Management of COVID-19 ICU-survivors in primary care: - a narrative review.

Many survivors of critical illness suffer from long-lasting physical, cognitive, and mental health sequelae. The number of affected patients is expected to markedly increase due to the COVID-19 pandemic. Many ICU survivors receive long-term care from a primary care physician. Hence, awareness and appropriate management of these sequelae is crucial. An interdisciplinary authorship team participated in a narrative literature review to identify key issues in managing COVID-19 ICU-survivors in primary care. The aim of this perspective paper is to synthesize important literature to understand and manage sequelae of critical illness due to COVID-19 in the primary care setting.

A customizable, open-source Winston-Lutz system for multi-target, single isocentre radiotherapy.

Objective. To present and share an open-source system (phantom and software) for verifying the targeting accuracy of linac-based, single-isocenter, multi-target radiotherapy. This quality assurance test extends the traditional Winston-Lutz test, which considers a single target located at isocentre.Approach. Plans for a 3D-printed phantom are provided, which can be customized to accommodate various target (BB) positions. Given BB positions and gantry/collimator/couch combinations, the software generates multi-leaf collimator positions to facilitate multi-target Winston-Lutz (MTWL) plan creation. The software determines deviations between detected and expected BB positions on MV images resulting from MTWL plan delivery. BBs are located using a Hough circle detection algorithm, which is modified to favour the detection of circles: (1) having a reasonable size, (2) that are contained within the radiation field, and (3) having reasonable pixel intensities. Validation was performed in two ways: (1) using synthetic data with zero targeting errors and (2) by measuring real linac targeting errors and comparing against results obtained using a commercial system.Main results. Validation using the synthetic data yielded a mean (maximum) absolute discrepancy of 0.11 mm (0.21 mm), which is comparable to the synthetic phantom resolution (0.2 mm). The mean (maximum) absolute discrepancy compared to the commercial system is 0.13 mm (0.43 mm). These values are similar to results obtained with repeated deliveries of the same MTWL plan with the same phantom setup. Both validation tests yield reasonable results and are therefore considered successful. The MTWL test was performed independently by three physicists on two linacs to investigate repeatability, resulting in a mean (maximum) absolute discrepancy of 0.14 mm (0.51 mm) among the various attempts.Significance. Successful completion of this quality assurance test, using our customizable and open-source system, provides confidence that multi-target, single isocentre radiotherapy treatments can be delivered with sufficient geometric accuracy according to the chosen tolerance level.

A site-specific standard for comparing dynamic solar ultraviolet protection characteristics of established tree canopies.

A standardised procedure for making fair and comparable assessments of the ultraviolet protection of an established tree canopy that takes into account canopy movement and the changing position of the sun is presented for use by government, planning, and environmental health authorities. The technique utilises video image capture and replaces the need for measurement by ultraviolet radiometers for surveying shade quality characteristics of trees growing in public parks, playgrounds and urban settings. The technique improves upon tree shade assessments that may be based upon single measurements of the ultraviolet irradiance observed from a fixed point of view. The presented technique demonstrates how intelligent shade audits can be conducted without the need for specialist equipment, enabling the calculation of the Shade Protection Index (SPI) and Ultraviolet Protection Factor (UPF) for any discreet time interval and over a full calendar year. •Tree shade UPF measurements are presented using video capture analysis of moving canopies•A standard method for making accurate assessments of tree shade has been developed•Tree shade comparisons are made without the need for specialist equipment.

The in vivo cytokine release profile following implantation.

There has been no comprehensive study that maps the production of the range of inflammatory cytokines following implantation of a material. There is an urgent requirement for specific data on the real time production of biological markers in order to study their effects in vitro and more accurately predict the in vivo response. This study determined the production of IL-1beta, IL-2, IL-4, IL-6, IL-10, IFNgamma and TNF-alpha in response to a synthetic material implanted in a rat soft tissue model for up to 90 days. IL-1 beta and TNF-alpha were elevated over the total experimental time course with values in the order of 500 pg/ml for IL-1beta and 40 pg/ml for TNF-alpha. The cytokines IL-2, IL-4, IL-6 and IL-10 were also detected and their production reduced with increasing time.

Panton-Valentine Leukocidin associated with community acquired methicillin resistant Staphylococcus aureus: a case report and review of interim guidelines.

We report a case of community acquired methicillin resistant Staphylococcus aureus pneumonia. The causative organism was positive for the toxin Panton-Valentine Leukocidin. This resulted in a severe pneumonia requiring a prolonged stay on our intensive care unit. This infection is becoming more common in the United Kingdom. It can cause a far more aggressive illness than the hospital acquired infection with a high mortality if it becomes an invasive infection. The Department of Health has recently produced interim guidelines for its treatment which we have also reviewed.

Inhibition of the integrin/FAK signaling axis and c-Myc synergistically disrupts ovarian cancer malignancy.

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 and JQ1 synergistically caused an arrest of tumor cells at the G2/M phase and a decrease in the XIAP-linked cell survival. Our subsequent mechanistic analyses indicate that this functional cooperation was strongly associated with the concomitant disruption of activation or expression of FAK and c-Myc as well as their downstream signaling through the PI3K/Akt pathway. In line with these observations, we detected a strong co-amplification or upregulation at genomic or protein level for FAK and c-Myc in a large portion of primary tumors in the TCGA or a local HGSOC patient cohort. Taken together, our results suggest that the integrin-FAK signaling axis and c-Myc synergistically drive cell proliferation, survival and oncogenic potential in HGSOC. As such, our study provides key genetic, functional and signaling bases for the small-molecule-based co-targeting of these two distinct oncogenic drivers as a new line of targeted therapy against human ovarian cancer.

Long-term study of re-infection following successful eradication of Helicobacter pylori infection.

BACKGROUND: 'Re-infection' with Helicobacter pylori after eradication has been estimated to occur in 0-14% of patients, although most so-called 're-infections' occur within the first year following 'eradication' and many may actually be due to recrudescence of a temporarily suppressed infection. AIM: To study the true re-infection rate, we have studied re-infection rates after eradication therapy by excluding the first year's data, minimizing the possible confounding effect of recrudescence. METHODS: All patients tested for H. pylori infection following eradication therapy between 1987 and 2004 were evaluated. Testing was carried out by urea breath test and gastric biopsy. Patients were included if they were found to be negative for H. pylori infection by testing at least 1 year following eradication and underwent at least one further test for H. pylori. RESULTS: 1162 patients met the inclusion criteria with median post-eradication follow-up of 3 years (1.5-14) including 4668 tests; 3319 years of follow-up were analysed. Thirteen cases of re-infection occurred (re-infection rate 0.4% per year). CONCLUSIONS: This large study of H. pylori re-infection avoided cases of recrudescence by excluding the first post-eradication year. True re-infection is probably less common than previously thought.

Host inflammatory response to NiCr, CoCr, and Ti in a soft tissue implantation model.

The inflammatory response to nickel chromium (NiCr), cobalt chromium (CoCr), and titanium (Ti) implants at 7 and 28 days was investigated using real-time PCR analysis along with histological and immunohistochemical staining. Contrasting inflammatory profiles were found in response to the different metal compositions. The inflammatory profile induced by CoCr remained consistent and elevated during the 28-day period with high cell counts associated with the implants and a progressive recruitment of T lymphocytes. The response to NiCr was also elevated, but with an initially low T-lymphocyte infiltration that increased by the later time period. Ti indicated an early increased inflammatory response that had reduced by 28 days. Changes in gene expression demonstrated that Ti induced very low levels of expression of the three inflammatory cytokine genes. NiCr initiated a significant upregulation in gene expression for IL-6 and TNF-alpha. CoCr resulted in the highest upregulation of IL-2 indicative of T-lymphocyte activation to this material.

Hormesis: U-shaped dose responses and their centrality in toxicology.

The fundamental nature of the dose response is neither linear or threshold, but rather U-shaped. When studies are properly designed to evaluate biological activity below the traditional toxicological threshold, low-dose stimulatory responses are observed with high frequency and display specific quantitative features. With a few exceptions, the low-dose stimulatory response is usually not more than twofold greater than the control response, with a stimulatory zone that is more variable, ranging from less than tenfold to more than several orders of magnitude of the dose. Considerable mechanistic evidence indicates that hormetic effects represent overcompensation in response to disruptions in homeostasis that are mediated by agonist concentration gradients with different affinities for stimulatory and inhibitory regulatory pathways.

Flow cytometric measurement of phagocytosis reveals a role for C3b in metal particle uptake by phagocytes.

A methodology for the quick and efficient study of phagocytosis has been developed. It uses the flow cytometer to exploit the change in size and granularity that occurs in cells upon the ingestion of particulate material. The numbers of cells that have phagocytosed particles can be calculated from the distinct shift in regions that occurs. The method also allows the factors governing phagocytosis to be studied in detail through the use of blocking agents or antibodies. Blood-derived monocytes were studied to investigate the role of complement in metal particle phagocytosis to further understand aseptic loosening. Factor C3b was found to be fundamental to the opsonization and phagocytosis of metal particles by monocytes.

February 2001: A 74 year old man with a history over 3 months of increasing dyspnea and malaise.

The February COM: A man of 78 years with idiopathic late-onset cerebellar ataxia developed renal failure in association with a high ESR and positive pANCA. This was complicated by a subclinical spinal subarachnoid hemorrhage which was related to necrotizing inflammation of small leptomeningeal vessels. Renal cortical infarcts were due to similar inflammation in arcuate and interlobular arteries. Spinal subarachnoid hemorrhage is rare and usually due to rupture of an arteriovenous malformation. However, an immunogenic connective tissue disorder should be considered in the differential diagnosis. In this case, the histology and results of an autoantibody screen support a diagnosis of microscopic polyangiitis.

Changing osteocalcin concentrations during pregnancy and lactation: implications for maternal mineral metabolism.

We measured serum osteocalcin concentrations in 82 pregnant and 21 nonpregnant women. Osteocalcin values declined in the second trimester, but returned to nonpregnant levels late in the third trimester. The mean serum osteocalcin concentration in 36 women during pregnancy (mean gestation, 26 weeks) of 2.8 ng/mL was significantly lower than that in nonpregnant women (6.4 ng/mL; P less than 0.001) or term pregnant women at delivery (6.1 ng/mL; n = 46). Serum immunoreactive PTH (iPTH) levels were significantly higher during pregnancy than in nonpregnant women [97 +/- 5 vs. 56 +/- 4 ng/L (mean +/- SE); P less than 0.001]. No significant correlations were found between maternal osteocalcin concentrations and serum phosphorus, alkaline phosphatase, or iPTH, but significant negative correlations were found between osteocalcin and total calcium or total protein. Osteocalcin concentrations in midtrimester amniotic fluid were very low (mean, 0.3 +/- 0.1 ng/mL; n = 11). In 29 lactating mothers, the mean serum osteocalcin level was 9.5 +/- 1.5 ng/mL, significantly higher than in any of the other groups (P less than 0.05), but their serum calcium and iPTH levels were normal. There was no correlation between serum osteocalcin and calcium or iPTH concentrations in lactating women. These changes are compatible with a sequence in which bone turnover is reduced during early pregnancy, rebounds in the third trimester, and increases in postpartum lactating women.

Hormesis as a biological hypothesis.

A comprehensive effort was undertaken to identify articles demonstrating chemical hormesis. Nearly 4000 potentially relevant articles were retrieved from preliminary computer database searches by using various key word descriptors and extensive cross-referencing. A priori evaluation criteria were established including study design features (e.g., number of doses, dose range), statistical analysis, and reproducibility of results. Evidence of chemical hormesis was judged to have occurred in approximately 350 of the 4000 studies evaluated. Chemical hormesis was observed in a wide range of taxonomic groups and involved agents representing highly diverse chemical classes, many of potential environmental relevance. Numerous biological end points were assessed; growth responses were the most prevalent, followed by metabolic effects, longevity, reproductive responses, and survival. Hormetic responses were generally observed to be of limited magnitude. The average low-dose maximum stimulation was approximately 50% greater than controls. The hormetic dose-response range was generally limited to about one order of magnitude, with the upper end of the hormetic curve approaching the estimated no observable effect level for the particular end point. Based on the evaluation criteria, high to moderate evidence of hormesis was observed in studies comprised of > 6 doses; with > 3 doses in the hormetic zone. The present analysis suggests that chemical hormesis is a reproducible and relatively common biological phenomenon. A quantitative scheme is presented for future application to the database.

A study of tissue interface membranes from revision accord knee arthroplasty: the role of T lymphocytes.

Despite four decades of advances in the design of orthopaedic devices aseptic loosening remains a major cause for the revision of total joint arthroplasty. This study used the techniques of immunohistochemistry and reverse transcription polymerase chain reaction to identify the inflammatory cell types, cytokines and chemokines within the interface tissue surrounding failed Accord Knee prostheses. Many T cells were identified within the tissue: however, the classical marker of activation, CD25 was expressed on very few cells. Molecular analysis failed to detect the synthesis of either Th1 or Th2 cytokines. These results suggest that the T cells are being actively recruited to the site of inflammation along the chemokine gradients but are not participating in a classical immune response.

Intravitreal sustained-release ganciclovir.

Current treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome involves frequent intravenous administration of sodium ganciclovir that often results in unacceptable side effects. We have developed devices that release ganciclovir at rates of 2 micrograms/h and 5 micrograms/h in vitro. When implanted into the vitreous of rabbit eyes, mean intravitreal ganciclovir levels of 9 mg/L and 16 mg/L were maintained for more than 80 and 42 days, respectively. Devices were well tolerated, with no toxic effects attributable to the polymers used in the devices. This investigation indicates that these devices can maintain therapeutic levels of drug for extended periods and are well tolerated in the rabbit eye. They may prove useful in the clinical management of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome.

Virilisation in a case of transitional cell carcinoma of the ovary.

A 52 year old woman presented with a five month history of emotional changes, voice changes, and of abdominal discomfort. Clinical, biochemical, and radiological examinations showed evidence of virilisation, raised testosterone, and a complex ovarian mass. Microscopy of the resection specimen showed the tumour to be a transitional cell carcinoma of the ovary with luteinisation and hyperplasia of the intervening stromal cells. This is a unique case of virilisation caused by transitional cell carcinoma of the ovary. Theories as to the origin of testosterone production in non-functioning ovarian tumours are discussed.

Predominant fatty variant of myofibroblastoma of breast.

Myofibroblastoma of the breast is an uncommon but well defined benign stromal tumour. This report describes a case in which the predominant histological component was mature adipose tissue and two further cases with a major adipocytic component. Although small foci of adipose tissue are a recognised feature of this tumour, the dominance of the histological pattern by fat has not been described previously, and the recognition of this variant is important to allow confident diagnosis and avoid confusion with other primary adipocytic or stromal lesions, especially in the setting of potential needle core biopsy of such a lesion.

Increased renal reabsorption of inorganic sulfate in third-trimester high-risk pregnancies.

Inorganic sulfate (SO4) is an essential metabolite for the synthesis of sulfated mucopolysaccharides and steroid sulfates in the fetus and placenta. The authors' previous study of pregnant women at delivery revealed a substantial increase in serum SO4 compared with nonpregnant adults. To determine whether or not this difference was related to altered renal handling, creatinine clearance and SO4 reabsorption was measured in 43 women in the third trimester of pregnancy and in 22 nonpregnant control subjects. Serum SO4 was 32% higher in the pregnant women than in control subjects. Urinary excretion of SO4 was unchanged, but absolute reabsorption of SO4 was significantly higher. Blood pressure, serum creatinine, and serum chloride were significant predictors of serum SO4. As a group, women with hypertension (diastolic blood pressure greater than 80 mmHg) had a significantly higher serum SO4 than those with normal blood pressure. One result of the increased SO4 reabsorption by maternal kidney is that it generates a larger maternal reservoir on which the fetoplacental unit can draw for its biosynthetic needs.

Do providers adhere to ACOG standards? The case of prenatal care.

OBJECTIVE: To examine the extent to which obstetric providers abide by prenatal practice guidelines published by ACOG. METHODS: The prenatal records were abstracted for low-risk patients initiating care with randomly selected urban obstetrician-gynecologists, rural obstetrician-gynecologists, urban family physicians, rural family physicians, and urban certified nurse-midwives in Washington state between September 1, 1988 and August 30, 1989. The prenatal care recorded in their medical charts was compared with the ACOG-recommended guidelines. RESULTS: Overall, providers of all five types adhered closely to the published standards. Certified nurse-midwives recorded a standard of practice that most closely matched that recommended by ACOG. Overall, there was less complete adherence in the recording of maternal height, fetal activity after 30 weeks' gestation, and fetal presentation at or after 36 weeks' gestation. Those laboratory tests that ACOG has recommended most recently (serum alpha-fetoprotein and diabetes screening) and those not recommended for routine use were ordered less often on average by providers. CONCLUSIONS: The cross-sectional nature of this study cannot demonstrate definitively that ACOG's guidelines have changed provider prenatal practices. However, these findings demonstrate that providers in varying specialties and geographic locations can adhere to a detailed set of clinical guidelines if they are appropriately disseminated and implemented.

Characteristics of physicians with obstetric malpractice claims experience.

This study compared the demographic and practice characteristics of physicians with and without obstetric malpractice experience. The sample consisted of 387 family physicians and 204 obstetricians in Washington state who were insured for obstetrics by a major malpractice carrier between January 1982 and June 1988. Fifty-three physicians (9%) had an obstetric malpractice claim during the study period. The approximate overall rate of obstetric malpractice claims was low: 0.32 per 1000 deliveries. The higher the total delivery volume (exposure), the greater the chance of having malpractice experience. Although physicians with practices of over 200 deliveries per year were more likely to have had malpractice experience, their risk of malpractice experience per delivery was lower than that of providers doing fewer than 200 deliveries per year. Our work suggests that insurers might consider basing obstetric malpractice premiums on numbers of deliveries rather than specialty.