Assessing resilience of healthcare infrastructure exposed to COVID-19: emerging risks, resilience indicators, interdependencies and international standards.

In the moment of preparation of this paper, the world is still globally in grip of the Corona (COVID-19) crisis, and the need to understand the broader overall framework of the crisis increases. As in similar cases in the past, also with this one, the main interest is on the "first response". Fully appreciating the efforts of those risking their lives facing pandemics, this paper tries to identify the main elements of the larger, possibly global, framework, supported by international standards, needed to deal with new (emerging) risks resulting from threats like Corona and assess the resilience of systems affected. The paper proposes that future solutions should include a number of new elements, related to both risk and resilience. That should include broadening the scope of attention, currently focused onto preparation and response phases, to the phases of "understanding risks", including emerging risks, and transformation and adaptation. The paper suggests to use resilience indicators in this process. The proposed approach has been applied in different cases involving critical infrastructures in Europe (energy supply, water supply, transportation, etc., exposed to various threats), including the health system in Austria. The detailed, indicator-based, resilience analysis included mapping resilience, resilience stress-testing, visualization, etc., showing, already before the COVID-19, the resilience (stress-testing) limits of the infrastructures. A simpler (57 indicator based) analysis has, then been done for 11 countries (including Austria). The paper links these results with the options available in the area of policies, standards, guidelines and tools (such as the RiskRadar), with focus on interdependencies and global standards-especially the new ISO 31,050, linking emerging risks and resilience.

Occipital osteomylelitis and epidural abscess after occipital nerve block: A case report.

Occipital neuralgia is a paroxysmal jabbing pain in the distribution of the greater or lesser occipital nerves accompanied by diminished sensation in the affected area. Occipital nerve block is a common diagnostic and therapeutic tool used in the course of occipital neuralgia and is considered a safe treatment with few localized adverse events. Occipital nerve block is also indicated for cervicogenic and cluster headache and is often used as a rescue treatment for headaches not responding to conventional therapies. We describe a case of epidural abscess formation 16 days following occipital nerve block in a patient with no underlying medical conditions. This case report emphasizes the importance of strict aseptic technique to reduce infection rates in patients undergoing this procedure, despite the overall safety of occipital nerve block. Clinicians must remain aware of acute and late complications arising postprocedure for the safe practice of this technique.

La névralgie occipitale est une douleur lancinante paroxystique dans la distribution des nerfs du grand ou du petit occipital qui s'accompagne d'une diminution des sensations dans la zone affectée. Le bloc du nerf occipital, un outil diagnostique et thérapeutique communément utilisé dans le cadre d'une névralgie occipitale, est considéré comme un traitement sécuritaire qui n'entraine que peu d'effets indésirables localisés. Le bloc du nerf occipital, également indiqué pour traiter la céphalée cervicogénique et la céphalée vasculaire de Horton, est souvent utilisé en tant que traitement de secours pour les céphalées qui ne répondent pas aux thérapies conventionnelles. Nous décrivons un cas de formation d'un abcès épidural 16 jours après le bloc du nerf occipital chez un patient sans affection médicale sous-jacente. L'étude de cas met l'accent sur l'importance d'une stricte conformité aux techniques d'asepsie afin de réduire les taux d'infection chez les patients soumis à cette procédure, malgré le caractère sécuritaire du bloc du nerf occipital. Les cliniciens doivent demeurer vigilants quant aux complications aigues et tardives qui peuvent survenir après la procédure afin d'appliquer cette technique de manière sécuritaire.

Structured Frameworks to Increase the Transparency of the Assessment of Benefits and Risks of Medicines: Current Status and Possible Future Directions.

Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions.

Improving the decision-making process for nonprescription drugs: a framework for benefit-risk assessment.

Nonprescription drugs pose unique challenges to regulators. The fact that the barriers to access are lower for nonprescription drugs as compared with prescription drugs may permit additional consumers to obtain effective drugs. However, the use of these drugs by consumers in the absence of supervision by a health-care professional may result in unacceptable rates of misuse and suboptimal clinical outcomes. A value-tree method is proposed that defines important benefit and risk domains relevant to nonprescription drugs. This value tree can be used to comprehensively identify product-specific attributes in each domain and can also support formal benefit-risk assessment using a variety of tools. This is illustrated here, using a modification of the International Risk Governance Council (IRGC) framework, a flexible tool previously applied in a number of fields, which systematizes an approach to issue review, early alignment of stakeholders, evaluation, and risk mitigation/management. The proposed approach has the potential to provide structured, transparent tools for regulatory decision making for nonprescription drugs.

An ethical appraisal of hormesis: toward a rational discourse on the acceptability of risks and benefits.

Hormesis has been defined as a dose-response relationship in which there is a stimulatory response at low doses but an inhibiting response at high doses, resulting in a U- or inverted U-shaped dose response. Until now, regulatory agencies have been reluctant to address this new insight or adjusted their routines for regulating such substances. Should regulators change their principles of decision making and standard setting in the light of the new insights from hormesis research? To answer this question, it is essential to review the ethical implications of hormesis in risk assessment and management. What kind of values should govern the regulation of substances and radiation that may cause positive and negative impacts at the same time (depending on dose and individual variability)? This article tries to address this problem. It deals with the basic ethical principles and foundations of risk management and introduces the essentials of ethics and the application of ethical principles to judging the acceptability of risks to humans and the environment. It will also discuss the merits of an analytic deliberative approach to evaluating complex risks and address the application of this discursive methods to risk management taking into account the hormesis challenge.

Risk perception and communication: lessons for the food and food packaging industry.

Health risks are front-page news. Be it bovine spongiform encephalitis (BSE), surface ozone, or radiation from transmitter stations or mobile phones, the popular press puts out a constant stream of risk warnings and sensational reports about potential health threats. This paper examines how the general public perceives and assesses such information when it comes to food and food packaging risks. In the first part, the basic components of food risks are discussed and then compared with the perceptions of these risks. The main emphasis is on the risks from food packaging. The term 'perception' as used in cognitive psychology applies to the mental processes through which a person takes in, deals with and assesses information from the environment (physical and communicative) via the senses. The last part of the paper deals with the consequences of risk assessment and risk perception for risk management and risk communication.

Fourth ventricular neurocytoma: case report and review of the literature.

OBJECTIVES: Central neurocytoma is a tumour that typically occurs in young adults in close association with the lateral and third ventricles of the cerebrum. METHODS: We report the unusual case of a central neurocytoma that developed in the fourth ventricle of a 59-year-old woman and metastasized to the upper cervical canal. Subtotal excision and adjuvant radiotherapy were used to treat the lesion. Microscopic evaluation, discussion of the pathologic differential diagnosis and theories of the histogenesis of the tumour are presented. RESULTS AND CONCLUSIONS: Fourth ventricular neurocytoma is rare and has only been reported twice previously. It appears most likely that this tumour arises from subependymal progenitor cell lines.

The changing character of regulation: a comparison of Europe and the United States.

European and U.S. regulatory policies have changed considerably over the past 30 years. In Europe, since the mid-1980s, consumer and environmental regulation has become more politically salient and regulations have by and large become stricter. On the other hand, in the United States consumer and environmental issues have become less salient and contentious, and regulations have not become (comparatively) stricter. This apparent "flip-flop" of regulatory systems has not been analyzed in much detail to date. This perspective is an attempt to analyze some examples in which it has occurred and identifies one possible cause--namely, credibility.

Can acromegaly be cured? A twenty year review

A retrospective review was performed on 41 patients under going transphenoidal surgery for treatment of acromegaly between 1977 and 1997. The mean age was 16.9 years (range 8-67). There were 28 (68.3 percent) male subjects. The mean follow-up was 4.4 years (range 0-17 years). 14 (34.1 percent) patients underwent postoperative adjuvant treatment with radiotherapy, bromocriptine or both. Three (7.3 percent) patients required a second transphenoidal procedure for persistent disease. Postoperatively 27 (65.9 percent) patients (3 had unknown postoperative growth hormone levels) had normalisation of growth hormone (GH) levels (<5 ng/ml). Of these, 5(20.8 percent) of 24 patients (excluding 3 who were lost to follow-up) had biochemical recurrence of disease. This yields surgical cure in 22 (57.9 percent) of 38 patients (excluding the three who were lost to follow-up). Of the fourteen patients who underwent adjuvant treatment 6 (42.3 percent) attained GH levels <5 ng/ml. Considering all treatments combined, 26 (74.3 percent) of 35 patients (6 lost to follow-up) achieved biochemical cure. These results compare favourably with previously reported cure rates in the literature. Transphenoidal surgery is the initial treatment of choice for acromegaly. An overview of the management of this fascinating neuroendocrine disorder will be presented.(AU)

Health impacts of large releases of radionuclides. Mental health, stress and risk perception: insights from psychological research.

Risk perceptions are only slightly correlated with the expected values of a probability distribution for negative health impacts. Psychometric studies have documented that context variables such as dread or personal control are important predictors for the perceived seriousness of risk. Studies about cultural patterns of risk perceptions emphasize different response sets to risk information, depending on cultural priorities such as social justice versus personal freedom. This chapter reports the major psychological research results pertaining to the factors that govern individual risk perception and discusses the psychometric effects due to people's risk perception and the experience of severe stress. The relative importance of the psychometric context variables, the signals pertaining to each health risks and symbolic beliefs are explained.

Pharmacokinetics of pretargeted monoclonal antibody 2D12.5 and 88Y-Janus-2-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) in BALB/c mice with KHJJ mouse adenocarcinoma: a model for 90Y radioimmunotherapy.

Three-step pretargeting for radioimmunotherapy in BALB/c mice with KHJJ tumors was done with monoclonal antibody (mAb) 2D12.5, which is specific for yttrium-1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) but nonspecific for the tumor. Tumor uptake was by passive diffusion of mAb through leaky neovasculature in the tumor. The three steps were: (a) anti-hapten mAb 2D12.5 (0 h); (b) polyvalent haptenprotein conjugate chase (20 h); and (c) 88Y-labeled monovalent DOTA or bivalent Janus-DOTA haptens (21 h) and organ and tumor bioassay (24 h). Rapid tumor (T) uptake and high tumor:blood ratio (T:BL) was seen 3 h after injection after step c. For monovalent 88Y-DOTA, T = 1.7%/g* and T:BL = 16:1; for bivalent 88Y-Janus-DOTA, T = 4.41%/g* and T:BL = 21:1 at 3 h (*, P < 0.001). Blood and bone plus marrow were << 1%/g, and liver was < 1%/g. The 24-h whole body retention was approximately 5% of injected dose with 1% in tumor (20% of total), 1.8% in other organs, and 2.2% in carcass; the 24-h whole body retention of covalent nonspecific antibody conjugates was > 80% of injected dose. The biological half-life in the tumor of 0.9 microCi 88Y-Janus-DOTA was approximately 24 h, measured daily for 5 days. Activity in microCi/g of tumor and blood for 90Y equimolar to the amount of 88Y injected (0.9 microCi 88Y = 0.744 pmol = 36.47 microCi 90Y) was used for calculating the area under the curve of tumor and blood in microCi-h/g of 90Y. The 90Y radiation absorbed dose (RAD) from multiplying microCi-h/g x the 90Y absorbed dose constant, 1.99 RAD-g/microCi-h, gave T = 89 RAD and BL = 3.7 RAD. The therapeutic ratio from RAD T:RAD BL = 24:1. These results indicate that pretargeting 90Y hapten-specific mAb for radioimmunotherapy has considerable promise.

Comparative toxicity studies of yttrium-90 MX-DTPA and 2-IT-BAD conjugated monoclonal antibody (BrE-3).

BACKGROUND: BrE-3 is monoclonal antibody that has promise for imaging and therapy of human adenocarcinoma. Because of observations in therapeutic trials of yttrium-90 (90Y) escape from radioimmunoconjugates and uptake by the skeleton with resultant bone marrow toxicity, the authors attempted to evaluate the importance of this factor by a comparison of the LD50 in healthy mice treated with 90Y that had been chelated with either of two high affinity chelators, methylbenzyldiethylene-triaminepentaacetic acid (MX-DTPA) or bromoacetamidobenzyl-1,4,7,10-tetraazocyclododecane- N,N',N'',N'''-tetraacetic acid (BAD). METHODS AND RESULTS: Bone marrow hematopoietic toxicity was dose-limiting and the source of death for both chelators. The LD50 for 90Y-BrE-3-MX-DTPA was 220.9 microCi, and that for 90Y-BrE-3-2IT-BAD and was 307.8 microCi. Whole-body autoradiography revealed substantially greater uptake of 90Y in the skeleton when MX-DTPA was used as the chelator. CONCLUSIONS: These observations suggest that 90Y escape to bone is a significant factor in the maximum tolerated dose of radioimmunoconjugate that can be used in therapeutic trials. These results probably underestimate the importance of 90Y escape since 90Y in the skeleton of patients is likely to be more significant than in mice because more of the 90Y energy is absorbed in the marrow of larger species.

Immunogenicity in rabbits and mice of an antibody-chelate conjugate: comparison of (S) and (R) macrocyclic enantiomers and an acyclic chelating agent.

The macrocyclic bifunctional chelating agent 2-(p-bromoacetamidobenzyl)-1,4,7,10-tetraazacyclododecanetetraa cetic acid (BAD), forms inert metal complexes ideal for radioimmunotherapy. Kosmas et al. (Cancer Res., 52: 904-911, 1992) found 2-imminothiolane linker-(S)-BAD monoclonal antibody HMFG1 highly immunogenic in patients. We studied the immunogenicity of (S) and (R) enantiomers of 2-imminothiolane linker-BAD rabbit IgG, monoclonal antibody Lym-1, and Lym-1 2-imminothiolane linker-(S)-bromoacetamidobenzyl-EDTA in 15 rabbits. Five groups of three each were given 0.1, 1.0, or 10 mg of 111In conjugate i.v., blood samples were taken daily for 14 days and biweekly for 70 days, and the plasma T1/2 was calculated. A drop in plasma 111In at 6-8 days coincided with the appearance of antibody on enzyme-linked immunosorbent assay. Specific anti-(S)-BAD, anti-(R)-BAD, anti-(S)-bromoacetamidobenzyl-EDTA, and anti-mouse IgG were measured. Rabbit IgG conjugates did not elicit an immune response. Mouse IgG conjugates were immunogenic on the first exposure, with both anti-1,4,7,10-tetraazacylododecane N,N',N'',N'''-tetraacetic acid and anti-mouse responses. Anti-1,4,7,10-tetraazacylododecane N,N',N'',N'''-tetraacetic acid was specific for the (S) or (R) enantiomer, but cross-reaction appeared with reboosting. A second injection of the opposite enantiomer gave a response to that enantiomer. Lym-1 bromoacetamidobenzyl-EDTA produced anti-bromoacetamidobenzyl-EDTA and anti-mouse response.

Large-scale synthesis of the bifunctional chelating agent 2-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetr aacetic acid, and the determination of its enantiomeric purity by chiral chromatography.

The attachment of radiometals to monoclonal antibodies for medical applications requires extreme stability under physiological conditions, with no significant release of metal. Chelators that can hold radiometals like 111In, 67Ga, and 90Y with high stability under these conditions are essential for radiotherapy or immunoscintigraphy. 2-(p-Nitrobenzyl)-1,4,7,10-tetraazacyclododecane- N,N',N'',N'''-tetraacetic acid (nitrobenzyl-DOTA) is one of the most promising bifunctional chelating agents. A large-scale synthesis of nitrobenzyl-DOTA is described. The overall yield for the nine-step synthesis sequence starting from nitrophenylalanine is 5.6%. Synthesis of nitrobenzyl-DOTA according to the new procedure yields up to approximately 10 g without special apparatus. Both enantiomers of the chiral chelate nitrobenzyl-DOTA have been prepared, and their enantiomeric purity has been checked by chiral chromatography.

Occult vascular malformations of the brain - abstract

Intracranial vascular malformations have been classically divided into four groups: arterio-venous malformations (AVMs), cavernous angiomas, venous angiomas and capillary telangiectasias. The AVMs are the best documented of these lesions and are readily characterized with cerebral angiography. The other malformations have previously been rarely diagnosed during life as they are usually not seen on cerebral angiograms. Recently, however, with the use of advanced neuro-imaging techniques these lesions have been increasingly recognized in association with intracranial haemorrhage and epilepsy. Cavernous angiomas, in particular, have a characteristic appearance on MRI scans. This paper will define these "occult" vascular malformations of the brain, their incidence, clinical presentation, natural history and issues related to management. The experience of the Department of Neurosurgery and the Division of Neuro-Radiology at the Victoria General Hospital in Halifax during 1990 will be summarized. Of over 1,200 consecutive cranial MRI scans, 18 cases of cavernous angiomas were encountered. Some of these caused intracerebral haemorrhage and others were seen in patients with complex countered. Some of these caused intracerebral haemorrhage and others were seen in patients with complex partial seizures. A surprising number were multiple and familial in occurrence. These lesions can present in the brain stem or spinal cord thus mimicking multiple sclerosis. The majority of them are asymptomatic and are incidental findings. Venous angiomas are, in fact, hamartomas and rarely lead to symptoms; because they drain normal neural tissue they cannot be sacrificed without risk of significant neurological sequelae. The emerging literature on angiographically occult vascular malformations of the brain will be reviewed (AU)

A comparison of early versus delayed surgery for ruptured intracranial aneurysms - abstract

The timing of surgical clipping for ruptured intracranial aneurysms has been a subject of debate for many years. Initial attempts at early surgery (within 24-72 hours) had disastrous results and led to the standard practice of delaying surgery for 7-10 days. The use of antifibrinolytic agents during this waiting period was shown to decrease the incidence of rebleeding but also seemed to cause increased frequency of ischaemic deficits and hydrocephalus. With the refinement of microneurosurgical techniques, early surgery for intracranial aneurysms underwent a rebirth in many centres over the last few years. This paper presents the experiences with aneurysm surgery at the Neurosurgical Unit Halifax, Nova Scotia over the four-year period 1984-1987. Ruptured aneurysms lead to subarachnoid haemorrhage in over 50 percent of the cases, arteriovenous malformations comprised 10 percent, and subarachnoid haemorrhage with normal angiography 25 percent of the total cases. During the period under review 25 patients presented with ruptured vertebrobasilar aneurysms and 211 patients presented with ruptured supratentorial aneurysms. The latter group form the basis for comparing results of early vs. delayed clipping for ruptured aneurysms. Despite the fact that the series comprised a consecutive, unmatched group of patients without any attempt at randomization, there were striking similarities in the mean ages, sex distribution and distribution of aneurysms at the various sites in the two groups being compared. Sixty-nine patients presented in good clinical condition after aneurysmal subarachnoid haemorrhage (Hunt & Hess Grades I and II). Twenty-nine patients (mean age 44.5 years) underwent early surgery and 40 (mean age 45 years) had delayed surgery. Despite the higher rebleed rate in the delayed group (12.5 percent vs. 0 percent) there was no statistically significant difference in the eventual outcome between the two groups (mortality rate and the quality of survival). Eighty-five of the patients had excellent outcomes. However, the length of hospital stay was significantly shorter in the patients operated on early (17 days vs. 30 days). Symptomatic vasospasm (40 percent) and hydrocephalus (10 percent) occurred with similar frequencies in both groups. Fifty-two patients presented in poor clinical condition after aneurysmal subarachnoid haemorrhage (Hunt & Hess Grades III and IV). Twenty-three patients (mean age 49.5 years) had early surgery and 29 patients (mean age 53 years) had delayed surgery. The mortality rate (approximately 25 percent) was similar in both groups. Rebleeding was the culprit in the delayed group (24 percent) whereas the surgical mortality was 26 percent in the early group. There was an equally high incidence of symptomatic vasospasm and hydrocephalus in both groups. The quality of survival was better in the early group but achieved statistical significance only in the number of patients making "excellent" recoveries (43 percent vs. 17 percent). The numbers of patients however were small. Aggressive treatment of acute hydrocephalus by ventricular drainage played a large part in improving the clinical status prior to surgery in the early group. As with previous studies (including a large co-operative series), we have been unable to show a really convincing advantage of early aneurysm surgery over delayed surgery if mortality rate and quality of survival are used as the basis of comparison. Clearly, a large scale randomized trial would have to be launched to answer this question conclusively. To answer the criticisms of ardent proponents of delayed surgery, however, we have confirmed that early surgery provides at least as good results. We have not found early surgery technically more difficult. It allows removal of large collections of subarachnoid blood and aggressive treatment of cerebral vasospasm and hydrocephalus and at the same time prevents rebleeding from the aneurysm. We feel early surgery will become more frequently used as newer methods of preventing cerebral vasospasm are discovered. The implications of our experiences to the situations that obtain in the Caribbean will be discussed (AU)

The incidence and pathology of breast cancer in Jamaica - abstract

Figures accumulated in the Jamaica Cancer Registry for the period 1958-1968 show that this cancer ranks second among all malignancies in females. The incidence is higher than that in Africa and in other underprivileged communities. The histological sub-division of these cancers will also be presented. Further work in Jamaica - and possibly other West Indian territories - should be undertaken to study possible explanations for the high incidence observed (AU)