The impact of different determinants on the dental caries experience of children living in Australia rural and urban areas.
Evidence suggests there are geographical variations in child oral health and this has prompted research into determinants of that variation. This study aimed to investigate factors attributable to the difference in child oral health between urban and rural areas in Australia. Data were from the National Child Oral Health Study 2012-14, a population-based study of 5- to 14-year-old children, who underwent oral epidemiological examinations by trained examiners. Caries prevalence (dmfs/DMFS > 0) and experience (dmfs/DMFS count) in the primary dentition (5- to 8-year-old) and permanent dentition (9- to 14-year-old) were calculated. Children were grouped by residential location (urban or rural areas). A parental questionnaire collected information on family socio-economic factors, and individual health behaviours (dental access, sugar consumption and toothbrushing). Residential history was used to calculate lifetime exposure to water fluoridation (WF). Analyses were weighted to produce population-representative estimates. The primary outcomes were assessed separately for the two groups in regression models with robust standard error estimation to estimate prevalence ratios and mean ratios and their 95% confidence intervals. Population Attributable Fractions were calculated using the population distribution of the exposures and their adjusted estimates. 10 581 5- to 8-year-old and 14 041 9- to 14-year-old children were included. Caries prevalence was higher in rural than in urban areas. In multivariable models, exposure to fluoridation, reason for dental visit and consumption of sugary beverages were consistently associated with caries prevalence and experience. WF coverage attributed to differences in caries prevalence (10% vs 21%) and experience (14% vs 35%) in the permanent dentition. High consumption of sugary beverages attributed to a higher primary and permanent dental caries experience in rural than in urban areas. Dental access was also attributed to the differences between the two areas. Factors at both community and individual levels attributed to the observed differences in child caries prevalence and experience between urban and rural areas.


Ice front blocking of ocean heat transport to an Antarctic ice shelf.
Mass loss from the Antarctic Ice Sheet to the ocean has increased in recent decades, largely because the thinning of its floating ice shelves has allowed the outflow of grounded ice to accelerate1,2. Enhanced basal melting of the ice shelves is thought to be the ultimate driver of change2,3, motivating a recent focus on the processes that control ocean heat transport onto and across the seabed of the Antarctic continental shelf towards the ice4-6. However, the shoreward heat flux typically far exceeds that required to match observed melt rates2,7,8, suggesting that other critical controls exist. Here we show that the depth-independent (barotropic) component of the heat flow towards an ice shelf is blocked by the marked step shape of the ice front, and that only the depth-varying (baroclinic) component, which is typically much smaller, can enter the sub-ice cavity. Our results arise from direct observations of the Getz Ice Shelf system and laboratory experiments on a rotating platform. A similar blocking of the barotropic component may occur in other areas with comparable ice-bathymetry configurations, which may explain why changes in the density structure of the water column have been found to be a better indicator of basal melt rate variability than the heat transported onto the continental shelf9. Representing the step topography of the ice front accurately in models is thus important for simulating ocean heat fluxes and induced melt rates.


Educational attainment and cognitive decline in old age.
Level of education is a well-established risk factor for Alzheimer disease but its relation to cognitive decline, the principal clinical manifestation of the disease, is uncertain. More than 6,000 older residents of a community on the south side of Chicago were interviewed at approximately 3-year intervals for up to 14 years. The interview included administration of four brief tests of cognitive function from which a previously established composite measure of global cognition was derived. We estimated the associations of education with baseline level of cognition and rate of cognitive change in a series of mixed-effects models. In an initial analysis, higher level of education was related to higher level of cognition at baseline, but there was no linear association between education and rate of change in cognitive function. In a subsequent analysis with terms to allow for nonlinearity in education and its relation to cognitive decline, rate of cognitive decline at average or high levels of education was slightly increased during earlier years of follow-up but slightly decreased in later years in comparison to low levels of education. Findings were similar among black and white participants. Cognitive performance improved with repeated test administration, but there was no evidence that retest effects were related to education or attenuated education's association with cognitive change. The results suggest that education is robustly associated with level of cognitive function but not with rate of cognitive decline and that the former association primarily accounts for education's correlation with risk of dementia in old age.


Lewis acid-mediated reactions of 1-cyclopropyl-2-arylethanone derivatives with allenic ester, ethyl acetoacetate, and methyl acrylate.
TMSOTf-mediated reactions of 2-aryl-1-(1-phenylcyclopropyl)ethanones 1 with allenic esters afford a novel method for the synthesis of 6-methyl-3a,7-diaryl-3,3a-dihydro-2H-benzofuran-4-one derivatives 2 in moderate yields. In addition, we also found that TMSOTf-mediated reactions of 1-cyclopropyl-2-arylethanones with ethyl acetoacetate can provide the corresponding 2,3-dihydrobenzofuran-4-ol and dihydrofuro[2,3-h]chromen-2-one in moderate yields via a sequential reaction involving a nucleophilic ring-opening reaction of the cyclopropane by H2O, one intermolecular aldol type reaction and two intramolecular aldol type reactions, a cyclic transesterification, dehydration, and aromatization. Moreover, by using methyl acrylate to replace allenic ester, the corresponding 7-aryl-3,5,6,7-tetrahydro-2H-benzofuran-4-one and 5-aryl-3,5,6,7-tetrahydro-2 H-benzofuran-4-one can be formed in moderate to high yields in the presence of Bi(OTf)2Cl. Plausible reaction mechanisms have also been provided on the basis of control experiments.


In vivo reflectance confocal microscopy characterization of silver deposits in localized cutaneous argyria.
Localized cutaneous argyria is a rare condition secondary to skin deposition of silver following exposure to substances containing this metal. The clinical appearance and dermoscopy findings require deep melanocytic lesions and particularly melanoma metastasis to be ruled out. Silver deposits are usually confirmed by scanning electron microscopy and/or energy-dispersive X-ray spectroscopy. Herein we describe the in vivo reflectance confocal microscopy (RCM) features observed in one case of localized cutaneous argyria. These features include the presence of a hyperrefractile network in the papillary dermis and a periadnexal dotted bright pattern. In vivo RCM might be a useful tool for an early diagnosis of this uncommon entity.


Epidemiological cut-off values for non-O1/ non-O139 Vibrio cholerae disc diffusion data generated by standardised methods.
This work generates the data needed to set epidemiological cut-off values for disc-diffusion zone measurements of Vibrio cholerae. The susceptibility of 147 European isolates of non-O1/non-O139 V. cholerae to 19 antibiotics was established using a standardised disc diffusion method which specified incubation of Mueller Hinton agar plates at 35°C. Epidemiological cut-off values were calculated by analysis of the zone size data with the statistically based normalised resistance interpretation method. Cut-off values for 17 agents were calculated by analysis of the aggregated data from all 4 laboratories participating in this study. The cut-off values calculated were ≥18 mm for amoxicillin/clavulanate, ≥18 mm for amikacin, ≥19 mm for ampicillin, ≥27 mm for cefepime, ≥31 mm for cefotaxime, ≥24 mm for ceftazidime, ≥24 mm for chloramphenicol, ≥31 mm for ciprofloxacin, ≥16 mm for erythromycin, ≥ 27 mm for florfenicol, ≥16 mm for gentamicin, ≥23 mm for imipenem, ≥25 mm for meropenem, ≥29 mm for nalidixic acid, ≥28 mm for norfloxacin, ≥13 mm for streptomycin and ≥23 mm for tetracycline. For the other 2 agents the data from 1 laboratory was excluded from the censored aggregation because the data from that laboratory was considered excessively imprecise. The cut-off values for these 2 agents calculated for the aggregation of the data from 3 laboratories were ≥23 mm for trimethoprim and ≥24 mm for trimethoprim/sulfamethoxazole. These zone size data will be submitted to the Clinical Laboratory Standards Institute (CLSI) and European Committee for Antimicrobial Susceptibility Testing (EUCAST) for their consideration in setting international consensus epidemiological cut-off values for non O1/non-O139 V. cholerae.


BioProspecting: novel marker discovery obtained by mining the bibleome.
BioProspecting is a novel approach that enabled our team to mine data related to genetic markers from the New England Journal of Medicine (NEJM) utilizing SNOMED CT and the Human Gene Onotology (HUGO). The Biomedical Informatics Research Collaborative was able to link genes and disorders using the Multi-threaded Clinical Vocabulary Server (MCVS) and natural language processing engine, whose output creates an ontology-network using the semantic encodings of the literature that is organized by these two terminologies. We identified relationships between (genes or proteins) and (diseases or drugs) as linked by metabolic functions and identified potentially novel functional relationships between, for example, genes and diseases (e.g. Article #1 ([Gene - IL27] = > {Enzyme - Dipeptidyl Carboxypeptidase 1}) and Article #2 ({Enzyme - Dipeptidyl Carboxypeptidase 1} < = [Disorder - Type II DM]) showing a metabolic link between IL27 and Type II DM). In this manuscript we describe our method for developing the database and its content as well as its potential to assist in the discovery of novel markers and drugs.


Workshop on growth factors.
The 'Workshop on Growth Factors' which took place at the Lugano Lymphoma Conference on June 8, 1990, included a presentation by Michael Sporn on the concept that loss of inhibitory control mechanisms may be important in the development and growth of human cancer. Examples illustrating this were taken from current experimental biology research into transforming growth factor beta (TGF-beta) interactions. Brian Durie presented recent data on the biology of interleukin-6 (IL-6) and its putative role in plasma cell diseases. These studies have culminated in the first clinical study of the role of an antibody to a growth factor as therapy for a human cancer (anti-IL-6 antibody as therapy for patients with myeloma). Derek Crowther presented data concerning the current clinical role of the haematopoietic growth factors in patients undergoing chemotherapy for cancer. Recent clinical research has established the role of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in improving the safety of high-dose or accelerated chemotherapy, and their use is associated with enhanced neutrophil recovery following ablative therapy and bone marrow rescue. This session was followed by the presentation of three papers concerning the use of G-CSF and GM-CSF in association with chemotherapy for patients with malignant lymphoma.


A multimethod assessment of psychosocial functioning and late effects in survivors of childhood cancer and hematopoietic cell transplant.
Previous research in childhood cancer and hematopoietic cell transplant (HCT) survivorship has relied on the use of standardized questionnaires that assess symptoms of psychological functioning but do not sufficiently capture the cancer survivorship experience. Study aims are to quantitatively and qualitatively assess the psychosocial functioning of pediatric cancer and HCT survivors seen in a multidisciplinary survivorship clinic, determine survivorship concerns, and assess potential demographic and medical correlates of psychosocial outcomes. Data were collected using a retrospective chart review of a parent-report questionnaire of the child's psychological functioning, responses to a semistructured interview that qualitatively assessed adjustment to life after treatment, and documented medical late effects. Results indicated the majority of survivors had healthy psychological adjustment based upon a parent-report questionnaire. However, nearly 72% of survivors reported 1 or more survivorship concerns during the interview, with the primary concerns being current and future health or physical functioning, including the possibility of cancer recurrence. A content analysis of the interview responses indicated HCT survivors had more school or cognitive functioning concerns compared with survivors who did not have an HCT. Further research should use survivorship-specific measures to better identify survivors at risk and determine the impact of late effects on their quality of life.


[Microsleep, sleepiness and driving performance in patients with sleep apnoea syndrome].
Especially during monitoring activities or car driving needing high vigilance, episodes of microsleep are extremely dangerous. Microsleep can be described by observing behaviour patterns or electrophysiological parameters. An early recognition of these episodes is desirable. In the automobile industry intensive development is ongoing to register sleepiness and subsequent microsleep during driving to avoid accidents. The monitoring of eyelid frequency and diameter of the pupil (eye tracking) are most promising. Compared with a reference population, the accident risk of patients with sleep-related breathing disorders is more than two-fold higher. But up to now there are no definitive criteria--neither subjective nor objective tests such as, for instance, driving simulators--to predict driving impairment. By means of screening examinations, patients with obstructive sleep apnoea syndrome (OSAS) should be detected because therapy with CPAP normalises the accident rate. A further measure to reduce the risk of accidents is the so-called alertness management where techniques are communicated to detect and avoid sleeping episodes.


Long-lasting effects of sedentarization-induced increase of fertility on labor force proportion in an Arab socieity: a case study in south Jordan.
Based on the authors' genealogical-demographic data of a Bedouin-origin clan in south Jordan which settled down in 1948, this paper aimed to report the long-lasting effects of increase in fertility induced by sedentarization on the labor force proportion, defined as percent of persons aged 15-64 years. The results highlighted that this proportion had an inverse relation with the total fertility rate and tended to fluctuate up to the present time with an interval of several decades, suggesting that a Bedouin-origin sedentarized group met alternately with the phase of high fertility and low proportion of labor force and the other phase of an opposite pattern. At present, unemployment of males, who have been engaged in subsistence and cash-earning work, was high especially in younger groups basically due to the narrow land of the clan (only 35 hectares for 456 people in 2005) for agriculture and the limited opportunities for cash-earning jobs. Taking into consideration that Bedouin-origin people sedentarized according to the government policy, it is needed for the government to support rural development plans of sedentarized Bedouin peoples.


Infant well-being following neonatal cardiac surgery.
To investigate infant well-being as measured by feeding and sleeping and parental support following discharge from the NICU in infants following major cardiac surgery. Infant feeding and sleeping have been identified as two of the most important concerns reported by parents. These concerns have been reported anecdotally for infants who have undergone cardiac surgery in the neonatal period. A prospective study using questionnaires and phone interviews followed a cohort of parents of neonates who underwent surgery in the neonatal period for congenital heart disease. The study was conducted using validated questionnaires and phone interviews with a semi-structured questionnaire. The questionnaires were administered prior to discharge from the NICU and interviews took place following discharge on five occasions within nine months. Fifty six infants and mothers were followed for nine months following discharge from NICU. Sixty-eight per cent were breastfeeding on discharge however the rates decline over time in line with healthy infants. Mothers were not bothered by their infant's sleep patterns which were consistent with those of healthy infants at six months. There were 37 episodes of re-hospitalisation and the average time of further surgery was five months following discharge from their initial period of hospitalisation. The issues from this pilot study warrant further investigation. Factors such as multiple hospitalisations, parent education and support may vary within contexts and need to be studied to ensure optimal supports are identified for this high risk population. This study identified several issues that can improve care provided to these infants and their parents. Support following discharge could include: lactation consultant to provide follow-up calls to identify concerns with breastfeeding, lactation course for paediatric nurses providing follow-up and education for Early Childhood Clinics on Congenital Heart Disease.


Use of Botulinum Toxin in Treating Rosacea: A Systematic Review.
Rosacea is a chronic skin disorder characterized by erythema, flushing, telangiectasia, papules and pustules, phymatous changes, and ocular involvement. The aim of this study was to examine all published research articles in which botulinum toxin was used to treat rosacea and to evaluate the efficacy and safety of this treatment. PubMed, Embase, Cochrane Library, and Web of Science database were used to identify articles eligible for systematic review on March 26, 2021. Prospective or retrospective studies which directly used botulinum toxin to treat rosacea were included and reviewed. Nine studies were included in this systematic review. Two were randomized controlled trials, graded as Level 2 for the quality of evidence. The total number of participants was 130, and the number of participants in each study ranged from 1 to 25. The improvement was observed in all studies in signs and symptoms compared with baseline. Adverse events were transitory and self-limited. Botulinum toxin could have overall satisfying efficacy and safety in the treatment of rosacea, though limited by small sample size, imperfect study design, and short follow-up visits.


Children benefit from morphological relatedness when they learn to spell new words.
Use of morphologically related words often helps in selecting among spellings of sounds in French. For instance, final /wa/ may be spelled oi (e.g., envoi "sendoff"), oit (e.g., exploit "exploit"), ois (e.g., siamois, "siamese"), or oie (e.g., joie "joy"). The morphologically complex word exploiter "to exploit", with a pronounced t, can be used to indicate that the stem exploit is spelled with a silent t. We asked whether 8-year-old children benefited from such cues to learn new spellings. Children read silently stories which included two target nonwords, one presented in an opaque condition and the other in a morphological condition. In the opaque condition, the sentence provided semantic information (e.g., a vensois is a musical instrument) but no morphological information that could justify the spelling of the target word's final sound. Such justification was available in the morphological condition (e.g., the vensoisist plays the vensois instrument, which justifies that vensois includes a final silent s). 30 min after having read the stories, children's orthographic learning was assessed by asking them to choose the correct spelling of each nonword from among three phonologically plausible alternatives (e.g., vensois, vensoit, vensoie). Children chose correct spellings more often in the morphological condition than the opaque condition, even though the root (vensois) had been presented equally often in both conditions. That is, children benefited from information about the spelling of the morphologically complex word to learn the spelling of the stem.


Effect of carotid occlusion and of perfusion pressure on renal function in conscious dogs.
We studied the effect of bilateral common carotid occlusion (implanted pneumatic cuffs) on renal blood flow (electromagnetic flowmeter) and renal function (implanted ureteral catheter) in nine chronically instrumented, conscious dogs on a high sodium diet (14 mmol/kg body weight per day). By means of suprarenal aortic constriction (pneumatic cuff) the influence of renal perfusion pressure was investigated. There was no change in renal blood flow or glomerular filtration rate (inulin clearance) with either reflexly increasing (+49.6%) or constant renal perfusion pressure. Carotid occlusion caused an increase of urine output by 80.5% and of sodium excretion by 85.3% due to a fall in fractional sodium reabsorption (-0.9%) when renal perfusion pressure was allowed to rise. Neither an increase of diuresis or sodium excretion nor an antinatriuresis was observed when renal perfusion pressure was kept constant during carotid occlusion. We conclude that, in conscious dogs at rest, the moderate sympathetic activation associated with carotid occlusion is too small to induce renal sympathetic vasoconstriction or antinatriuresis. The "carotid sinus polyuria" is a pressure-diuresis.


[Role of valvular insufficiency of the femoral vein in clinical course and relapse of lower limb varicosity].
The authors carried out a comparative analysis of 488 patients with varicose disease. Of these, 107 patients suffered from class 4 varicosity and reflux along the femoral vein down to the middle third of the femur and below with the duration of more than 1.5 s, and 381 subjects had class 2 - 3 varicose disease without reflux along the femoral vein. The patients in the both groups were sex- and age-matched, with the overwhelming majority of them being women. Group One patients in the preoperative period had clinical class II and III chronic venous insufficiency (CVI) according to the CEAP classification, with the prevailing of class III. The majority of these patients were postoperatively transferred to CVI of clinical classes 0 and I. A similar picture with a difference in the outcome was observed in Group Two patients, the majority of whom had clinical class II CVI according to the CEAP classification, with the overwhelming majority of them having postoperatively been transferred to clinical class 0 and I CVI. Initially, all the patients from Groups One and Two were diagnosed to have been suffering from varicosity of lower-limb subcutaneous veins. During one year after the operation, varicosity was virtually absent in the patients of the both groups, however by ten years of dispensary follow-up the pathology was observed to have reappeared in approximately the same percentage of the patients involved. Studying the long-term surgical outcomes showed that the number of relapsing varicosity in the both groups did not differ significantly, having amounted to 25% and 23% of the patients in Groups One and Two, respectively. According to the findings obtained, the relapses having developed in the overwhelming majority of the patients in the both groups were caused by a reflux along the perforated veins, which either reappeared, or had not been duly removed intraoperatively, as well as by a long stump of the great saphenous vein with an altered influx, or varicosity in the previously intact basin. The integral score of the quality of life (according to the CIVIQ 2 scale) in the groups after the operations did not differ significantly. However, within the groups, there was certain difference between the subgroups comprising the patients in whom complete recovery was attained and those having developed relapses, with this difference in Group One patients commencing to emerge approximately after 7 - 8 postoperative months, to become statistically significant by the 4th - 5th year of the dispensary follow-up, while in Group Two patients this difference began to be seen as early as 2 months after surgery, also becoming statistically reliable 4 - 5 years later. According to our findings, a vertical venous reflux is not the cause of recurrent lower limb varicosity, nor does the dynamics of the quality of life of the patients involved depend upon either presence or absence of a reflux. Therefore, a reflux along the femoral vein does not exert any significant influence on either the course, or relapses of varicose disease.


Recognition and Management of Cutaneous Polyarteritis Nodosum Versus Livedoid Vasculitis: A Case Report.
Cutaneous polyarteritis nodosum (CPAN) is a vasculitis of small and medium-sized muscular arteries of the dermis and subcutaneous tissue with no associated systemic involvement. A common presentation of CPAN can be misinterpreted as a non-invasive form of livedoid vasculitis, synonymous with the "atrophie blanche" which similarly presents as ivory-white stellate-shaped scars. Although hyperpigmentation can also be present, as seen in our 47-year-old female patient, cutaneous polyarteritis nodosum is unique due to the etiology of the inflammatory illness which requires a deep, segmented skin biopsy for diagnosis in order to identify the vessel inflammation. In this case report, we discuss a patient with a 20-year history of painful, recurrent ulcerations and polyneuritis with previous ulcer eruptions that healed as ivory-white stellate scarring. AB cutaneous forms of polyarteritis nodosum (PAN) may be only one manifestation of the disease, with other presentations in association with multi-organ system disease. This report will discuss the necessity of a high index of clinical suspicion with a clinical presentation similar to that of our patient. We will discuss the importance of early recognition and diagnosis of cutaneous vasculitis, such as CPAN, based on clinical presentation and history in hopes of limiting morbidity and the risk of progression to systemic forms of the disease.


Clinical, Pathological, and Prognostic Characteristics of Glomerulonephritis Related to Staphylococcal Infection.
Staphylococcal infection has become a common cause of postinfectious glomerulonephritis in the past 3 decades. Because few investigations focus on this disease, the demographics and clinicopathological features of glomerulonephritis related to staphylococcal infection are not well characterized. We conducted a pooled analysis of published literature in electronic databases and analyzed the clinical features, laboratory findings, and histopathological changes. The patients were divided into 4 groups based on their prognosis: remission, persistent renal dysfunction, end-stage renal disease (ESRD), or death. A logistic regression model was used to identify the determinants of disease outcome. A total of 83 (64 men) patients with glomerulonephritis related to staphylococcal infection from 31 reports were analyzed. The mean age was 58 years (58 ± 17). Majority of the reports originated from Taiwan, Japan, and the United States. Clinical characteristics of the cases were hematuria (82/83), proteinuria (78/83), and acute kidney injury (75/83). Visceral abscesses (26/83) and skin infections (24/83) were the common sites of infection. Methicillin-resistant Staphylococcus aureus was the most common pathogen. The dominant or codominant deposition of IgA or C3 along the glomeruli was an important feature identified by immunofluorescence. There were 19 patients (22.9%) that progressed to dialysis-dependent ESRD. Twelve patients (14.5%) died. A univariate regression analysis indicated that diabetes mellitus (DM) (odds ratio [OR] 2.96; 95% confidence interval [CI] 1.03-8.48; P = 0.04) and age (OR 4.80; 95% CI 1.84-12.53; P = 0.001) were risk factors for ESRD or death. A multivariate regression analysis also revealed that age (OR 4.90; 95% CI 1.82-13.18; P = 0.002) and DM (OR 3.07; 95% CI 0.98-9.59; P = 0.05) were independent risk factors for unfavorable prognosis. Glomerulonephritis related to staphylococcal infection has different features than typical postinfectious glomerulonephritis. The diagnosis of glomerulonephritis related to staphylococcal infection relies on immunofluorescence and electron microscopy findings. Age and DM are independent risk factors of poor prognosis for glomerulonephritis related to staphylococcal infection.


Genomic diversity of Vibrio spp. and metagenomic analysis of pathogens in Florida Gulf coastal waters following Hurricane Ian.
Changing climatic conditions influence parameters associated with the growth of pathogenic Vibrio spp. in the environment and, hence, are linked to increased incidence of vibriosis. Between 1992 and 2022, a long-term increase in Vibrio spp. infections was reported in Florida, USA. Furthermore, a spike in Vibrio spp. infections was reported post Hurricane Ian, a category five storm that made landfall in Florida on 28 September 2022. During October 2022, water and oyster samples were collected from three stations in Lee County in an area significantly impacted by Ian. Vibrio spp. were isolated, and whole-genome sequencing and phylogenetic analysis were done, with a focus on Vibrio parahaemolyticus and Vibrio vulnificus to provide genetic insight into pathogenic strains circulating in the environment. Metagenomic analysis of water samples provided insight with respect to human health-related factors, notably the detection of approximately 12 pathogenic Vibrio spp., virulence and antibiotic resistance genes, and mobile genetic elements, including the SXT/R391 family of integrative conjugative elements. Environmental parameters were monitored as part of a long-term time series analysis done using satellite remote sensing. In addition to anomalous rainfall and storm surge, changes in sea surface temperature and chlorophyll concentration during and after Ian favored the growth of Vibrio spp. In conclusion, genetic analysis coupled with environmental data and remote sensing provides useful public health information and, hence, constitute a valuable tool to proactively detect and characterize environmental pathogens, notably vibrios. These data can aid the development of early warning systems by yielding a larger source of information for public health during climate change. Evidence suggests warming temperatures are associated with the spread of potentially pathogenic Vibrio spp. and the emergence of human disease globally. Following Hurricane Ian, the State of Florida reported a sharp increase in the number of reported Vibrio spp. infections and deaths. Hence, monitoring of pathogens, including vibrios, and environmental parameters influencing their occurrence is critical to public health. Here, DNA sequencing was used to investigate the genomic diversity of Vibrio parahaemolyticus and Vibrio vulnificus, both potential human pathogens, in Florida coastal waters post Hurricane Ian, in October 2022. Additionally, the microbial community of water samples was profiled to detect the presence of Vibrio spp. and other microorganisms (bacteria, fungi, protists, and viruses) present in the samples. Long-term environmental data analysis showed changes in environmental parameters during and after Ian were optimal for the growth of Vibrio spp. and related pathogens. Collectively, results will be used to develop predictive risk models during climate change.


Crystal Structures of Fumarate Hydratases from Leishmania major in a Complex with Inhibitor 2-Thiomalate.
Leishmaniases affect the poorest people on earth and have no effective drug therapy. Here, we present the crystal structure of the mitochondrial isoform of class I fumarate hydratase (FH) from Leishmania major and compare it to the previously determined cytosolic Leishmania major isoform. We further describe the mechanism of action of the first class-specific FH inhibitor, 2-thiomalate, through X-ray crystallography and inhibition assays. Our crystal structures of both FH isoforms with inhibitor bound at 2.05 Å resolution and 1.60 Å resolution show high structural similarity. These structures further reveal that the selectivity of 2-thiomalate for class I FHs is due to direct coordination of the inhibitor to the unique Fe of the catalytic [4Fe-4S] cluster that is found in class I parasitic FHs but is absent from class II human FH. These studies provide the structural scaffold in order to exploit class I FHs as potential drug targets against leishmaniases as well as Chagas diseases, sleeping sickness, and malaria.


Diagnostic and Cost Implications of the 2020 AUA Microhematuria Guidelines: Modeling Impact in a Large Public Health Care System.
We sought to model the diagnostic recommendations and associated costs of new hematuria guidelines regarding referral patterns, procedure utilization and urothelial cell carcinoma (UCC) detection. Patients with microhematuria were identified retrospectively. Initial encounter data were collected from January 2017 to May 2018 from a large public health care system; followup was continued to December 2020. Risk stratification was performed based on the American Urological Association 2020 microhematuria guidelines, and disease outcomes were analyzed within this framework. The guideline-recommended workups and costs were modeled; cost data were sourced from the Centers for Medicare & Medicaid Services Medicare Physician Fee Schedule and Clinical Laboratory Fee Schedule for 2020. Modeled diagnostic volumes and costs were assessed for 2020 and 2012 microhematuria guidelines, respectively. Of the 3,789 patients included for analysis, 1,382 (36.5%), 1,026 (27.1%) and 1,381 (36.4%) were retroactively stratified as low risk, intermediate risk (InR) and high risk (HiR), respectively. A total of 19 cases of UCC (17 bladder, 2 upper tract) were diagnosed, of which 84% were HiR. For high-grade UCC, 92% of cases were HiR. The 2020 guidelines recommended renal ultrasound for 1,117 InR cases, computerized tomography urogram (CTU) for 1,476 HiR cases, and cystoscopy for 2,593 InR and HiR cases combined. Total costs were $1,905,236 (2012) versus $1,260,677 (2020), driven mainly by CTU costs. Per-cancer detected costs were $100,276 (2012) versus $61,760 (2020). In retrospect, the 2020 guidelines would have effectively risk-stratified microhematuria cases for detection of malignancies. As compared to the 2012 guidelines, application of the 2020 guidelines would result in significant changes to diagnostic and procedural volumes, while substantially reducing total and per-patient costs.


Characteristics of US-Born Versus Foreign-Born Americans of African Descent With Chronic Hepatitis B.
Hepatitis B virus (HBV) infection is more common in African Americans than in white Americans. We compared the epidemiologic, clinical, and virological characteristics of US-born African Americans (USAAs) to those of foreign-born African Americans (FBAAs) with chronic hepatitis B. The adult cohort study of the Hepatitis B Research Network enrolls patients with HBV infection from 21 clinical sites in the United States and Canada. A total of 237 (15%) of the adult participants with chronic HBV infection that were enrolled from January 20, 2011, to October 2, 2013, were of African descent, including 57 USAAs and 180 FBAAs (76%). Compared with FBAAs, USAAs were older and more likely to have acquired HBV through sexual exposure, to be HBeAg-positive, to have higher HBV DNA levels, and to be infected with HBV genotype A2. FBAAs from West Africa were more likely to have elevated serum alanine aminotransferase (72% vs. 50%; P < 0.01) and higher HBV DNA levels (median, 3.2 log10 IU/mL vs. 2.8 log10 IU/mL; P = 0.03) compared with East African FBAAs. The predominant HBV genotype among West African FBAAs was E (67%), whereas genotypes A (78%) and D (16%) were common in East African FBAAs. Significant differences were found between USAAs and FBAAs, highlighting the need for tailored strategies for prevention and management of chronic HBV infection for African Americans.


Serious anaphylactic reactions due to protamine sulfate: a systematic literature review.
Anaphylactic reactions caused by injection of protamine sulfate during cardiac surgery are a well-known complication. A systematic literature review was therefore conducted to gather evidence of the knowledge concerning these side effects, and to see if any prospective randomized studies supported this. Studies investigating the effect of protamine sulfate in human beings were extracted from MEDLINE, Embase and the Cochrane Library, retrieving 487 articles. Abstracts were evaluated by both authors, and referred articles not found in the primary search were furthermore extracted from reviews and case reports, resulting in a total of 272 relevant articles. Of these, 9 retrospective studies and 16 prospective studies were performed in an evidence-based manner. However, only 3 of the 16 prospective articles had an optimal design as far as inclusion criteria, randomization, and description of symptoms were concerned. Incidence of anaphylactic reactions in the prospective studies was 0.69% compared to 0.19% in the retrospective studies, but caution should be taken due to a pronounced heterogeneity of those studies. One study found heparinase I unsuitable as replacement for protamine sulfate. Overall, our findings support the low incidence of anaphylactic reactions reported in previous studies, but of note only few prospective investigations was conducted on the subject. Our study also emphasizes the need for critical appraisal of many routine procedures: in all aspects of medical care, systematic literature review conducted in a well-structured, repeated manner should be given high priority.


Analyzing latent state-trait and multiple-indicator latent growth curve models as multilevel structural equation models.
Latent state-trait (LST) and latent growth curve (LGC) models are frequently used in the analysis of longitudinal data. Although it is well-known that standard single-indicator LGC models can be analyzed within either the structural equation modeling (SEM) or multilevel (ML; hierarchical linear modeling) frameworks, few researchers realize that LST and multivariate LGC models, which use multiple indicators at each time point, can also be specified as ML models. In the present paper, we demonstrate that using the ML-SEM rather than the SL-SEM framework to estimate the parameters of these models can be practical when the study involves (1) a large number of time points, (2) individually-varying times of observation, (3) unequally spaced time intervals, and/or (4) incomplete data. Despite the practical advantages of the ML-SEM approach under these circumstances, there are also some limitations that researchers should consider. We present an application to an ecological momentary assessment study (N = 158 youths with an average of 23.49 observations of positive mood per person) using the software Mplus (Muthén and Muthén, 1998-2012) and discuss advantages and disadvantages of using the ML-SEM approach to estimate the parameters of LST and multiple-indicator LGC models.


Identification of Tspan9 as a novel platelet tetraspanin and the collagen receptor GPVI as a component of tetraspanin microdomains.
Platelets are essential for wound healing and inflammatory processes, but can also play a deleterious role by causing heart attack and stroke. Normal platelet activation is dependent on tetraspanins, a superfamily of glycoproteins that function as 'organisers' of cell membranes by recruiting other receptors and signalling proteins into tetraspanin-enriched microdomains. However, our understanding of how tetraspanin microdomains regulate platelets is hindered by the fact that only four of the 33 mammalian tetraspanins have been identified in platelets. This is because of a lack of antibodies to most tetraspanins and difficulties in measuring mRNA, due to low levels in this anucleate cell. To identify potentially platelet-expressed tetraspanins, mRNA was measured in their nucleated progenitor cell, the megakaryocyte, using serial analysis of gene expression and DNA microarrays. Amongst 19 tetraspanins identified in megakaryocytes, Tspan9, a previously uncharacterized tetraspanin, was relatively specific to these cells. Through generating the first Tspan9 antibodies, Tspan9 expression was found to be tightly regulated in platelets. The relative levels of CD9, CD151, Tspan9 and CD63 were 100, 14, 6 and 2 respectively. Since CD9 was expressed at 49000 cell surface copies per platelet, this suggested a copy number of 2800 Tspan9 molecules. Finally, Tspan9 was shown to be a component of tetraspanin microdomains that included the collagen receptor GPVI (glycoprotein VI) and integrin alpha6beta1, but not the von Willebrand receptor GPIbalpha or the integrins alphaIIbbeta3 or alpha2beta1. These findings suggest a role for Tspan9 in regulating platelet function in concert with other platelet tetraspanins and their associated proteins.


Personalized Protein Supplementation Improves Total Protein, Leucine, and Energy Intake in (Pre)Sarcopenic Community-Dwelling Older Adults in the ENHANce RCT.
Recommendations concerning protein quantity, source, and leucine intake for older adults are difficult to reach by regular dietary intake. This randomized clinical trial assesses in sarcopenic community-dwelling older adults (i) the regular (non-supplemented) daily protein and leucine intake; and (ii) the effect of personalized protein supplementation (aiming for an evenly distributed total protein intake of 1.5 g·kg-1·d-1 of body mass, accounting for energy intake) on regular and total (dietary and supplemental) intake. A preliminary feasibility study in participants of the ongoing Exercise and Nutrition for Healthy AgeiNg (ENHANce) study was performed with the objective to assess the intake and distribution of regular dietary protein and leucine, protein source and energy intake in (pre)sarcopenic community-dwelling older adults. Moreover, this study aimed to assess if personalized protein supplementation was feasible without negatively affecting regular dietary intake. ENHANce (NCT03649698) is a 5-armed RCT that assesses the effect of anabolic interventions on physical performance in (pre)sarcopenic older adults. In August 2019, n = 51 participants were included in ENHANce with complete available data on dietary intake at screening and thus eligible for inclusion in present analysis. Of these, n = 35 participants completed the intervention period of ENHANce at the moment of analysis, allowing an exploration of the effect of supplementation on regular dietary intake. The regular dietary protein intake of 51 (pre)sarcopenic adults (73.6 ± 6.5 years) was 1.06 ± 0.3 g·kg-1·d-1 of body mass. Protein supplementation (n = 20) improved total protein intake to 1.55 ± 0.3 g·kg-1·d-1 of body mass (P < 0.001) without affecting regular dietary protein (P = 0.176) or energy intake (P = 0.167). Placebo supplementation (n = 15) did not affect regular dietary protein intake (P = 0.910) but decreased regular dietary energy intake (P = 0.047). Regular leucine intake was unevenly distributed over the day, but increased by supplementation at breakfast (P < 0.001) and dinner (P = 0.010) to at least 2.46 g leucine·meal-1, without reducing regular dietary leucine intake (P = 0.103). Animal-based protein intake-the main protein source-was not affected by supplementation (P = 0.358). Personalized protein supplementation ensured an adequate quantity and even distribution of protein and leucine over the day, without affecting regular dietary protein or energy intake.


In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase.
Human norovirus causes approximately 219,000 deaths annually, yet there are currently no antivirals available. A virtual screening of commercially available drug-like compounds (~300,000) was performed on the suramin and PPNDS binding-sites of the norovirus RNA-dependent RNA polymerase (RdRp). Selected compounds (n = 62) were examined for inhibition of norovirus RdRp activity using an in vitro transcription assay. Eight candidates demonstrated RdRp inhibition (>25% inhibition at 10 µM), which was confirmed using a gel-shift RdRp assay for two of them. The two molecules were identified as initial hits and selected for structure-activity relationship studies, which resulted in the synthesis of novel compounds that were examined for inhibitory activity. Five compounds inhibited human norovirus RdRp activity (>50% at 10 µM), with the best candidate, 54, demonstrating an IC50 of 5.6 µM against the RdRp and a CC50 of 62.8 µM. Combinational treatment of 54 and the known RdRp site-B inhibitor PPNDS revealed antagonism, indicating that 54 binds in the same binding pocket. Two RdRps with mutations (Q414A and R419A) previously shown to be critical for the binding of site-B compounds had no effect on inhibition, suggesting 54 interacts with distinct site-B residues. This study revealed the novel scaffold 54 for further development as a norovirus antiviral.


Automatic and motivational correlates of physical activity: does intensity moderate the relationship?
The purpose of this study was to examine the predictive capability of a habit construct, controlling for intention and perceived behavioral control, with moderate and strenuous intensity physical activity. This approach was expanded through an examination of whether conscious deliberation in the initiation of physical activity would attenuate these findings and a test of the intention-habit interaction. Participants were 337 undergraduate students who completed the habit measure and measures of intention, deliberation, and perceived behavioral control phrased in either moderate or vigorous intensities at time 1. This was followed by a measure of behaviour 2 weeks later. Results using stacked structural equation models (moderate and vigorous intensity) demonstrated the direct effect of habit and accounted for a significant effect on physical activity after controlling for intention and perceived behavioral control; this effect was invariant to intensity and conscious deliberation. A 3-way interaction, however, was identified for the habit X intention relationship and intensity. In the moderate intensity condition, individuals who reported higher habits showed a lower intention-behavior relationship when compared with those who reported modest or low habits. By contrast, individuals who reported high habit levels in the vigorous physical activity condition demonstrated a larger intention-behavior relationship than their modest and low habit counterparts. The results support the notions that some properties of physical activity may have an automatic component and that habits may be important to physical activity action initiation.


Extended-wear soft contact lenses for vision studies in monkeys.
The authors have designed and produced extended-wear contact lenses for rhesus monkeys. High-plus lenses to correct neonatal aphakia as well as lenses dyed black for use as occluders to treat amblyopia have been evaluated. Four infant monkeys fitted with soft lenses have successfully worn these extended-wear lenses almost continuously throughout their first year of life. These experiments demonstrate that rhesus monkeys tolerate extended-wear contact lenses well when these lenses are correctly designed, comfortably fitted, and their wear carefully monitored. Furthermore, the results demonstrate that usable levels of vision can be maintained in monocularly aphakic infant monkeys. Since similar methods are now used to treat children with monocular cataracts, our animal model using extended-wear contact lenses on young monkeys should facilitate new and clinically relevant amblyopia experiments.


Implantation increases tensile strength and collagen content of self-assembled tendon constructs.
Tissue-engineered tendons, derived from an autologous cell source, have the potential to provide an ideal replacement graft that is biologically compatible and has the ability to adapt to the specific mechanical requirements of the in vivo environment. Scaffold-free tendon constructs have been successfully engineered in vitro. However, when compared against native tendons the constructs demonstrate both a lower tensile strength and collagen content. We hypothesized that the in vitro environment lacks certain environmental stimuli and that implantation in vivo would facilitate the maturation of engineered tissues. Using primary Achilles tendon fibroblasts from adult rats, self-organizing constructs were created in vitro. Tendon constructs were implanted subcutaneously into the groins of adult rats for 4 wk, while controls remained in vitro. Implanted constructs increased in stiffness by three orders of magnitude when compared with the in vitro controls (7,500 vs. 22.3 kPa). This increase in tangent modulus correlated with a significant increase in collagen content, as measured by hydroxyproline concentration, from 3.9% for the in vitro controls to 22.7% in the in vivo conditioned group. In addition, collagen fiber diameter increased from 22.0 to 75.4 nm as a result of in vivo implantation. The tensile strength and collagen content of in vivo conditioned constructs were similar to the values determined for neonatal rat tibialis anterior tendons.


Ability profile of the elite volleyball player.
The aim of this study was to examine the cognitive, motor, and perceptual abilities of elite volleyball players. These abilities were considered responsible for high quality performance by expert athletes. The elite group was formed with 12 members of the Greek Junior National Volleyball team. A group of 18 physical education students were the novice athletes. The measured abilities were selected by expert volleyball coaches as those most important for an elite athlete. Analysis showed differences between the abilities of the two groups of athletes were significant. An ability profile for the elite volleyball player can be formed.


Localization of antigen in tissue cells; V. Capsular polysaccharide of Friedländer bacillus, type B, in the mouse.
The fate of the capsular polysaccharide of Friedländer B bacillus in the mouse after its intravenous administration was studied by means of homologous antibody labelled with fluorescein. The results indicate that this acid polysaccharide, like pneumococcal polysaccharide, types II and III, was rapidly taken up by phagocytic cells throughout the body, where it persisted in decreasing concentration for more than 33 days. It was widely distributed in the capillary endothelium and on collagenous fibres in all organs. It made a transient appearance in or on lymphocytes in the spleen and lymph nodes. It was found in the hepatic epithelium and in the bile; in the juxtaglomerular segment of the distal renal tubule and in an occasional cast in the lumens of collecting tubules; in the epithelium of some uterine glands; and in cells in the steroid-secreting tissues of the ovary, suprarenal cortex, and perhaps of the testis. In joints the synovial membranes contained large amounts of antigen, and some also penetrated into cartilage cells adjacent to the joint cavity. Osteoblasts and a few osteocytes also took up the polysaccharide. When administered by inhalation, the polysaccharide was found in high concentration in the pulmonary macrophages but could not be found constantly in other lung elements.


Roots of neuroanatomy, neurology, and neurosurgery as found in the Bible and Talmud.
Historical observations and interpretations regarding the treatment of components of the nervous system can be found in the writings of the Bible and Talmud. A review of topics germane to modern neuroanatomy, neurology, and neurosurgery from these early, rich writings is presented herein. These historic writings provide a glimpse into the early understanding, description, and treatment of pathologies of the nervous system.


Effectiveness of Specialized Nutritious Foods and Social and Behavior Change Communication Interventions to Prevent Stunting among Children in Badakhshan, Afghanistan: Protocol for a Quasi-Experimental Study.
Stunting predominantly occurs during the first 1000 days of life and continues to the age of five years. We will aim to assess the effectiveness of specialized nutritious foods (SNF)and social and behavior change communication (SBCC) strategies during the first 1000 days of life to prevent stunting among children in two rural districts of Badakhshan, Afghanistan. This will be a quasi-experimental pre-post study with the control group utilizing qualitative and quantitative methods. Before launching the program, formative research will be conducted on the acceptability, appropriate use and SBCC strategies needed to support the introduction of intervention package. Repeated cross-sectional baseline and endline surveys will be conducted in both the intervention and the control districts. After the formative research and baseline household survey, an intervention focusing on the provision of SNF, targeting pregnant and lactating women and children 6-23 months, and SBCC strategies will be implemented for at least 12 months. The primary outcome will be a reduction in the prevalence of stunting among children under two years in the intervention group compared to the control group. We will aim to compare the intervention and control group between the pre- and post-intervention assessments to isolate the effect of the intervention by difference-in-differences estimates. The program monitoring and evaluation component will examine the quality of implementation, acceptability of intervention, identification of potential barriers and to learn how to enhance the program's effectiveness through ongoing operational improvements. The results will be beneficial to design interventions to prevent stunting within Afghanistan and other low-middle-income countries.


Human embryos cultured in vitro to 14 days.
We know a great deal about the development of the mammalian embryo until the time that the blastocyst implants into the uterus. With model organisms such as the mouse, we have also developed a considerable understanding of development immediately around gastrulation as embryos can be recovered at this stage for short-term in vitro culture. However, the intervening period of development remained a 'black box' because it takes place as the blastocyst is implanting into the uterus. Over the past 6 years, techniques pioneered and developed in Magdalena Zernicka-Goetz's laboratory for the in vitro culture of embryos through these implantation stages have opened up this box, affording the first glimpse of embryonic development through these previously hidden stages. Remarkably, the techniques developed with mouse embryos are equally applicable to human embryos, ushering the very first opportunities for studying our own development throughout this time. Here, I outline how the culture methods were developed, paving the way to culture of the human embryo to the point of gastrulation, an accomplishment recognized as the People's Choice for the Scientific Breakthrough of 2016 in Science magazine. I also discuss the new ethical challenges raised by the possibility of extending the time limits for human embryo culture.


[The pharmacokinetics of different drug forms of nifedipine when used singly and in a course as monotherapy and in combination with Cordanum and triampur preparations in patients with arterial hypertension].
Pharmacokinetics of three drugs derived from nifedipine: corinfar, corinfar retard, and SL adalate in the cases of a single and course administration in patients with arterial hypertension and the effect of cordanum and triampur on pharmacokinetics of corinfar retard in combined repeated administration have been studied. The studies were carried out in 6 groups of patients with arterial Hypertension, each group included 10 patients. Nifedipine concentration in blood plasma was determined using a special HPLC procedure within 24 h after administration of the drugs at a dose 20 mg. A pharmacokinetic characteristics of new drug adalate SL with two-step liberation of nifedipine. A possibility of autoinhibition was noted for corinfar and adalate SL in course therapy. A conclusion was made that cordanum and triampur did not affect the pharmacokinetics of corinfar retard.


Asian rhinoplasty techniques.
Asian rhinoplasty is a broad term that refers to a set of rhinoplasty techniques commonly used in Asian populations. Although these techniques are well developed and documented in Asian languages, there are relatively few English-language articles on the subject, and even fewer on current debates and controversies among plastic surgeons. Knowledge of these different techniques is essential to perform an adequate rhinoplasty in Asians. For Western patients, reduction rhinoplasty with dorsal hump rasping and lower lateral cartilage resection is classic. In contrast, silicone implant augmentation rhinoplasty is the most commonly used technique in Orientals. This article focuses on current rhinoplasty practices and controversies in Asia. It reviews morphologic differences between the Oriental and Western noses, as well as common patient requests. Polytetrafluoroethylene (Gore-Tex) and silicone implant augmentation are discussed. A new augmentation rhinoplasty with diced cartilage is described in more detail.


Pollination syndromes in a Caatinga plant community in northeastern Brazil: seasonal availability of floral resources in different plant growth habits.
To describe plant phenological patterns and correlate functioning for the quantity and quality of resources available for the pollinator, it is crucial to understand the temporal dynamics of biological communities. In this way, the pollination syndromes of 46 species with different growth habits (trees, shrubs, herbs, and vines) were examined in an area of Caatinga vegetation, northeastern Brazil (7° 28' 45″ S and 36° 54' 18″ W), during two years. Flowering was monitored monthly in all the species, over two years (from January 2003 to December 2004). Pollination syndromes were characterised based on floral traits such as size, colour, morphology, symmetry, floral resources, as well as on direct visual observation of floral visitors on focal plants and published information. We observed differences among the plant growth habits with respect to floral traits, types of resources offered, and floral syndromes. The flowering periods of the species varied among floral syndrome groups. The majority of the melittophilous species flowered during the rainy season in the two study years, while the species of the other pollination syndroms flowered at the end of the dry season. An asynchrony of flowering was noted among the chiropterophilous species, while the phalenophilous group concentrated during the rainy season. The overall availability of floral resources was different during the rainy and the dry seasons, and also it varied among plants with different growth habits. The availability of oil-flowers coincided with the period of low nectar availability. We observed a relationship between the temporal distribution of the pollination syndromes and the availability of floral resources among each growth habits in this tropical ecosystem. Resource allocation in seasonal environments, such as the Caatinga, can function as a strategy for maintaining pollinators, facilitating therefore the reproductive success of plant species. The availability of floral resources during all the year, specially in seasonal environments such as the Caatinga, may function as a strategy to maintain pollinator populations ensuring the reproductive success of the plants.


Down-regulated paxillin suppresses cell proliferation and invasion by inhibiting M2 macrophage polarization in colon cancer.
The paxillin and M2 macrophage are all involved in cell proliferation and tumor progression, and this study aims to explore the interaction between them in colon cancer and the role of paxillin in cancer progression. Expression of mRNAs and proteins was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, separately. Endogenous expression of genes was modulated by recombinant plasmids and cell transfection. The levels of cytokines were determined by enzyme-linked immunosorbent assay (ELISA). The cell viability, invasion and migration were detected using the MTT assay, the transwell assay and the wound-healing cell migration assay, respectively. A nude mouse model for human colon cancer was constructed for tumor orthotopic expression. Paxillin was up-regulated in tumor-associated macrophages (TAMs). Paxillin was up-regulated in process of M2 macrophage polarization. M2 macrophage polarization was inhibited with paxillin suppressed. Down-regulated paxillin inhibited cell proliferation and invasion in colon cancer through suppressing M2 macrophage polarization. PI3k/Akt inhibitor repressed M2 macrophage polarization through down-regulating paxillin. PI3k/Akt inhibitor inhibited the function of the macrophage in promoting cell proliferation and invasion of colon cancer through down-regulating paxillin. Down-regulated paxillin in macrophages inhibited tumor growth of colon cancer. With the PI3K/AKT pathway inhibited, down-regulated paxillin suppressed colon cancer cell proliferation and invasion by inhibiting the M2 macrophage polarization, thereby restraining the tumor progression.


Fibromyalgia and chronic widespread pain in patients with inflammatory bowel disease: a cross sectional population survey.
To assess the prevalence of fibromyalgia (FM) and chronic widespread pain (CWP) in a population based cohort of patients with inflammatory bowel disease (IBD). Patients in a prospective survey on newly diagnosed IBD were, 5 years after study entry, invited to a clinical examination including the investigation of musculoskeletal manifestations. A total of 521 patients were examined, corresponding to 80% of surviving cases with definite diagnoses of ulcerative colitis (UC) and Crohn's disease (CD). The diagnoses of FM and CWP strictly followed the American College of Rheumatology classification criteria of 1990. At clinical examination, FM was diagnosed in 18 patients (3.5%), 3.7% with UC and 3.0% with CD. The prevalence was 6.4% in females and 0.4% in males. Thirty-eight patients (7.3%) had CWP (8.5% with UC; 4.8% with CD). The female:male ratio was 27:3 in the UC group and 8:0 in CD. In 19 patients (50%), CWP occurred after onset of IBD. No correlation with the extent of intestinal inflammation and the occurrence of FM and CWP was found. The prevalences of FM and CWP in patients with IBD were similar to those of the general population. There were no differences in prevalence of FM and CWP between UC and CD. Chronic idiopathic inflammation of the intestine does not appear to predispose to chronic widespread pain.


Is there a relationship between thoracic dimensions and pulmonary function in early-onset scoliosis?
Cross-sectional retrospective analysis. To examine the degree of correlation between thoracic dimension outcome measures and pulmonary function in early-onset scoliosis (EOS). Change in thoracic dimension (TD) measurements and spine length are commonly reported outcome measures after treatment for EOS. Although ultimately improving or maintaining pulmonary function is the goal of EOS treatment strategies, it is unclear whether commonly reported 2-dimensional TD measurements represent good predictors of pulmonary function. A cross-sectional analysis of patients including all diagnoses obtained from 2 EOS databases containing TD measurements and pulmonary function data was performed. Relationships between individual TD measurements and pulmonary function measurements were assessed using the Pearson correlation analysis. TD measurements (pelvic inlet width, T1-T12 height, T1-S1 height, and coronal chest width) and standard pulmonary function measurements were compared. TD percentiles normalized for pelvic inlet width were also calculated and correlated with pulmonary function measurement percentiles. Univariate and multivariate linear regression analyses determined whether TD measurements could predict pulmonary function. There were 121 patients (65 females, 56 males) in the study. Mean age at evaluation was 9.3 years (range, 2.7-18.1 yr). T1-T12 height, T1-S1 height, maximal chest width, and pelvic inlet width were all significantly correlated with forced air volume expelled in 1 second, total forced air volume, and total lung capacity (correlation coefficients [r] 0.33-0.61; all P<0.001). T1-T12 predicted percentile (normalized for pelvic width) was significantly correlated with forced air volume expelled in 1 second and total forced air volume predicted percentiles (r=0.32, P<0.001 and r=0.27, P=0.004, respectively). Regression analysis determined that T1-T12 percentile was a significant predictor of forced air volume expelled in 1 second percentile and total forced air volume percentiles. Regression analysis found no predictive factors of total lung capacity percentile. Traditional 2-dimensional TD measurements (T1-T12 height) used to measure outcomes in EOS can be used as weak predictors of pulmonary function outcome. However, better outcome measures need to be developed, such as 3-dimensional and dynamic measurements. 3.


Targeting IL-1β as an immunopreventive and therapeutic modality for K-ras-mutant lung cancer.
K-ras-mutant lung adenocarcinoma (KM-LUAD) is associated with abysmal prognosis and is tightly linked to tumor-promoting inflammation. A human mAb, canakinumab, targeting the proinflammatory cytokine IL-1β, significantly decreased the risk of lung cancer in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study. Interestingly, we found high levels of IL-1β in the lungs of mice with K-rasG12D-mutant tumors (CC-LR mice). Here, we blocked IL-1β using an anti-IL-1β mAb in cohorts of 6- or 14-week-old CC-LR mice to explore its preventive and therapeutic effect, respectively. IL-1β blockade significantly reduced lung tumor burden, which was associated with reprogramming of the lung microenvironment toward an antitumor phenotype characterized by increased infiltration of cytotoxic CD8+ T cells (with high IFN-γ and granzyme B expression but low programmed cell death 1 [PD-1] expression) while suppressing neutrophils and polymorphonuclear (PMN) myeloid-derived suppressor cells. When querying the Cancer Genome Atlas data set, we found positive correlations between IL1B expression and infiltration of immunosuppressive PMNs and expression of their chemoattractant, CXCL1, and PDCD1 expressions in patients with KM-LUAD. Our data provide evidence that IL-1β blockade may be a preventive strategy for high-risk individuals and an alternative therapeutic approach in combination with currently available treatments for KM-LUAD.


Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world and its incidence is increasing rapidly. NAFLD is a spectrum ranging from simple steatosis, which is relatively benign hepatically, to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis. Obesity, insulin resistance, type 2 diabetes mellitus, and dyslipidemia are the most important risk factors for NAFLD. Due to heavy enrichment with metabolic risk factors, individuals with NAFLD are at significantly higher risk for cardiovascular disease. Individuals with NAFLD have higher incidence of type 2 diabetes. The diagnosis of NAFLD requires imaging evidence of hepatic steatosis in the absence of competing etiologies including significant alcohol consumption. Liver biopsy remains the gold standard for diagnosing NASH and for determining prognosis. Weight loss remains a cornerstone of treatment. Weight loss of ~5% is believed to improve steatosis, whereas ~10% weight loss is necessary to improve steatohepatitis. A number of pharmacologic therapies have been investigated to treat NASH, and agents such as vitamin E and thiazolidinediones have shown promise in select patient subgroups.


Very low helminth infection in sheep grazed on pastures fertilised by sewage sludge or cattle slurry.
Helminth infection acquired by lambs grazing on pastures fertilised either by urban sewage sludge or cattle slurry were studied in temperate Central Western France. The aim was to assess the risk of larval cestodoses in lambs after sewage application and of digestive tract nematode infection following the slurry application. Twenty-six sheep were allocated on two paddocks of 0.7 ha, one fertilised with sludge and the other with cattle slurry. The delay between application and actual grazing was 6 weeks; grazing on these paddocks extended from mid July to beginning of November 2002. The herbage biomass was slightly increased in the sludge paddock but it did not result in an increase of lamb live weight, compared with the slurry paddock. The lambs did not acquire cysticercosis or any other larval cestodoses in the sewage sludge group and only very limited infections with Cooperia spp. and Nematodirus spp. were observed in the slurry group. It was concluded that in our conditions the helminth risk was extremely low and was not a cause of restriction of the use of these biowastes.


Giant angular dispersion mediated by plasmonic modal competition.
We report on the modal competition mediated angular dispersion by heterogeneously coupled plasmonic waveguides. By varying the wavelength of the excitation, the surface waves propagate alongside the upper and lower interfaces can be manipulated in coupled, decoupled, and cutoff regimes. Depending on the coupling states, the output beam can be steered between +15° and -17° for wavelength from λ = 695 nm to λ = 675 nm. The maximum achieved angular dispersion can be as large as 2.1°/nm. This finding may revolutionize current design concept of spectrometers, providing a significant way to scale down the form factor further into nano-size.


[The flu far and near: comparing the 1918 and 2009 pandemics].
In this debate, Latin American historians compare the 1918-1919 flu pandemic with the one sweeping the continent in 2009, focusing especially on the experiences in Mexico, Argentina, and Brazil. They analyze the strategies adopted on both occasions, above all isolation measures, port and airport surveillance, and urban interventions. Comparisons are drawn between the actions of federal and local governments, positions taken by doctors and the media, and people's behavior, particularly regarding fear and death. The debaters also analyze the performance of assistance structures, the treatment and prevention measures recommended by public health agencies and private groups with a vested interest in drug sales, and popular and home remedies. The debate extends to how the 1918 experience has influenced the evaluation of today's crisis and what legacy it may leave behind.


New COVID-19 Cases and Hospitalizations Among Adults, by Vaccination Status - New York, May 3-July 25, 2021.
Data from randomized clinical trials and real-world observational studies show that all three COVID-19 vaccines currently authorized for emergency use by the Food and Drug Administration* are safe and highly effective for preventing COVID-19-related serious illness, hospitalization, and death (1,2). Studies of vaccine effectiveness (VE) for preventing new infections and hospitalizations attributable to SARS-CoV-2, the virus that causes COVID-19), particularly as the B.1.617.2 (Delta) variant has become predominant, are limited in the United States (3). In this study, the New York State Department of Health linked statewide immunization, laboratory testing, and hospitalization databases for New York to estimate rates of new laboratory-confirmed COVID-19 cases and hospitalizations by vaccination status among adults, as well as corresponding VE for full vaccination in the population, across all three authorized vaccine products. During May 3-July 25, 2021, the overall age-adjusted VE against new COVID-19 cases for all adults declined from 91.7% to 79.8%. During the same period, the overall age-adjusted VE against hospitalization was relatively stable, ranging from 91.9% to 95.3%. Currently authorized vaccines have high effectiveness against COVID-19 hospitalization, but effectiveness against new cases appears to have declined in recent months, coinciding with the Delta variant's increase from <2% to >80% in the U.S. region that includes New York and relaxation of masking and physical distancing recommendations. To reduce new COVID-19 cases and hospitalizations, these findings support the implementation of a layered approach centered on vaccination, as well as other prevention strategies such as masking and physical distancing.


Monocyte chemoattractant protein-1 (CCL-2) integrates mechanical and endocrine signals that mediate term and preterm labor.
Recent evidence suggests that leukocytes infiltrate uterine tissues at or around the time of parturition, implicating inflammation as a key mechanism of human labor. MCP-1 (also known as C-C chemokine motif ligand 2, CCL-2) is a proinflammatory cytokine that is up-regulated in human myometrium during labor. Myometrium was collected from pregnant rats across gestation and at labor. Total RNA and proteins were subjected to real-time PCR and ELISA, respectively. Ccl-2 gene and protein expression was significantly up-regulated in the gravid rat myometrium before and during labor, which might suggest that it is regulated positively by mechanical stretch of the uterus imposed by the growing fetus and negatively by physiological withdrawal of progesterone (P4). We confirmed in vivo that: 1) administration of P4 receptor antagonist RU486 induced an increase in Ccl-2 mRNA and preterm labor, whereas 2) artificial maintenance of elevated P4 levels at late gestation caused a significant decrease in gene expression and blocked labor; 3) Ccl-2 was elevated specifically in the gravid horn of unilaterally pregnant rats suggesting that mechanical strain imposed by the growing fetus controls its expression in the myometrium; 4) in vitro static mechanical stretch of primary rat myometrial smooth muscle cells (25% elongation) induced a release of Ccl-2 protein, which was repressed by pretreatment with P4 (1 microM); and 5) stretch enhanced their monocyte chemoattractant activity. These data indicate that Ccl-2 protein serves to integrate mechanical and endocrine signals contributing to uterine inflammation and the induction of labor and thus may represent a novel target for therapeutic prevention of preterm labor in humans.


Use of atracurium in patients with or without renal failure.
Nine patients with normal renal function, and eight renal failure patients scheduled for renal transplantation, were anesthetized under nitrous oxide and isoflurane to determine the influence of renal function on the effect of atracurium. Atracurium 0.5 mg/kg, was given as an iv bolus, followed by 0.2 mg/kg as maintenance dose. The onset times, duration of action, duration of maintenance dose and recovery times of neuromuscular blockade were recorded and compared. There were no differences in the pharmacodynamics except that the uremic patients had slightly longer recovery time. It is concluded that atracurium is an ideal drug for uremic patients.


Quantifying Unnecessary Normal Tissue Complication Risks due to Suboptimal Planning: A Secondary Study of RTOG 0126.
The purpose of this study was to quantify the frequency and clinical severity of quality deficiencies in intensity modulated radiation therapy (IMRT) planning in the Radiation Therapy Oncology Group 0126 protocol. A total of 219 IMRT patients from the high-dose arm (79.2 Gy) of RTOG 0126 were analyzed. To quantify plan quality, we used established knowledge-based methods for patient-specific dose-volume histogram (DVH) prediction of organs at risk and a Lyman-Kutcher-Burman (LKB) model for grade ≥2 rectal complications to convert DVHs into normal tissue complication probabilities (NTCPs). The LKB model was validated by fitting dose-response parameters relative to observed toxicities. The 90th percentile (22 of 219) of plans with the lowest excess risk (difference between clinical and model-predicted NTCP) were used to create a model for the presumed best practices in the protocol (pDVH0126,top10%). Applying the resultant model to the entire sample enabled comparisons between DVHs that patients could have received to DVHs they actually received. Excess risk quantified the clinical impact of suboptimal planning. Accuracy of pDVH predictions was validated by replanning 30 of 219 patients (13.7%), including equal numbers of presumed "high-quality," "low-quality," and randomly sampled plans. NTCP-predicted toxicities were compared to adverse events on protocol. Existing models showed that bladder-sparing variations were less prevalent than rectum quality variations and that increased rectal sparing was not correlated with target metrics (dose received by 98% and 2% of the PTV, respectively). Observed toxicities were consistent with current LKB parameters. Converting DVH and pDVH0126,top10% to rectal NTCPs, we observed 94 of 219 patients (42.9%) with ≥5% excess risk, 20 of 219 patients (9.1%) with ≥10% excess risk, and 2 of 219 patients (0.9%) with ≥15% excess risk. Replanning demonstrated the predicted NTCP reductions while maintaining the volume of the PTV receiving prescription dose. An equivalent sample of high-quality plans showed fewer toxicities than low-quality plans, 6 of 73 versus 10 of 73 respectively, although these differences were not significant (P=.21) due to insufficient statistical power in this retrospective study. Plan quality deficiencies in RTOG 0126 exposed patients to substantial excess risk for rectal complications.


[Successful treatment of an infant with fulminant hepatitis by factor VII concentrate].
A 2-month-old boy was admitted to our hospital because of poor sucking and jaundice. There were no abnormalities during the whole period of pregnancy and at birth. His mother was a HBeAb positive HBsAg carrier, but prophylactic maneuver such as anti-HB immunoglobulin and HB vaccine was not performed on him at birth. Physical examination on admission revealed mild disturbance of consciousness. The laboratory findings showed marked increments of serum bilirubin, GOT, GPT, and NH3, and prolongation of prothrombin time, activated partial thromboplastin time and hepaplastin test. Thus, he was diagnosed as fulminant hepatitis and treated with exchange transfusion once or twice a day. Biochemical data improved gradually, but hypocoagulable states remained unchanged. At that time we decided to use Factor VII concentrate, because we found that, among several coagulation factors, factor VII activity decreased most rapidly after exchange transfusion. The alternate therapy of exchange transfusion and Factor VII concentrate improved his coagulation abnormality without any side effects. Our experience suggests that the combination therapy of exchange transfusion and Factor VII concentrate may be useful for management of fulminant hepatitis, particularly for uncontrollable coagulopathy.


Lateral calcaneal artery skin flap for posterior heel coverage.
The lateral calcaneal artery flap is a neurovascular flap from the lateral side of the calcaneus consisting of the lateral calcaneal artery, sural nerve, and small saphenous vein. It is most useful in coverage of defects over the posterior heel with or without exposure of the tendo Achilles. The donor site is covered with a split-thickness skin graft. Preoperative planning for this flap must include Doppler examination of the course of the artery, as well as documentation of the presence of the other pedal pulses. Disadvantages to use of the flap are the skin depression at the donor site and a loss of two-point discrimination along the dorsolateral foot caused by transfer of the sural nerve.


The role of follow-up radiographic studies in nonoperative management of spleen trauma.
The management of splenic injuries has evolved significantly in recent years from an operative to a nonoperative approach in stable patients with blunt abdominal trauma. The management of these patients with serial radiographic studies before hospital discharge remains controversial. We reviewed the management of 90 patients retrospectively who were admitted to our Level II trauma center with splenic injuries secondary to blunt trauma to determine the value of serial radiographic studies. Forty-seven (52%) patients underwent immediate laparotomy. Forty-three (48%) patients were managed conservatively without surgery. All nonoperative patients had an initial CT of the abdomen to evaluate their abdominal injuries. Among the 43 patients managed without surgery 31 had no follow-up radiographic studies. Twelve patients had follow-up studies before discharge. Two of these 12 patients subsequently underwent splenectomy. Both had developed hypotension, tachycardia, and a decreasing hematocrit, which prompted their repeat radiographic studies. Ten patients had no change in their clinical status and showed no significant change in the radiographic injury pattern to the spleen. One patient who was initially managed nonoperatively became hemodynamically unstable with increasing abdominal pain and subsequently underwent splenectomy without follow-up radiographic studies. The remaining 30 patients who had no follow-up studies had no significant change in their clinical abdominal examinations and had no further complications from their splenic injuries. Routine follow-up radiographic evaluations are not necessary in the nonoperative management of stable patients with splenic injuries.


Body posture and breathing frequency in newborn mammals.
The effects of changing body posture on breathing frequency (f) of anesthetized newborn rats, rabbits, and dogs have been studied. No significant changes were observed between horizontal postures (supine, prone, left, and right lateral). In the vertical head-down position, most of the animals did not show any significant variation of f. Breathing rate dropped significantly in the head-up position, and in all the animals, it was still below the horizontal value 1 min after the vertical head-up tilting. After bilateral vagotomy, no significant change with body posture occurred. In unanesthetized newborns, the +45 degree head-up tilting only occasionally caused a drop of f and to a lesser extent than after anesthesia. By comparing these results with those reported in adults, it is concluded that the postural effects of f are less evident in the newborn than in the adult. Even if a quantitative difference in the mechanical events after the change in body posture is the most likely explanation of the lower sensitivity of the newborn, other nonmechanical factors could also be involved.


A Clinical Monitoring Approach for Early Onset Sepsis: A Community Hospital Experience.
A serial clinical examination approach to screen late preterm and term neonates at risk for early onset sepsis has been shown to be effective in large academic centers, resulting in reductions in laboratory testing and antibiotic use. The implementation of this approach in a community hospital setting has not been reported. Our objective was to adapt a clinical examination approach to our community hospital, aiming to reduce antibiotic exposure and laboratory testing. At a community hospital with a level III NICU and >4500 deliveries annually, the pathway to evaluate neonates ≥35 weeks at risk for early onset sepsis was revised to focus on clinical examination. Well-appearing neonates regardless of perinatal risk factor were admitted to the mother baby unit with serial vital signs and clinical examinations performed by a nurse. Neonates symptomatic at birth or who became symptomatic received laboratory evaluation and/or antibiotic treatment. Antibiotic use, laboratory testing, and culture results were evaluated for the 14 months before and 19 months after implementation. After implementation of the revised pathway, antibiotic use decreased from 6.7% (n = 314/4694) to 2.6% (n = 153/5937; P < .001). Measurement of C-reactive protein decreased from 13.3% (n = 626/4694) to 5.3% (n = 312/5937; P < .001). No cases of culture-positive sepsis occurred, and no neonate was readmitted within 30 days from birth with a positive blood culture. A screening approach for early onset sepsis focused on clinical examination was successfully implemented at a community hospital setting resulting in reduction of antibiotic use and laboratory testing without adverse outcomes.


Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome.
To assess the effect of erythropoietin (EPO) plus granulocyte-colony stimulating factor (G-CSF) treatment on survival and leukemic transformation in myelodysplastic syndrome (MDS). We compared the long-term outcome of patients with MDS treated with EPO plus G-CSF (n = 121) with untreated patients (n = 237) with MDS using multivariate Cox regression with delayed entry, for the first time adjusting for all major prognostic variables (WHO classification, karyotype, cytopenias, level of transfusion-need, age, and sex). The erythroid response rate to EPO plus G-CSF was 39%, and the median response duration 23 months (range, 3 to 116+). In the multivariate analysis, treatment was associated with improved overall survival (hazard ratio, 0.61; 95% CI, 0.44 to 0.83; P = .002). Interestingly, this positive association was primarily observed in patients requiring fewer than 2 units of RBCs per month. Treatment was not linked to the rate of acute myeloid leukemia in any defined subgroup, including patients with an increase of marrow blasts or an unfavorable karyotype. The inherent risk of leukemic evolution in MDS makes the current investigation highly relevant, in light of the recent reports of potential negative effects of EPO treatment on outcome in patients with cancer. We conclude that treatment of anemia in MDS with EPO plus G-CSF may have a positive impact on outcome in patients with no or low transfusion need, while not affecting the risk of leukemic transformation.


Effect of culture medium, host strain and oxygen transfer on recombinant Fab antibody fragment yield and leakage to medium in shaken E. coli cultures.
Fab antibody fragments in E. coli are usually directed to the oxidizing periplasmic space for correct folding. From periplasm Fab fragments may further leak into extracellular medium. Information on the cultivation parameters affecting this leakage is scarce, and the unpredictable nature of Fab leakage is problematic regarding consistent product recovery. To elucidate the effects of cultivation conditions, we investigated Fab expression and accumulation into either periplasm or medium in E. coli K-12 and E. coli BL21 when grown in different types of media and under different aeration conditions. Small-scale Fab expression demonstrated significant differences in yield and ratio of periplasmic to extracellular Fab between different culture media and host strains. Expression in a medium with fed-batch-like glucose feeding provided highest total and extracellular yields in both strains. Unexpectedly, cultivation in baffled shake flasks at 150 rpm shaking speed resulted in higher yield and accumulation of Fabs into culture medium as compared to cultivation at 250 rpm. In the fed-batch medium, extracellular fraction in E. coli K-12 increased from 2-17% of total Fab at 250 rpm up to 75% at 150 rpm. This was partly due to increased lysis, but also leakage from intact cells increased at the lower shaking speed. Total Fab yield in E. coli BL21 in glycerol-based autoinduction medium was 5 to 9-fold higher at the lower shaking speed, and the extracellular fraction increased from ≤ 10% to 20-90%. The effect of aeration on Fab localization was reproduced in multiwell plate by variation of culture volume. Yield and leakage of Fab fragments are dependent on expression strain, culture medium, aeration rate, and the combination of these parameters. Maximum productivity in fed-batch-like conditions and in autoinduction medium is achieved under sufficiently oxygen-limited conditions, and lower aeration also promotes increased Fab accumulation into extracellular medium. These findings have practical implications for screening applications and small-scale Fab production, and highlight the importance of maintaining consistent aeration conditions during scale-up to avoid changes in product yield and localization. On the other hand, the dependency of Fab leakage on cultivation conditions provides a practical way to manipulate Fab localization.


Factors facilitating acceptable mammography services for women with disabilities.
Prior research has described general barriers to breast cancer screening for women with disabilities (WWD). We explored specific accommodations described as necessary by WWD who have accessed screening services, and the presence of such accommodations in community-based screening programs. We surveyed WWD in the Carolina Mammography Registry to determine what accommodations were needed when accessing breast screening services, and whether or not these needs were met. The sample of 1,348 WWD was identified through a survey of limitations, with a response rate of 45.5% (4,498/9,885). Of the 1,348 WWD eligible for the second survey, 739 responded for a response rate of 54.8%. The most frequently needed accommodations were an accessible changing area with a bench (60.0%), oral description of the procedure by the technologist (60.5%), and handicapped/accessible parking (27.6%). Handicapped parking was the need most likely to go unmet (3.1%). Most needs are being met by radiology facilities and staff, and the few needs going unmet are related to the physical/built environment. Overall, for WWD who are in screening, the mammography system seems to be more accessible than generally perceived.


Nedd4 family-interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4 family proteins.
The ability to remove unwanted proteins is an important cellular feature. Classically, this involves the enzymatic addition of ubiquitin moieties followed by degradation in the proteasome. Nedd4 proteins are ubiquitin ligases important not only for protein degradation, but also for protein trafficking. Nedd4 proteins can bind to target proteins either by themselves or through adaptor protein Ndfip1 (Nedd4 family-interacting protein 1). An alternative mechanism for protein removal and trafficking is provided by exosomes, which are small vesicles (50-90-nm diameter) originating from late endosomes and multivesicular bodies (MVBs). Exosomes provide a rapid means of shedding obsolete proteins and also for cell to cell communication. In the present work, we show that Ndfip1 is detectable in exosomes secreted from transfected cells and also from primary neurons. Compared with control, Ndfip1 increases exosome secretion from transfected cells. Furthermore, while Nedd4, Nedd4-2, and Itch are normally absent from exosomes, expression of Ndfip1 results in recruitment of all three Nedd4 proteins into exosomes. Together, these results suggest that Ndfip1 is important for protein trafficking via exosomes, and provides a mechanism for cargoing passenger proteins such as Nedd4 family proteins. Given the positive roles of Ndfip1/Nedd4 in improving neuronal survival during brain injury, it is possible that exosome secretion provides a novel route for rapid sequestration and removal of proteins during stress.


Maternal smoking and congenital heart defects in the Baltimore-Washington Infant Study.
We investigated associations between maternal cigarette smoking during the first trimester and the risk of congenital heart defects (CHDs) among the infants. The Baltimore-Washington Infant Study was the first population-based case-control study of CHDs conducted in the United States. Case and control infants were enrolled during the period 1981-1989. We excluded mothers with overt pregestational diabetes and case mothers whose infants had noncardiac anomalies (with the exception of atrioventricular septal defects with Down syndrome) from the analysis, which resulted in 2525 case and 3435 control infants. Self-reported first-trimester maternal cigarette consumption was ascertained via an in-person interview after delivery. Associations for 26 different groups of CHDs with maternal cigarette consumption were estimated by using logistic regression models. Odds ratios (ORs) corresponded to a 20-cigarette-per-day increase in consumption. We observed statistically significant positive associations between self-reported first-trimester maternal cigarette consumption and the risk of secundum-type atrial septal defects (OR: 1.36 [95% confidence interval (CI): 1.04-1.78]), right ventricular outflow tract defects (OR: 1.32 [95% CI: 1.06-1.65]), pulmonary valve stenosis (OR: 1.35 [95% CI: 1.05-1.74]), truncus arteriosus (OR: 1.90 [95% CI: 1.04-3.45]), and levo-transposition of the great arteries (OR: 1.79 [95% CI: 1.04-3.10]). A suggestive association was observed for atrioventricular septal defects among infants without Down syndrome (OR: 1.50 [95% CI: 0.99-2.29]). These findings add to the existing body of evidence that implicates first-trimester maternal cigarette smoking as a modest risk factor for select CHD phenotypes.


Living on climate-changed country: indigenous health, well-being and climate change in remote Australian communities.
Closing the gap between the health and well-being status of Indigenous people living in remote areas of northern Australia and non-Indigenous Australians has long been a major target of federal health policy. With climate projections suggesting large increases in hot spells in desert regions and more extremes in rainfall in other areas of the north, direct and indirect impacts resulting from these changes are likely to further entrench this health and well-being disparity. This paper argues that it is time to explicitly draw on Indigenous definitions of health, which directly address the need to connect individual and community health to the health of their country, in order to develop effective climate adaptation and health strategies. We detail how current health policies overlook this 'missing' dimension of Indigenous connection to country, and why that is likely to be detrimental to the health and well-being of people living in remote communities in a climate-changed future.


Transferability of a EUnetHTA relative effectiveness assessment to low- and middle-income countries setting.
In 2020, European Network for Health Technology Assessment (EUnetHTA) published a relative effectiveness analysis (REA) of Pretomanid in combination with Bedaquiline and Linezolid for the treatment of extensively drug-resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB) (REA PTJA14). This REA may have a significant value for low- and middle-income countries (LMICs) outside Europe, particularly those with a high burden of drug-resistant TB. This commentary focuses on whether the REA PTJA14 can be transferred and to what extent a REA can be translated to LMICs context outside Europe. We found that the assessments on the clinical effectiveness and risks of bias reported in REA PTJA14 are useful for LMICs outside Europe. The highly standardized management of TB will support the applicability of the REA to LMICs outside of Europe. Transferring this REA can reduce workload and efficiently use limited resources to conduct health technology assessment (HTA). However, the transfer should consider several critical issues, including variations in health system delivery and clinical practice and setting-specific constraints. In the TB context, the differences in the current standard treatment for XDR or nonresponsive MDR TB, resources availability for drug-resistant TB management, and how healthcare is delivered in the countries can complicate the applicability of the REA PTJA14. Given that LMICs have limitations in doing HTA, it is now critical to develop standard guidelines for transferring REA or other HTA results from high-income countries or other LMICs to maximize the benefits of the REA for LMICs outside Europe.


[Comparative study of health care costs for patients using home oxygen therapy or those in waiting lists].
Home oxygen therapy is the only intervention that significantly prolongs survival of patients with chronic obstructive pulmonary disease. Since this therapy is expensive, it is imperative to calculate its cost-benefit ratio. To compare health care costs for patients in a home oxygen therapy program, with those of a similar group of patients in a waiting list for this therapy. A retrospective analysis of 21 patients on home oxygen therapy for 36 months or less and a group of 13 patients in the waiting list during a similar lapse. Medical consultations, drugs delivered and the cost of oxygen therapy were considered among ambulatory costs. Hospitalization costs included the number of days on regular or intermediary care beds, laboratory tests and drugs delivered. The annual health care costs for patients on home oxygen therapy were 709,656 Chilean pesos and the costs for patients in the waiting list were 797,320 Chilean pesos. The overall health care costs of home oxygen therapy are similar to the cost required by patients with chronic obstructive pulmonary disease remaining in waiting lists.