 53 % for head, neck, thorax and abdomen/pelvis, respectively, (P < 0.05). The mAsmod was lower than the preselected mAs with the exception of the 10-year-old phantom. In paediatric and adult phantoms, the mAsmod ranged from 44 and 53 for weak to 117 and 93 for strong modulation strength, respectively. At the same exposure parameters image noise increased with body size (P < 0.05). CONCLUSIONS: The ATCM system studied here may affect dose differently for different patient habitus. Dose may decrease for overweight adults but increase for children older than 5 years old. Care should be taken when implementing ATCM protocols to ensure that image quality is maintained. KEY POINTS: • ATCM efficiency is related to the size of the patient's body. • ATCM should be activated without caution in overweight adult individuals. • ATCM may increase radiation dose in children older than 5 years old. • ATCM efficiency depends on the protocol selected for a specific anatomical region. • Modulation strength may be appropriately tuned to enhance ATCM efficiency.

Assessing the impact of the COVID­19 pandemic health protocols on the hygiene status of swimming pools of hotel units.

With the onset of the coronavirus disease 2019 (COVID-19) pandemic, numerous countries imposed strict lockdown measures and travel bans, resulting in the closure of hotels. Over time, the opening of hotel units was gradually allowed, and new strict regulations and protocols were issued to ensure the hygiene and safety of swimming pools in the era of COVID-19. The present study aimed to evaluate the implementation of strict health COVID-19-related protocols in hotel units during the 2020 summer tourist season concerning microbiological hygiene and physicochemical parameters of water, and to compare the data with those from the 2019 tourist season. For this reason, 591 water samples from 62 swimming pools were analyzed, of which 381 samples were for the 2019 tourist season and 210 samples were for the 2020 tourist season. To examine the presence of Legionella spp, 132 additional samples were taken from 14 pools, of which 49 in 2019 and 83 in 2020. In 2019, 2.89% (11/381) of the samples were out of legislative limits (0/250 mg/l) regarding the presence of Escherichia coli (E. coli), 9.45% (36/381) were out of acceptable limits (0/250 mg/l) regarding the presence of Pseudomonas aeruginosa (P. aeruginosa) and 8.92% (34/381) had residual chlorine levels <0.4 mg/l. In 2020, 1.43% (3/210) of the samples were out of the legislative limits as regards the presence of E. coli, 7.14% (15/210) were out of acceptable limits regarding the presence of P. aeruginosa and 3.33% (7/210) of the samples measured residual chlorine levels <0.4 mg/l. The risk ratio (RR) in relation to the presence of E. coli due to incorrect compliance with the requirements for residual chlorine was calculated for 2019 at 8.50, while in 2020 it was calculated at 14.50 (P=0.008). The RR of the presence of P. aeruginosa due to inappropriate residual chlorine requirements was calculated in 2019 at 2.04 (P=0.0814), while in 2020 it was calculated at 2.07 (P=0.44). According to the microbiological hygiene and physicochemical parameters of the water samples studied, there was a significant improvement due to the strict protocols for the swimming pools in the summer season of 2020 compared to the tourist season of 2019, namely 72.72% (E. coli), 58.33% (P. aeruginosa), 79.41% (of residual chlorine <0.4 mg/l) in the three main parameters studied. Finally, an increased colonization by Legionella spp. detected in the internal networks of the hotels due to the non-operation of the hotels during the lockdown, the improper disinfection and stagnant water in the internal water supply networks. Specifically, in 2019, 95.92% (47/49) of the samples tested negative and 4.08% (2/49) tested positive (≥50 CFU/l) for Legionella spp., compared to 2020 where 91.57% (76/83) of the samples tested negative and 8.43% (7/83) tested positive.

Assessment of abdominal organ dose and image quality in varying arc trajectory interventional C-arm cone beam CT.

PURPOSE: The aim of this study was to investigate the effect of varying arc exposure trajectory on radiation dose to radiosensitive organs and to assess image quality in abdominal C-arm cone beam computed tomography (CBCT) interventional procedures using a latest generation system. METHODS: An anthropomorphic phantom that simulates the average adult individual was used. Individual-specific Monte Carlo (MC) simulation dosimetry was performed to estimate organ doses (OD) in abdominal C-arm CBCT. Seven examination protocols prescribed by the system for vascular and soft tissue CBCT, were simulated. These protocols are differentiated in the range of the arc exposure trajectory and the level of radiation dose delivered to the patient. OD was estimated for liver, adrenals, kidneys, pancreas, stomach, gall bladder, spleen, bone and skin. Image noise, signal to noise ratio (SNR), contrast to noise ratio (CNR) and in-plane spatial resolution were assessed using CT-specific image quality assessment phantoms. RESULTS: OD was found to depend on the range of arc trajectory and was higher for posterior located organs. In vascular protocols OD ranged from 4.75 mGy for skin to 0.60 mGy for bone. Image noise was higher in vascular protocols than in soft tissue ones. SNR and CNR were significantly modified among different soft tissue protocols (P < 0.05). In-plane spatial resolution was found 0.80 lp/mm in vascular as opposed to 0.41 lp/mm in soft tissue protocols. CONCLUSIONS: The current results may be used to estimate OD for different examination protocols and enable operators choose the appropriate acquisition protocol on the preprogrammed interventional task.

Re-Starting the Cruise Sector during the COVID-19 Pandemic in Greece: Assessing Effectiveness of Port Contingency Planning.

Coronavirus disease (COVID-19) outbreaks on board cruise ships early in the pandemic highlighted gaps worldwide in public health emergency contingency plans (PHECPs) for responding to unknown threats. To restart cruise operations in 2021 and respond to potential COVID-19 outbreaks, a major tourist-based Greek island port (Port A) developed a COVID-19 PHECP. We assessed plan effectiveness by reviewing epidemiological data and monitoring outcomes, followed by an intra-action review (IAR) analyzing three event responses. From May to December 2021, 118 calls from 23 cruise ships with 119,930 passengers were recorded, with 29 COVID-19 cases in 11 cruises on board 7 ships. No outbreak was recorded during the study period. Strengths of the introduced PHECP included commitment of senior management; a core multi-disciplinary team of local authorities/ship agents involved in design and execution; interoperability agreements for port and ships' PHECPs; cruise industry commitment to compliance; and pre-existing scenarios considering capacity needs. Central government coordination for preparedness planning at local ports is essential for successful responses. Monitoring local and country level response capacities is critical to inform planning, risk assessment, and decision-making. Immediately recording ports' response actions provides the basis to capture lessons and improve contingency plans. To facilitate communication and common response protocols between European and non-European ports, IARs should be conducted between countries.

Dual-energy CT angiography in imaging surveillance of endovascular aneurysm repair - Preliminary study results.

PURPOSE: To investigate the value of dual-energy CT imaging to discriminate low- from high- risk type II endoleaks (T2EL) after endovascular aneurysm repair (EVAR). METHOD: Study participants were consecutive patients referred for CT at 1-month post-EVAR. CT imaging acquisition included a dual-energy CT angiography (DECTA) and a delayed single-energy CT (SECT) imaging. Patients diagnosed with T2EL were re-examined at 6-months post-EVAR to assess the aneurysm sac growth (ASG). Upon ASG recorded, patients were categorized as having low- (group A) or high- risk (group B) T2EL. DECTA image data were employed to calculate the normalized effective atomic number (NZeff), the normalized iodine concentration, the slope of HUendoleak/HUaorta against monochromatic energy, the dual-energy index and an improvised endoleak index (EI) for each T2EL. Statistical analysis was employed to compare all above parameters regarding their ability to differentiate low- from high- risk T2EL. RESULTS: Among 40 patients examined at 1-month post-EVAR, 14 patients were diagnosed with T2EL. NZeff and EI were found to be significantly lower in group A. NZeff was found to have the highest power to discriminate high-risk T2EL with an area-under-curve of 86.7%, showing100% specificity and 60% sensitivity. The optimal contrast-to-noise ratio for T2EL demonstrated a median peak conspicuity level at 54-keV. The mean effective dose from DECTA and SECT scans was 27.8% lower compared to the sum of three SECT acquisitions. CONCLUSIONS: NZeff and EI were found to have a significant power in predicting the aggressiveness of T2EL lesions. Virtual monochromatic images at 54-keV may enhance T2EL detection efficiency.

Paraoxonase 2 (PON2) Deficiency Reproduces Lipid Alterations of Diabetic and Inflammatory Glomerular Disease and Affects TRPC6 Signaling.

Diabetes and inflammatory diseases are associated with an altered cellular lipid composition due to lipid peroxidation. The pathogenic potential of these lipid alterations in glomerular kidney diseases remains largely obscure as suitable cell culture and animal models are lacking. In glomerular disease, a loss of terminally differentiated glomerular epithelial cells called podocytes refers to irreversible damage. Podocytes are characterized by a complex ramified cellular architecture and highly active transmembrane signaling. Alterations in lipid composition in states of disease have been described in podocytes but the pathophysiologic mechanisms mediating podocyte damage are unclear. In this study, we employ a genetic deletion of the anti-oxidative, lipid-modifying paraoxonase 2 enzyme (PON2) as a model to study altered cellular lipid composition and its effects on cellular signaling in glomerular disease. PON2 deficiency reproduces features of an altered lipid composition of glomerular disease, characterized by an increase in ceramides and cholesterol. PON2 knockout mice are more susceptible to glomerular damage in models of aggravated oxidative stress such as adriamycin-induced nephropathy. Voltage clamp experiments in cultured podocytes reveal a largely increased TRPC6 conductance after a membrane stretch in PON2 deficiency. Correspondingly, a concomitant knockout of TRPC6 and PON2 partially rescues the aggravated glomerular phenotype of a PON2 knockout in the adriamycin model. This study establishes PON2 deficiency as a model to investigate the pathophysiologic mechanisms of podocyte dysfunction related to alterations in the lipid composition, as seen in diabetic and inflammatory glomerular disease. Expanding the knowledge on these routes and options of intervention could lead to novel treatment strategies for glomerular disease.

Mosquito population structure, pathogen surveillance and insecticide resistance monitoring in urban regions of Crete, Greece.

BACKGROUND: In Greece vector borne diseases (VBD) and foremost West Nile virus (WNV) pose an important threat to public health and the tourist industry, the primary sector of contribution to the national economy. The island of Crete, is one of Greece's major tourist destinations receiving annually over 5 million tourists making regional VBD control both a public health and economic priority. METHODOLOGY: Under the auspices of the Region of Crete, a systematic integrative surveillance network targeting mosquitoes and associated pathogens was established in Crete for the years 2018-2020. Using conventional and molecular diagnostic tools we investigated the mosquito species composition and population dynamics, pathogen infection occurrences in vector populations and in sentinel chickens, and the insecticide resistance status of the major vector species. PRINCIPAL FINDINGS: Important disease vectors were recorded across the island including Culex pipiens, Aedes albopictus, and Anopheles superpictus. Over 75% of the sampled specimens were collected in the western prefectures potentially attributed to the local precipitation patterns, with Cx. pipiens being the most dominant species. Although no pathogens (flaviviruses) were detected in the analysed mosquito specimens, chicken blood serum analyses recorded a 1.7% WNV antibody detection rate in the 2018 samples. Notably detection of the first WNV positive chicken preceded human WNV occurrence in the same region by approximately two weeks. The chitin synthase mutation I1043F (associated with high diflubenzuron resistance) was recorded at an 8% allelic frequency in Lasithi prefecture Cx. pipiens mosquitoes (sampled in 2020) for the first time in Greece. Markedly, Cx. pipiens populations in all four prefectures were found harboring the kdr mutations L1014F/C/S (associated with pyrethroid resistance) at a close to fixation rate, with mutation L1014C being the most commonly found allele (≥74% representation). Voltage gated sodium channel analyses in Ae. albopictus revealed the presence of the kdr mutations F1534C and I1532T (associated with putative mild pyrethroid resistance phenotypes) yet absence of V1016G. Allele F1534C was recorded in all prefectures (at an allelic frequency range of 25-46.6%) while I1532T was detected in populations from Chania, Rethymnon and Heraklion (at frequencies below 7.1%). Finally, no kdr mutations were detected in the Anopheles specimens included in the analyses. CONCLUSIONS/SIGNIFICANCE: The findings of our study are of major concern for VBD control in Crete, highlighting (i) the necessity for establishing seasonal integrated entomological/pathogen surveillance programs, supporting the design of targeted vector control responses and; ii) the need for establishing appropriate insecticide resistance management programs ensuring the efficacy and sustainable use of DFB and pyrethroid based products in vector control.

Individualized assessment of radiation dose in patients undergoing coronary computed tomographic angiography with 256-slice scanning.

BACKGROUND: Available data on the radiation burden from coronary computed tomography (CT) angiography (CCTA) are mostly limited to effective dose estimates. This study provides individualized estimates of doses and associated life attributable risks of radiation-induced cancer in a clinical patient population undergoing 256-slice CCTA. METHODS AND RESULTS: Typical retrospectively and prospectively ECG-gated CCTA exposures in a 256-slice CT scanner were simulated on 52 patient-specific voxelized phantoms. Dose images depicting the dose deposition on the exposed region were generated, and normalized organ doses for all primarily irradiated radiosensitive organs were derived and correlated to patient body habitus. Lung, breast, and esophagus absorbed doses were then determined in 136 consecutive patients subjected to CCTA. Projected life attributable risks of radiation-induced cancer were estimated through the use of appropriate sex-, age- and organ-specific cancer risk factors and compared with corresponding nominal cancer risks. The total projected life attributable risk of radiogenic cancer after CCTA decreases steeply with age at exposure, and lung cancer constitutes the most probable detriment for both sexes. The relative risks of lung cancer associated with prospectively ECG-gated CCTA were 1.0032 and 1.0008 for women and men, respectively. The mean total projected life attributable risks were estimated to be 24.9±7.4 and 71.5±30.0 per 100,000 women undergoing prospectively and retrospectively ECG-gated CCTA, respectively. The corresponding values for men were 7.3±1.3 and 31.4±5.0 per 100 000 patients. CONCLUSIONS: The mean projected life attributable risks of radiation-induced cancer in a typical clinical patient cohort undergoing standard prospectively ECG-gated CCTA with a 256-slice scanner were found to inconsequentially increase the natural cancer incidence rates.