Does medical futility matter in 'do not attempt CPR' decision-making?

The current demographical trend towards an increasingly elderly population combined with advances in end of life care calls for a deeper understanding and common terminology about the concept of futility and additional influences on the resuscitation decision-making process. Such improved understanding of medical futility and other contributing factors when making DNACPR orders would help to ensure that clinicians make appropriate and thoughtful decisions on whether to recommend resuscitation in a patient. When estimating medical futility a physician should consider the chance of survival over different time periods and balance this against the chance of adverse outcomes. This information can then be offered to the patient (or the relatives) so that the patient's views about what is acceptable for the survival chance, length and type of survival can be factored into the eventual decision. Given the lack of evidence in this area and the poor level of patient knowledge and the emotive nature of the topic, it is not surprising that clinicians find such discussions hard.

Impact of the COVID-19 Pandemic on Outcomes for Patients with Lung Cancer Receiving Curative-intent Radiotherapy in the UK.

AIMS: Previous work found that during the first wave of the COVID-19 pandemic, 34% of patients with lung cancer treated with curative-intent radiotherapy in the UK had a change to their centre's usual standard of care treatment (Banfill et al. Clin Oncol 2022;34:19-27). We present the impact of these changes on patient outcomes. MATERIALS AND METHODS: The COVID-RT Lung database was a prospective multicentre UK cohort study including patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between April and October 2020. Data were collected on patient demographics, radiotherapy and systemic treatments, toxicity, relapse and death. Multivariable Cox and logistic regression were used to assess the impact of having a change to radiotherapy on survival, distant relapse and grade ≥3 acute toxicity. The impact of omitting chemotherapy on survival and relapse was assessed using multivariable Cox regression. RESULTS: Patient and follow-up forms were available for 1280 patients. Seven hundred and sixty-five (59.8%) patients were aged over 70 years and 603 (47.1%) were female. The median follow-up was 213 days (119, 376). Patients with stage I-II non-small cell lung cancer (NSCLC) who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.859) or death (P = 0.884); however, they did have increased odds of grade ≥3 acute toxicity (P = 0.0348). Patients with stage III NSCLC who had a change to their radiotherapy had no significant increase in distant relapse (P = 0.216) or death (P = 0.789); however, they did have increased odds of grade ≥3 acute toxicity (P < 0.001). Patients with stage III NSCLC who had their chemotherapy omitted had no significant increase in distant relapse (P = 0.0827) or death (P = 0.0661). CONCLUSION: This study suggests that changes to radiotherapy and chemotherapy made in response to the COVID-19 pandemic did not significantly affect distant relapse or survival. Changes to radiotherapy, namely increased hypofractionation, led to increased odds of grade ≥3 acute toxicity. These results are important, as hypofractionated treatments can help to reduce hospital attendances in the context of potential future emergency situations.

Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas.

BACKGROUND: Multiple meningiomas occur in <10% of meningioma patients. Their development may be caused by the presence of a predisposing germline mutation in the neurofibromatosis type 2 (NF2) gene. The predisposing gene in patients with non-NF2 associated multiple meningiomas remains to be identified. Recently, SMARCB1 was reported to be a potential predisposing gene for multiple meningiomas in a family with schwannomatosis and multiple meningiomas. However, involvement of this gene in the development of the meningiomas was not demonstrated. RESULTS: Five affected members of a large family with multiple meningiomas were investigated for the presence of mutations in SMARCB1 and NF2. A missense mutation was identified in exon 2 of SMARCB1 as the causative germline mutation predisposing to multiple meningiomas; furthermore, it was demonstrated that, in accordance with the two-hit hypothesis for tumourigenesis, the mutant allele was retained and the wild-type allele lost in all four investigated meningiomas. In addition, independent somatically acquired NF2 mutations were identified in two meningiomas of one patient with concomitant losses of the wild-type NF2 allele. CONCLUSION: It is concluded that, analogous to the genetic events in a subset of schwannomatosis associated schwannomas, a four-hit mechanism of tumour suppressor gene inactivation, involving SMARCB1 and NF2, might be operative in familial multiple meningiomas associated meningiomas.

Facial injury patterns in a UK paediatric population aged under 13 years.

BACKGROUND: The aims of this study were to present the demographics and mechanisms of facial injury in UK children, and to establish the nature and anatomical location of facial injury in this age group. METHODS: Patient data were collected retrospectively over 1 year from a paediatric Emergency Department in South East Scotland. Medical notes were examined for all patients coded on the electronic patient record as having any facial injury. RESULTS: 593 patients attended with a facial injury. The median age of patients was 4.7 years. (IQR 2.4-7.5 years.), and the male to female ratio of facial injuries was 2:1. Injuries were predominantly from falls. Assault or violence was uncommon. Most common sites of facial injury were the lower third of the face and dento-alveolar injury. Facial fractures were rare and radiographic facial imaging was infrequently performed. Only eight facial fractures were diagnosed. 4.5% of all patients were admitted to hospital; 23% of the children were referred on to other specialities for follow-up, of these over half were to a dentist. CONCLUSIONS: A large number of children presented with facial injuries during the study period. Facial lacerations, oral trauma and dental trauma were the most common injuries. The majority of patients were dealt with without admission or referral to another speciality.

Frenal injury in children is not pathognomic of non-accidental injury.

Upper labial frenal tear in infants is classically taught as having associations with non-accidental injury. Collection of data for a 12-month period in our paediatric facial injury study revealed that this injury pattern is common in ambulant children and was associated with other facial trauma. In assessing the possibility of this injury being due to abuse, the importance of the mobility of the child and the mechanism of the injury are paramount.

Hybridization between escaped domestic and wild American mink (Neovison vison).

The release of domesticated organisms into natural populations may adversely affect these populations through predation, resource competition, and the introduction of disease. Additionally, the potential for hybridization between wild and domestic conspecifics is of great concern because it can alter the evolutionary integrity of the affected populations. Wild American mink (Neovison vison) populations may be threatened not only by competition for resources with domestic mink originating from farms, but by breeding with such escapees. Using 10 microsatellite loci, we genotyped mink from Ontario, Canada, sampled from two farms, two putatively mixed populations in regions surrounding the mink farms, and two wild populations with no recent history of mink farming. Using individual-based Bayesian population assignment, we identified four population clusters, including one wild, and three domestic populations. The latter were not clustered by farm but rather by distinct line-bred colour phases. Population clustering also identified domestic and hybrid mink in the free-ranging populations. Nearly two-thirds of the mink sampled in the two putatively mixed populations (78% and 43%) were either farm escapees or descendants of escapees. Principal components analysis of allele frequencies supported our Bayesian assignment results. The power of our assignment test was assessed using simulated hybrid genotypes which suggested that our overall correct classification rate was 96.2%. The overwhelming presence of domestic animals and their hybridization with mink in natural populations is of great concern for the future sustainability of wild mink populations.

A case of amyoplasia in a monochorionic twin pregnancy: a sequela from twin-twin transfusion syndrome?

OBJECTIVE: To present and discuss the sonographic and clinical findings in one twin of a monochorionic pair affected by amyoplasia. METHODS: On ultrasound examination at 21 weeks in a monochorionic twin pregnancy, twin I was smaller, hydropic, with multiple contractures consistent with amyoplasia and oligohydramnios. Twin II was anatomically normal with polyhydramnios. RESULTS: The twins were delivered at 28 weeks' gestation. The clinical findings were consistent with twin-twin transfusion syndrome (TTTS). CONCLUSION: It is postulated that TTTS may be a causative factor in the excessive incidence of amyoplasia in monozygotic twin pregnancy.

A case of thanatophoric dysplasia: the early prenatal 2D and 3D sonographic findings and molecular confirmation of diagnosis.

OBJECTIVE: To present the early 2D and 3D ultrasound findings and the molecular confirmation in a case of thanatophoric dysplasia. METHODS: On ultrasound examination, there was frontal bossing, increased nuchal translucency and short limbs at 12 weeks' gestation and a small thorax and short and bowed long bones on 3D at 16 weeks. Amniocentesis and DNA analysis confirmed the mutation of FGFR3 gene indicating thanatophoric dysplasia. RESULTS: After medical termination of pregnancy, the postmortem X-ray and pathology examination findings were consistent with the diagnosis. CONCLUSION: 3D anatomy scan and molecular confirmation may be helpful in early diagnosis and genetic counseling of thanatophoric dysplasia.

Five cases of isolated glycerol kinase deficiency, including two families: failure to find genotype:phenotype correlation.

Little is understood of the genotype/phenotype correlations in X linked glycerol kinase deficiency (GKD) where most cases are caused by extensive deletions of Xp21, which often include genes flanking the GK locus. Few cases of isolated GKD have been investigated where the phenotype is not influenced by neighbouring genes. In this paper, we present the mutation data from four confirmed and one suspected case of non-deletion, isolated, X linked GKD and therefore extend the base of patients that can allow an assessment of genotype/phenotype correlations for this disease. The mutations found were two terminations leading to premature truncation of the GK polypeptide chain, one insertion, and an amino acid substitution. Phenotypic variation was observed in two families, where there was more than one affected subject carrying the same mutation, confirming previous studies that suggest there is no correlation between disease severity and genotype. Furthermore, the nature of the mutation in different families does not appear to influence the spectrum of phenotypic variation. In addition, one coding polymorphism in exon 3 has been found. The characterisation of the gene structure has been completed and shows that instead of 19 there are 21 exons.

Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome.

Cohen syndrome is a rare, recessively inherited condition associated with facial dysmorphism, developmental delay, and visual disability. A delay in making the diagnosis commonly occurs, contributed to by the lack of a definitive molecular test and the clinical variability of published case reports. A specific clinical phenotype has been delineated in a homogeneous cohort of Finnish Cohen syndrome patients, but the applicability of their diagnostic criteria to non-Finnish patients has been debated. Detailed delineation of Cohen syndrome in patients from outside Finland is therefore warranted. We report on the clinical features of 33 non-Finnish Cohen syndrome patients. Variability within the clinical spectrum is identified and the natural history of Cohen syndrome described. Diagnostic guidelines for facilitating accurate and early diagnosis are discussed. Results from molecular genetic analysis using markers located within the previously mapped COH1 critical region support allelic but not genetic heterogeneity in this UK cohort.

Correlation between thyrotropin-displacing activity and human thyroid-stimulating activity by immunoglobulins from patients with Graves' disease and other thyroid disorders.

Several reports have been published on the anti-TSH receptor antibody in putative autoimmune thyroid disorders using a radioreceptor assay. We have carried out correlative studies between the ability of serum immunoglobulins to displace radiolabeled TSH from the thyroid plasma membrane receptor [TSH-displacing activity (TDA)] and that of actual stimulation of the human thyroid gland [human thyroid-stimulating activity (hTSA)] in Graves' and other thyroid diseases and in control subjects. TDA was assayed by the use of a radioligand technique, while the activation of adenylate cyclase in human thyroid slices was measured as an index of hTSA. The same immunoglobulins were employed for both assays. In this series, positive TDA and hTSA values were found in 70.4% and 81.5% of the samples in active untreated Graves' disease, respectively. Samples from normal persons and from several patients with toxic nodular goiter gave generally negative results in both assays; in a small proportion of patients with either subacute thyroiditis or Hashimoto's thyroiditis, the TDA was positive but hTSA proved to be negative. In Graves' disease (including those patients on propylthiouracil) in remission and treated with 131I, the correlation between TDA and hTSA was not significant (r = 0.309; P greater than 0.1); even when the procedures were compared in the untreated group alone, there was no significant correlation between the two activities (r = 0.309, P greater than 0.1). These studies indicate that 1) significant TDA and hTSA are observed in Graves' disease; nevertheless, the correlation between them is not significant; 2) the hTSA assay appears to be more sensitive and specific than the TDA assay; and 3) TDA may not be synonymous with thyroid stimulation.

Adenovirus type 41 lacks an RGD alpha(v)-integrin binding motif on the penton base and undergoes delayed uptake in A549 cells.

Human adenovirus (Ad) types 2, 3 and 12 are known to interact with cell surface integrins alpha(v)beta(3) and alpha(v)beta(5) through an RGD motif carried by the penton base. This interaction is thought to augment virus entry after initial contact between the fiber and specific receptor(s). Ad40 and Ad41 are the only members of the human subgroup F adenoviruses. The penton base protein sequence of one Ad40 strain is known to carry the motif RGAD rather than RGD, suggesting that not all human adenoviruses use the above integrins for cell entry. We confirmed that different genomic variants of Ad40 all carry an RGAD motif on the penton base, and found that the Ad41 prototype and several other genomic variants of Ad41 carry the motif IGDD in place of RGAD or RGD. This region is most likely exposed on the Ad41 particle, but attempts to block Ad41 infectivity using a homologous peptide were unsuccessful. Infectivity of an Ad41 preparation as measured by fluorescent focus assay in A549 cells was highly dependent on the length of the adsorption period, indicating that fiber-mediated attachment is inefficient in these cells. Moreover, Ad41 virions adsorbed for 1 h were internalized in a semi-linear fashion over 8 h. This inefficient uptake may be a direct consequence of independence of subgroup F adenoviruses from alpha(v)beta(3) and alpha(v)beta(5) integrin-mediated endocytosis. Ad40 and Ad41 may thus have lost or may never have developed a dependence on the penton base RGD motif for entry.

Characterization of fastidious adenovirus types 40 and 41 by DNA restriction enzyme analysis and by neutralizing monoclonal antibodies.

The DNA of 48 strains of adenovirus type 40 (Ad40) and of 128 strains of adenovirus type 41 (Ad41), isolated between 1971 and 1986 from various countries, was characterized by restriction enzyme analysis using nine and ten restriction endonucleases respectively. Five new DNA variants of Ad40 and 18 new DNA variants of Ad41 were detected. Most of the restriction sites which differed among the various DNA variants appeared to be distributed at random over the entire length of the viral genomes of the two serotypes. The number of restriction sites by which two DNA variants differed from each other was used as a measure of their relatedness. Several clusters of closely related DNA variants were observed for each of the two serotypes. The 35 DNA variants of Ad40 and Ad41 were used to test monoclonal antibody preparations for their range of reactivity in a neutralization assay. One monoclonal antibody (5-8), raised against Ad40 strain Dugan, showed type-specific neutralization of all 11 Ad40 DNA variants tested. Six monoclonal antibodies, raised against Ad41 strain Tak, neutralized different proportions of the variants of Ad41. Two of these preparations (1-21 and 3-19) neutralized all 24 Ad41 DNA variants, while a third (1-23) reacted with only 12 Ad41 variants. Three other monoclonal antibody preparations (3-10, 3-18, 7-14) reacted specifically with only 6 of these 12 variants. The patterns of reactivity with the monoclonal antibody preparations correlated with the presence or absence of a HindIII restriction site at 56 map units and of an EcoRI restriction site at 52 map units on the Ad41 DNA. This region of the adenovirus DNA codes for the hexon protein, which is known to contain the type-specific neutralizing antigenic determinants.

In vitro growth of some fastidious adenoviruses from stool specimens.

Sixty-seven stool specimens from 51 children, positive for adenoviruses by electron microscopy and negative for growth in human-embryo kidney cells, were tested for growth in Chang conjunctiva cells. Twenty-eight specimens caused a cytopathic effect over more than one passage in these cultures, and several adenovirus strains grew better at 33 degree C than at 37 degree C. Most of the culture-positive specimens also induced the development of adenovirus antigens in KB cells detectable by a group-specific indirect immunofluorescence test. Twenty-four of the 25 fastidious strains tested were antigenically related and were distinct from the established serotypes commonly isolated from stools.

The innervation of salivary glands as revealed by morphological methods.

Salivary secretion is nerve mediated. The salivary glands are supplied by parasympathetic and sympathetic efferent nerves which travel to the glands by separate routes. Once in the glands the axons from each type of nerve intermingle and travel together in association with Schwann cells, forming Schwann-axon bundles. Two types of neuro-effector relationships exist with salivary parenchymal and myoepithelial cells: epilemmal (outside the parenchymal basement membrane) and hypolemmal (within the parenchymal basement membrane). Their relative frequencies with either type of nerve differ greatly between glands and species. Salivary blood vessels receive epilemmal innervations by both sympathetic and parasympathetic axons. The classical transmitters--acetylcholine in parasympathetic and noradrenaline in sympathetic axons--are stored in small vesicles. A variety of non-conventional neuropeptide transmitters have also been found in salivary nerves by immunohistochemistry, and they occur in large dense-cored vesicles. Prolonged high frequency stimulation has been found to cause depletion of large dense-cored vesicles from glandular nerves. In recent years afferent nerves have started to be identified and are found in greatest numbers around the main salivary ducts, where they may form a hypolemmal association with the epithelial cells. Functional studies demonstrate complex interactions between parasympathetic and sympathetic nerves. Morphological assessments of changes in the parenchymal cells after nerve stimulations or denervations add greatly to our understanding of the nerve functions. At least four types of influence can be exerted on salivary parenchymal cells by the nerves: hydrokinetic (water mobilizing), proteokinetic (protein secreting), synthetic (inducing synthesis), and trophic (maintaining normal functional size and state). In respect to each role, wide glandular and species differences exist between the relative contributions made by each type of nerve.

Peptidases involved in the catabolism of neurotensin: inhibitor studies using superfused rat hypothalamic slices.

In order to identify which peptidases are involved in the catabolism of neurotensin in the CNS, [3H-Tyr3,11]-neurotensin was superfused over rat hypothalamic slices in the presence and absence of peptidase inhibitors. The degree of degradation of the peptide was determined by reverse phase HPLC separation of 3H-labelled neurotensin from 3H-labelled products. Very little degrading activity was released from the slice into the medium during the superfusion. In the absence of inhibitors, 20 to 50% of 3H-neurotensin was degraded giving mainly 3H-Tyr along with other unidentified 3H-labelled products. Inhibitors of endopeptidase 24.11 (phosphoramidon) and proline endopeptidase (antibody) had no effect on the degradation. Captopril, an inhibitor of angiotensin converting enzyme, had a small inhibitory effect. In contrast, dynorphin(1-13), an inhibitor of a soluble, thiol dependent metallopeptidase which hydrolyses neurotensin at Arg8-Arg9, gave greater than 80% inhibition of 3H-neurotensin degradation in the slice preparation. 1,10-Phenanthroline, an inhibitor of metallopeptidases, was also an effective inhibitor. The dynorphin sequence responsible for the inhibition contains the Arg6-Arg7 bond. Other peptides (bradykinin and angiotensin) which are substrates of the soluble metallopeptidase also inhibited neurotensin breakdown by the slice. This evidence suggests that this thiol dependent metalloendopeptidase is the major neurotensin catabolizing enzyme in hypothalamic slices.

An assessment of optimal conditions for amplification of HIV cDNA using Thermus aquaticus polymerase.

Optimal conditions for in-vitro enzymatic DNA amplification using Thermus aquaticus polymerase were defined using env and gag sequences of human immunodeficiency virus type I as templates. It was found that specific amplification of the target sequence occurred when the primer annealing temperature was above 55 degrees C. Polymerase added once at the beginning of the procedure was sufficient for good results. Deoxynucleotide and primer concentrations and chain elongation time were not found to be important as long as they were kept above a critical level. Differences were noted between the efficiency of specific amplification from purified plasmid and genomic DNA. A rapid and simple method without the use of radioactive reagents for confirmation of a suggestive positive result on gel electrophoresis using restriction enzyme digestion of the amplified products is described. Some possible drawbacks of the technique particularly if used as a diagnostic tool are discussed.

Reverse transcription and subsequent DNA amplification of rubella virus RNA.

A method is described whereby rubella virus RNA was reverse transcribed and the resulting cDNA enzymatically amplified using Taq polymerase. The reactions were carried out in a single reaction vessel, with only minor modifications to the buffer conditions between the reverse transcription and the subsequent amplification step. Using an oligonucleotide probe to the E1 glycoprotein region and limited restriction endonuclease mapping, the resulting amplified products were shown to be specific for rubella virus. This method was also successfully applied to crude cell lysates, without the need for RNA purification. The possible applications of the polymerase chain reaction as applied to RNA sequences are discussed.

Use of post-mortem human synaptosomes for studies of metabolism and transmitter amino acid release.

Synaptosomes have been prepared from human brain obtained at autopsies carried out up to 24 h postmortem (p.m.). They showed generally good retention of morphology, as well as accumulation of tissue potassium and linear rates of oxygen uptake. In response to veratrine depolarization they showed increased respiration rate, decreased tissue potassium content and the specific release of transmitter amino acids. Regression analysis indicated that metabolically and functionally active preparations may be obtained up to ca. 25 h p.m. Preparations obtained from patients dying with brain injury were inactive.

Breast cancer in two sisters with Friedreich's ataxia.

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder causing progressive ataxia and dysarthria. We report two sisters who had breast cancer aged 39 years and 42 years and who both developed a late onset form of FRDA with onset of neurological symptoms in their thirties. We discuss whether there may be an association between the late onset form of FRDA and malignancy.