Establishing an SEIR-based framework for local modelling of COVID-19 infections, hospitalisations and deaths.

Without timely assessments of the number of COVID-19 cases requiring hospitalisation, healthcare providers will struggle to ensure an appropriate number of beds are made available. Too few could cause excess deaths while too many could result in additional waits for elective treatment. As well as supporting capacity considerations, reliably projecting future "waves" is important to inform the nature, timing and magnitude of any localised restrictions to reduce transmission. In making the case for locally owned and locally configurable models, this paper details the approach taken by one major healthcare system in founding a multi-disciplinary "Scenario Review Working Group", comprising commissioners, public health officials and academic epidemiologists. The role of this group, which met weekly during the pandemic, was to define and maintain an evolving library of plausible scenarios to underpin projections obtained through an SEIR-based compartmental model. Outputs have informed decision-making at the system's major incident Bronze, Silver and Gold Commands. This paper presents illustrated examples of use and offers practical considerations for other healthcare systems that may benefit from such a framework.

A One-Year Survey of Norovirus in UK Oysters Collected at the Point of Sale.

Contamination of bivalve shellfish, particularly oysters, with norovirus is recognised as a food safety risk and a potential contributor to the overall burden of gastroenteritis in the community. The United Kingdom (UK) has comprehensive national baseline data on the prevalence, levels, and seasonality of norovirus in oysters in production areas resulting from a previous two-year study (2009-2011). However, previously, data on final product as sold to the consumer have been lacking. As part of a wider project to establish the overall burden of foodborne norovirus in the UK, this study aimed to address this data gap. A one-year survey of oysters collected from the point-of-sale to the consumer was carried out from March 2015 to March 2016. A total of 630 samples, originating in five different European Union Member States, were collected from 21 regions across the UK using a randomised sampling plan, and tested for norovirus using a method compliant with ISO 15216-1, in addition to Escherichia coli as the statutory indicator of hygiene status. As in the previous production area study, norovirus RNA was detected in a high proportion of samples (68.7%), with a strong winter seasonality noted. Some statistically significant differences in prevalences and levels in oysters from different countries were noted, with samples originating in the Netherlands showing lower prevalences and levels than those from either the UK or Ireland. Overall, levels detected in positive samples were considerably lower than seen previously. Investigation of potential contributing factors to this pattern of results was carried out. Application of normalisation factors to the data from the two studies based on both the numbers of norovirus illness reports received by national surveillance systems, and the national average environmental temperatures during the two study periods resulted in a much closer agreement between the two data sets, with the notably different numbers of illness reports making the major contribution to the differences observed in norovirus levels in oysters. The large majority of samples (76.5%) contained no detectable E. coli; however, in a small number of samples (2.4%) levels above the statutory end product standard (230 MPN/100 g) were detected. This study both revealed the high prevalence of norovirus RNA in oysters directly available to the UK consumer, despite the high level of compliance with the existing E. coli-based health standards, while also highlighting the difficulty in comparing the results of surveys carried out in different time periods, due to variability in risk factors.

Overexpression of the carbohydrate binding module from Solanum lycopersicum expansin 1 (Sl-EXP1) modifies tomato fruit firmness and Botrytis cinerea susceptibility.

Firmness, one of the major determinants of postharvest quality and shelf life of fruits is determined by the mechanical resistance imposed by the plant cell wall. Expansins (EXP) are involved in the non-hydrolytic metabolic disassembly of plant cell walls, particularly in processes where relaxation of the wall is necessary, such as fruit development and ripening. As many carbohydrate-associated proteins, expansins have a putative catalytic domain and a carbohydrate-binding module (CBM). Several strategies have been pursued to control the loss of fruit firmness during storage. Most of the approaches have been to suppress the expression of key enzymes involved in the cell wall metabolism, but this is the first time that a CBM was overexpressed in a fruit aimed to control cell wall degradation and fruit softening. We report the constitutive overexpression of the CBM of Solanum lycopersicum expansin 1 (CBM-SlExp1) in the cell wall of tomato plants, and its effects on plant and fruit phenotype. Overexpression of CBM-SlExp1 increased the mechanical resistance of leaves, whereas it did not modify plant growth and general phenotype. However, transgenic plants showed delayed softening and firmer fruits. In addition, fruits were less susceptible to Botrytis cinerea infection, and the "in vitro" growth of the fungus on media containing AIR from the pericarp of transgenic fruits was lower than controls. The possibility of overexpressing a CBM of a fruit-specific expansin to control cell wall degradation and fruit softening is discussed.

The intersection between cell wall disassembly, ripening, and fruit susceptibility to Botrytis cinerea.

Fruit ripening is characterized by processes that modify texture and flavor but also by a dramatic increase in susceptibility to necrotrophic pathogens, such as Botrytis cinerea. Disassembly of the major structural polysaccharides of the cell wall (CW) is a significant process associated with ripening and contributes to fruit softening. In tomato, polygalacturonase (PG) and expansin (Exp) are among the CW proteins that cooperatively participate in ripening-associated CW disassembly. To determine whether endogenous CW disassembly influences the ripening-regulated increase in necrotropic pathogen susceptibility, B. cinerea susceptibility was assessed in transgenic fruit with suppressed polygalacturonase (LePG) and expansin (LeExp1) expression. Suppression of either LePG or LeExp1 alone did not reduce susceptibility but simultaneous suppression of both dramatically reduced the susceptibility of ripening fruit to B. cinerea, as measured by fungal biomass accumulation and by macerating lesion development. These results demonstrate that altering endogenous plant CW disassembly during ripening influences the course of infection by B. cinerea, perhaps by changing the structure or the accessibility of CW substrates to pathogen CW-degrading enzymes. Recognition of the role of ripening-associated CW metabolism in postharvest pathogen susceptibility may be useful in the design and development of strategies to limit pathogen losses during fruit storage, handling, and distribution.

Transgenic expression of pear PGIP in tomato limits fungal colonization.

Transgenic tomato plants expressing the pear fruit polygalacturonase inhibitor protein (pPGIP) were used to demonstrate that this inhibitor of fungal pathogen endopolygalacturonases (endo-PGs) influences disease development. Transgenic expression of pPGIP resulted in abundant accumulation of the heterologous protein in all tissues and did not alter the expression of an endogenous tomato fruit PGIP (tPGIP). The pPGIP protein was detected, as expected, in the cell wall protein fraction in all transgenic tissues. Despite differential glycosylation in vegetative and fruit tissues, the expressed pPGIP was active in both tissues as an inhibitor of endo-PGs from Botrytis cinerea. The growth of B. cinerea on ripe tomato fruit expressing pPGIP was reduced, and tissue breakdown was diminished by as much as 15%, compared with nontransgenic fruit In transgenic leaves, the expression of pPGIP reduced lesions of macerated tissue approximately 25%, a reduction of symptoms of fungal growth similar to that observed with a B. cinerea strain in which a single endo-PG gene, Bcpg1, had been deleted (A. ten Have, W. Mulder, J. Visser, and J. A. L. van Kan, Mol. Plant-Microbe Interact. 11:1009-1016, 1998). Heterologous expression of pPGIP has demonstrated that PGIP inhibition of fungal PGs slows the expansion of disease lesions and the associated tissue maceration.

An expansin gene expressed in ripening strawberry fruit.

Tissue softening accompanies the ripening of many fruit and initiates the processes of irreversible deterioration. Expansins are plant cell wall proteins proposed to disrupt hydrogen bonds within the cell wall polymer matrix. Expression of specific expansin genes has been observed in tomato (Lycopersicon esculentum) meristems, expanding tissues, and ripening fruit. It has been proposed that a tomato ripening-regulated expansin might contribute to cell wall polymer disassembly and fruit softening by increasing the accessibility of specific cell wall polymers to hydrolase action. To assess whether ripening-regulated expansins are present in all ripening fruit, we examined expansin gene expression in strawberry (Fragaria x ananassa Duch.). Strawberry differs significantly from tomato in that the fruit is derived from receptacle rather than ovary tissue and strawberry is non-climacteric. A full-length cDNA encoding a ripening-regulated expansin, FaExp2, was isolated from strawberry fruit. The deduced amino acid sequence of FaExp2 is most closely related to an expansin expressed in early tomato development and to expansins expressed in apricot fruit rather than the previously identified tomato ripening-regulated expansin, LeExp1. Nearly all previously identified ripening-regulated genes in strawberry are negatively regulated by auxin. Surprisingly, FaExp2 expression was largely unaffected by auxin. Overall, our results suggest that expansins are a common component of ripening and that non-climacteric signals other than auxin may coordinate the onset of ripening in strawberry.

Attention deficit hyperactivity disorder associated with orbitofrontal epilepsy in a father and a son.

The authors report on a father and son with frontal lobe epilepsy and symptoms of attention deficit hyperactivity disorder (ADHD). Attention deficit hyperactivity is a syndrome defined by criteria that include inattention, impulsive behavior, impaired concentration and motor restlessness. It does not require medical or neurobehavioral evaluation to determine an underlying etiology. The father is a 45-year-old man evaluated for possible ADHD. His referral came after the diagnosis of ADHD in his 6-year-old son who responded well to treatment with methylphenidate HCL. Neurobehavioral evaluation of the father suggested frontal lobe dysfunction. Magnetic resonance imaging and electroencephalography (EEG) were normal. Brain 99mTc HMPAO single-photon emission computed tomography (SPECT) revealed left orbitofrontal hypoperfusion. Additional history from his wife revealed episodic symptoms suggestive of nonconvulsive epilepsy that included nonresponsive staring, complex automatic behavior, and amnesic lacunas. Treatment of the father with carbmazepine produced dramatic improvement. Subsequent evaluation of his son, currently on maintenance treatment with methylphenidate HCL for ADHD, elicited a history consistent with atonic and simple motor partial epilepsy. The son's brain SPECT revealed bilateral orbitofrontal hypoperfusion defects. Attention deficit hyperactivity disorder is a syndrome that may be caused by frontal lobe lesions or epilepsy. In the setting of possible ADHD, neurological evaluation is warranted. Although overreliance on structural imaging or EEG in such an evaluation must be discouraged, brain SPECT may be useful to evaluate patients with symptoms of attention disorders for frontal epilepsy.

Emotions and cognitions associated with bingeing and weight control behavior in bulimia.

The examination of cognitions and emotions during the bulimic cycle is critical in understanding possible maintenance factors involved in bulimia. In this study, 22 bulimics and 22 nonbulimics recorded their thoughts and feelings every 2 waking hours over a 6-day period. Bulimics additionally recorded their moods and thoughts during their binges and compensatory behaviors (e.g., purging, exercise). Higher levels of negative affect were reported at all stages of the cycle compared to baseline, although negative affect decreased after the compensatory behavior stage. Subjects also reported stronger distorted cognitions before and after the binge compared to baseline. One of the distorted cognitions (feeling fat) decreased in strength after subjects engaged in compensatory behavior. Additional analyses revealed that most levels of negative affect and distorted cognitions were elevated prior to binges as compared to meals. Finally, negative affect and distorted cognitions were stronger after binges than after meals.

The protective effects of education on simulated brain injury.

Disturbed intellectual function is an important determinant of long-term recovery after head injury. Residual behavioral disability depends largely upon which hemisphere is damaged and the site of injury within the hemisphere. Resulting neurobehavioral syndromes vary with the pattern of brain insult. While this correlation is important, it is still not well understood how damage to single neurons translates into abnormal behavior. In addition, no currently available technology permits in vivo evaluation of such cells in normal or injured states. While research into brain trauma traditionally emphasize single cell pathology, this level of study is insufficient to clarify how individual cell activity contributes to higher cognition. In contrast, neural network simulations may partially fill this void by predicting biological function. Here, we present data generated by a three-layer neural network that employs the ALOPEX algorithm, capable of learning 10 words. The addition of Gaussian distributed noise into connection weights strengths damaged the network's function; interestingly, the rate and extent of network impairment depended upon the level of learning that occurred during the training period, in agreement with human studies that demonstrate a protective effect of education on subsequent brain injury. Damage to input signals resulted in similar effects on network function. Accordingly, such simulations offer powerful evidence that human behavior may be considered in terms of neuronal cell populations and efforts to preserve brain function at the time of injury should emphasize maintaining neural connections.

Structure and expression of an inhibitor of fungal polygalacturonases from tomato.

A polygalacturonase inhibitor protein (PGIP) was characterized from tomato fruit. Differential glycosylation of a single polypeptide accounted for heterogeneity in concanavalin A binding and in molecular mass. Tomato PGIP had a native molecular mass of 35 to 41 kDa, a native isoelectric point of 9.0, and a chemically deglycosylated molecular mass of 34 kDa, suggesting shared structural similarities with pear fruit PGIP. When purified PGIPs from pear and tomato were compared, tomato PGIP was approximately twenty-fold less effective an inhibitor of polygalacturonase activity isolated from cultures of Botrytis cinerea. Based on partial amino acid sequence, polymerase chain reaction products and genomic clones were isolated and used to demonstrate the presence of PGIP mRNA in both immature and ripening fruit as well as cell suspension cultures. Nucleotide sequence analysis indicates that the gene, uninterrupted by introns, encodes a predicted 36.5 kDa polypeptide containing amino acid sequences determined from the purified protein and sharing 68% and 50% amino acid sequence identity with pear and bean PGIPs, respectively. Analysis of the PGIP sequences also revealed that they belong to a class of proteins which contain leucine-rich tandem repeats. Because these sequence domains have been associated with protein-protein interactions, it is possible that they contribute to the interaction between PGIP and fungal polygalacturonases.

Senile dementia of extreme aging: a common disorder of centenarians.

To study dementia in the extremely aged, I evaluated 40 centenarians with a mean age of 101.6 years (range: 100-107). The group completed 5.8 years of education, on average. Bradyphrenia and bradykinesia were common and most had impaired awareness and concern. The Folstein Mini-Mental State Exam and Washington University's Clinical Dementia Rating Scale indicated moderately advanced dementia in more than half; 4 had a clinical pattern that suggested senile dementia of the Alzheimer's type. A common pattern of dementia emerged consisting of preserved awareness of the environment, normal participation in conversations, mild bradyphrenia and bradykinesia with normal latency to respond to questions and memory impairment with diminished ability to learn new information. They had a constricted universe with limited awareness of events outside their personal sphere; they repeated themes and topics endlessly. This study suggests senile dementia is common in centenarians.

Development of scale-down techniques for investigation of recombinant Escherichia coli fermentations: acid metabolites in shake flasks and stirred bioreactors.

We have developed shake-flask screening conditions that are predictive of specific expression of the chimeric toxin, TGF alpha-PE40, by recombinant Escherichia coli JM109 in stirred bioreactors. When a nutrient-rich stirred bioreactor medium was used in shake flasks, neither the extent of growth nor the specific level of recombinant protein expression duplicated the performance in stirred bioreactor fermentations. Incomplete oxidation of glucose and concomitant accumulation of organic acid metabolites, as well as oxygen limitation and lack of pH control, were examined as contributors to the poorer performance in the flask. The medium buffering capacity, initial glucose level, and flask aeration were evaluated to establish the limits of "scale-down" conditions for expression both in a complex nutrient medium (M101) similar to that used in stirred bioreactors and in a defined (FM) medium. Acid metabolites and ethanol were measured as indicators of carbon flow from glucose as well as indirect indicators of oxygen limitation. For the complex M101 medium, optimal shake-flask performance in 250-mL, nonbaffled flasks at 37 degrees C occurred with 0.3 x medium strength, supplementation with 0.3 m HEPES buffer (pH 7.5), and 10 mL of medium per flask. Cultures grown under these conditions produced a maximum density of 3.6 g of dry cell weight/L (as estimated by absorbance measurements at 600 nm) and maintained a pH near neutrality. Additionally, metabolite markers of anaerobic or microaerobic conditions, such as ethanol, lactate, and pyruvate, were not detected, and specific expression of TGF alpha-PE40 was comparable to stirred bioreactors induced for expression at various biomass levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Convex third ventricle: a possible sign for dementia using MRI.

The shape and thickness of the third ventricles were studied with magnetic resonance imaging in 46 patients under evaluation for memory impairment. We compared this population with 23 subjects imaged for other reasons. The study group consisted of patients with diagnoses of probable dementia of the Alzheimer's type (DAT; 35.6%), multi-infarct dementia (MID; 22.2%), depression (8.9%), alcoholic dementia (6.7%), other dementias (OD; 13.2%) and no dementia (6.7%). Within the study group, there were no significant differences across diagnostic categories for duration of symptoms or level of education. Patients with DAT were, however, more impaired than others (Mini-Mental State Examination scores: DAT 14.6 [+/- 8.2] versus MID 17.4 [+/- 6.2] versus OD 21.2 [+/- 6.4]). Demented subjects were more likely than nondemented individuals to have a convex third ventricle and greater wall separation. The results suggest that the shape of the third ventricle may correlate with dementia. Possibly, the dorsal medial nucleus of the thalamus is involved in the dementia.

Molecular characterization of a polygalacturonase inhibitor from Pyrus communis L. cv Bartlett.

A polygalacturonase inhibitor glycoprotein with an apparent molecular mass of 43 kD was purified from pear (Pyrus communis L. cv Bartlett) fruit. Chemical deglycosylation of this protein decreased the molecular mass to 34 kD. Gas chromatographic analysis suggests that N-linked glycosylation accounts for the majority of sugar moieties. Partial amino acid sequence analysis of the purified polygalacturonase inhibitor protein provided information used to amplify a corresponding cDNA by polymerase chain reactions. Multiple cloned products of these reactions were sequenced and the same open reading frame was identified in all of the products. It encodes a 36.5-kD polypeptide containing the amino acid sequences determined by protein sequencing and predicts a putative signal sequence of 24 amino acids and seven potential N-glycosylation sites. The expression of polygalacturonase inhibitor is regulated in a tissue-specific manner. Activity and mRNA level were much higher in fruit than in flowers or leaves.

A retrospective study of syphilis seropositivity in a cohort of demented patients.

A retrospective study of 376 patients with dementia was performed to determine the rate of syphilis seropositivity. Subjects were seen over a 2.5-year period and received medical, social, psychiatric, neurological, and laboratory evaluations. Mean age was 74 years and 73% were women. Diagnoses included Alzheimer's disease (AD; 29.8%), vascular dementia (VascD; 24.7%), combined AD/VascD (14.3%), and other diagnoses (31.2%). Dementia was moderately advanced with a mean Folstein Mini-Mental State Score of 16. Fluorescent treponemal antibody absorption tests (FA) were performed on 338 of the patients with 10.9% being reactive. Two of nine subjects with reactive FA's had reactive rapid plasma reagin tests.

Physiological effects of TGF(alpha)-PE40 expression in recombinant Escherichia coli JM109.

Physiological effects of isopropyl-thiogalactopyranoside (IPTG) induction were examined in Escherichia coli strain JM109 expressing a fusion protein composed of transforming growth factor alpha and a 40-kD portion of Pseudomonas aeruginosa exotoxin A (TGF(alpha)-PE40) under control of the tac promoter. Fermentations at the 15-L scale in complex medium compared growth and metabolite profiles of the untransformed JM109 host strain, the strain transformed with the vector lacking the TGF(alpha)-PE40 open reading frame (JM109[pKK2.7]), and the strain with the complete plasmid for TGF(alpha)-PE40 expression (JM109[pTAC-TGF57-PE40]). Metabolite and growth profiles of JM109 (pTAC-TGF57-PE40) cultures changed significantly in IPTG-induced versus uninduced cultures. Prior to induction, glucose was metabolized to acetate or completely oxidized to CO(2). Following induction, pyruvate was also excreted in addition to acetate. In the absence of inducer, pyruvate was excreted by JM109 (pTAC-TGF57-PE40) only when dissolved oxygen levels fell to less than 10% of saturation (microaerobic rather than anaerobic conditions). The untransformed JM109 host strain or JM109 (pKK2.7) did not excrete pyruvate in the presence or absence of inducer, although JM109 (pKK2.7) exhibited a pattern of growth following addition of IPTG that closely resembled JM109 (pTAC-TFG57-PE40). Fermentations of JM109 (pTAC-TFG57-PE40) in a synthetic medium supported lower expression levels, but resulted in similar alterations in metabolite profiles. Induction in synthetic medium resulted in pyruvate excretion without further acetate accumulation. Taken together, these data suggest that one consequence of TGF(alpha)-PE40 expression in JM109 is altered patterns of pyruvate oxidation.

Brain imaging techniques in the diagnosis of dementia.

Various recently developed brain imaging techniques used to assist in the diagnosis of dementia are reviewed. The methods reviewed are x-ray computed tomography scan imaging, magnetic resonance imaging, positron emission tomography, and the older techniques of pneumoencephalography and radioisotope cisternography. It was concluded that while these techniques often offer excellent diagnostic information, none of them provides a definitive characteristic image for Alzheimer's disease.

Five studies testing two new egoistic alternatives to the empathy-altruism hypothesis.

The empathy-altruism hypothesis claims that prosocial motivation associated with feeling empathy for a person in need is directed toward the ultimate goal of benefiting that person, not toward some subtle form of self-benefit. We explored two new egoistic alternatives to this hypothesis. The empathy-specific reward hypothesis proposes that the prosocial motivation associated with empathy is directed toward the goal of obtaining social or self-rewards (i.e., praise, honor, and pride). The empathy-specific punishment hypothesis proposes that this motivation is directed toward the goal of avoiding social or self-punishments (i.e., censure, guilt, and shame). Study 1 provided an initial test of the empathy-specific reward hypothesis. Studies 2 through 4 used three procedures to test the empathy-specific punishment hypothesis. In Study 5, a Stroop procedure was used to assess the role of reward-relevant, punishment-relevant, and victim-relevant cognitions in mediating the empathy-helping relationship. Results of these five studies did not support either the empathy-specific reward or the empathy-specific punishment hypothesis. Instead, results of each supported the empathy-altruism hypothesis. Evidence that empathic emotion evokes altruistic motivation continues to mount.

Speech and language alterations in multi-infarct dementia.

Speech and language functions were assessed in 18 patients with multi-infarct dementia (MID) and 14 with dementia of the Alzheimer type (DAT). The age range and dementia severity of the two groups were comparable. We used a speech and language battery assessing 37 elements of verbal output to characterize alterations in the patients. MID patients had more abnormalities of motor aspects of speech, whereas DAT patients had empty speech, more marked anomia, and relative sparing of motor speech functions. The results demonstrate that speech and language differ in MID and DAT. In addition, MID patients exhibited common clinical features despite the heterogeneity of the syndrome.