Pooled prevalence of lymphopenia in all-cause hospitalisations and association with infection: a systematic review and meta-analysis.

BACKGROUND: Lymphopenia is defined as a decrease below normal value (often 1.0 x 109 cells/L) of blood circulating lymphocyte count. In the general population, lymphopenia is associated with an increased risk of hospitalisation secondary to infection, independent of traditional clinical risk factors. In hospital, lymphopenia is associated with increased risk of healthcare-associated infection and mortality. By summarising lymphopenia's prevalence and impact on clinical outcomes, we can identify an at-risk population and inform future studies of immune dysfunction following severe illness. METHODS: Peer-reviewed search strategy was performed on three databases. Primary objective was to summarise the pooled prevalence of lymphopenia. Primary outcome was infection including pre-existing lymphopenia as a risk factor for admission with infection and as an in-hospital risk factor for healthcare-associated infection. Secondary outcomes were length of stay and mortality. Mortality data extracted included in-hospital, 28/30-day ('early'), and 90-day/1-year ('late') mortality. Meta-analysis was carried out using random-effects models for each outcome measure. Heterogeneity was assessed using I2 statistic. Joanna Briggs Institute checklist for cohort studies was used to assess risk of bias. The protocol was published on PROSPERO. RESULTS: Fifteen observational studies were included. The pooled prevalence of lymphopenia in all-cause hospitalisations was 38% (CI 0.34-0.42, I2= 97%, p< 0.01). Lymphopenia was not associated with an infection diagnosis at hospital admission and healthcare associated infection (RR 1.03; 95% CI 0.26-3.99, p=0.97, I2 = 55% and RR 1.31; 95% CI 0.78-2.20, p=0.31, I2=97%, respectively), but was associated with septic shock (RR 2.72; 95% CI 1.02-7.21, p=0.04, I2 =98%). Lymphopenia was associated with higher in-hospital mortality and higher 'early' mortality rates (RR 2.44; 95% CI 1.71-3.47, p < 0.00001, I2 = 89% and RR 2.05; 95% CI 1.64-2.56, p < 0.00001, I2 = 29%, respectively). Lymphopenia was associated with higher 'late' mortality (RR 1.59; 1.33-1.90, p < 0.00001, I2 = 0%). CONCLUSIONS: This meta-analysis demonstrates the high prevalence of lymphopenia across all-cause hospitalisations and associated increased risk of septic shock, early and late mortality. Lymphopenia is a readily available marker that may identify immune dysfunctional patients. Greater understanding of immune trajectories following survival may provide insights into longer-term poor clinical outcomes.

Service user perspectives on social prescribing services for mental health in the UK: a systematic review.

AIM: To thematically synthesise adult service users' perspectives on how UK-based social prescribing services support them with their mental health management. METHODS: Nine databases were systematically searched up to March 2022. Eligible studies were qualitative or mixed methods studies involving participants aged ⩾ 18 years accessing social prescribing services primarily for mental health reasons. Thematic synthesis was applied to qualitative data to create descriptive and analytical themes. RESULTS: 51,965 articles were identified from electronic searches. Six studies were included in the review (n = 220 participants) with good methodological quality. Five studies utilised a link worker referral model, and one study a direct referral model. Modal reasons for referral were social isolation and/or loneliness (n = 4 studies). Two analytical themes were formulated from seven descriptive themes: (1) person-centred care was key to delivery and (2) creating an environment for personal change and development. CONCLUSIONS: This review provides a synthesis of the qualitative evidence on service users' experiences of accessing and using social prescribing services to support their mental health management. Adherence to principles of person-centred care and addressing the holistic needs of service users (including devoting attention to the quality of the therapeutic environment) are important for design and delivery of social prescribing services. This will optimise service user satisfaction and other outcomes that matter to them.

Objective clinical measurement of physical functioning after treatment for lower extremity sarcoma - A systematic review.

BACKGROUND: Physical impairments and activity restrictions cause significant morbidity after surgery for sarcoma. Yet objective assessment of key components of balance, gait and physical activity (PA), using valid and reliable outcome measures, is lacking in routine clinical practice. PURPOSE OF REVIEW: We therefore performed a systematic review to identify studies quantifying balance, gait and PA in clinically useful ways, after treatment for lower extremity sarcoma. PATIENTS AND METHODS: Relevant articles quantifying balance, gait and PA in patients who underwent surgery for lower extremity bone or soft tissue sarcoma were identified from Medline, Embase, Scopus, and Web of Science up to February 2016. Results were compiled by principal research findings, objective measures used, their ability to detect differences between important clinical groups, change over time and reliability. RESULTS: Eighteen articles were included. Surgery had a significant impact on outcomes (p < 0.05). A wide range of measures and concerns about accuracy of measurement were noted, as gait and PA measures did not discriminate between distinct clinical groups such as limb sparing surgery and amputation, and did not detect changes over time. Few studies investigated reliability (n = 1) and sensitivity to change (n = 4). CONCLUSION: There is a deficit of studies quantifying balance, gait and PA in patients with lower extremity sarcoma. Studies did not use consistent, valid and reliable instruments. There is an urgent need to develop novel objective measures of physical functioning in this patient group to encourage evidence-based clinical care.

TMJ Disc Displacement without Reduction Management: A Systematic Review.

Various interventions have been used for the management of patients with temporomandibular joint (TMJ) disc displacement without reduction (DDwoR), but their clinical effectiveness remains unclear. This systematic review investigated the effects of these interventions and is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic and manual searches up to November 1, 2013, were conducted for English-language, peer-reviewed, publications of randomized clinical trials comparing any form of conservative or surgical interventions for patients with clinical and/or radiologic diagnosis of acute or chronic DDwoR. Two primary outcomes (TMJ pain intensity and maximum mouth opening) and a number of secondary outcomes were examined. Two reviewers performed data extraction and risk of bias assessment. Data collection and analysis were performed according to Cochrane recommendations. Twenty studies involving 1,305 patients were included. Data analysis involved 21 comparisons between a variety of interventions, either between interventions, or between intervention and placebo or no intervention. Meta-analysis on homogenous groups was conducted in 4 comparisons. In most comparisons made, there were no statistically significant differences between interventions relative to primary outcomes at short- or long-term follow-up (p > .05). In a separate analysis, however, the majority of reviewed interventions reported significantly improved primary outcome measures from their baseline levels over time (p < .05). Evidence levels, however, are currently insufficient for definitive conclusions, because the included studies were too heterogeneous and at an unclear to high risk of bias. In view of the comparable therapeutic effects, paucity of high-quality evidence, and the greater risks and costs associated with more complex interventions, patients with symptomatic DDwoR should be initially treated by the simplest and least invasive intervention.

Cellular heterogeneity in the expression of the delta-crystallin gene in non-lens tissue.

RNA transcripts of the delta-crystallin genes, which code for the major chicken lens protein, have been detected at low levels in many non-lens tissues. Here it is demonstrated by in situ hybridisation that these transcripts are concentrated at a high level in small, infrequent clusters of cells in many non-lens tissues. While the nuclei of these cells are very heavily labelled, there is only light labelling of the cytoplasm. The unlabelled cells surrounding the labelled clusters are of similar morphology and staining properties as the labelled cells, and all have the characteristic morphology of cells of the embryonic tissue used. With the exception of neural retina, it is not yet known whether the labelled clusters are found in specific locations in the tissues, or whether they arise at random.

The expression of chick alpha A2-crystallin RNA during lens development and transdifferentiation.

During development of the vertebrate lens, the lens epithelium undergoes a final stage of differentiation into lens fibre cells, during which the major lens proteins, the crystallins, are synthesised. Lentoids, comprising clusters of lens fibre cells can also be produced by transdifferentiation from certain non-lens tissues, including neural retina and pigmented retinal epithelium. We have isolated an alpha A2-crystallin genomic probe and used it to study the transcription and processing of alpha A2-crystallin mRNA both during lens development and transdifferentiation. We relate these results to earlier measurements in this laboratory of delta-crystallin transcription and alpha- and delta-crystallin protein synthesis, to compare the expression of these two sets of genes. Tissue specific differences in gene expression were found. delta-crystallin mRNA is transcribed before alpha A2-crystallin RNA in the lens, but after it in transdifferentiating neural retina and pigmented epithelia.

Chicken lens delta-crystallin gene expression and methylation in several non-lens tissues.

RNA sequences coding for the most abundant chicken lens proteins, delta-crystallin, were detected at very low levels in day old post hatch chick lung, heart, kidney and liver, and in 6 day embryo headless bodies. The pattern of cytosine methylation within the CCGG sequences of the delta-crystallin genes was also examined and shown to vary in several non-lens tissues, from several stages of development. Embryonic neural retina, which expresses a higher level of delta-crystallin RNA than the above tissues, is no less methylated in the sites studied than the tissues which have no association with the eye, and is actually more heavily methylated than the kidney. Thus no obvious correlation was found between undermethylation and gene expression.

The pattern of DNA methylation in the delta-crystallin genes in transdifferentiating neural retina cultures.

Terminally differentiated lens fibre cells are formed in the vertebrate lens throughout life. Lens fibre cells may also be obtained by an in vitro process termed transdifferentiation, from certain tissues of different developmental origin from lens, such as embryo neural retina. delta-Crystallin is the major protein in the chick embryo lens fibre cells, and also in transdifferentiated lens cells obtained from cultured embryonic neural retina. Lens crystallin proteins and mRNA are present at low levels in the intact embryonic neural retina but are no longer detectable in the early stages of neural retina cell culture. However, levels rise steeply in the later stages and crystallins become the major products in terminally transdifferentiating neural retina cultures. We have used this system to test the hypothesis that the patterns of DNA methylation in particular genes are correlated with gene expression. A number of developmentally regulated genes have been found to be undermethylated in tissues where they are expressed, and methylated in tissues where they are not. However this correspondence does not always hold true. Eight-day-old embryonic neural retina was cultured for the period of time during which crystallin gene expression increases 100-fold. DNA methylation in the delta-crystallin gene region was analysed at several stages of cell culture by using the restriction endonucleases HpaII and MspI which cleave at the sequence CCGG. The former enzyme cannot cleave internally methylated cytosine (CmCGG) while the latter cannot cleave externally methylated cytosine (mCCGG). We detect no change in the methylation of CCGG sites within the delta-crystallin gene regions during transdifferentiation. Since dramatic changes in delta-crystallin gene expression occur during this process we conclude that large scale alterations in the pattern of DNA methylation are not a necessary accompaniment to changes in gene activity.

The pattern of expression of chick delta-crystallin genes in lens differentiation and in trans-differentiating cultured tissues.

During development of the vertebrate lens, the lens epithelium undergoes a final stage of differentiation into lens fibre cells. Lens fibre cells can also be produced by trans-differentiation from certain extralenticular structures, all of which are of different developmental origin from lens, including embryonic neural retina and retinal pigmented epithelium. Delta-crystallin is the major lens protein in the chick and appears first in development; it is the major product in trans-differentiated retina of younger embryos. In both normal differentiation and trans-differentiation an increase of delta-crystallin coding RNA is detectable in the nucleus of cells prior to their terminal differentiation into lens fibres. The increase in transcription of delta-crystallin genes accompanying final differentiation of lens fibres, appears to take place slightly in advance of an increase in the capacity to process and transport this mRNA to the cytoplasm.

Variation in the DNA methylation pattern of expressed and nonexpressed genes in chicken.

Using methyl-sensitive and -insensitive restriction enzymes, Hpa II and Msp I, the methylation status of various chicken genes was examined in different tissues and developmental stages. Tissue-specific differences in methylation were found for the delta-crystallin, beta-tubulin, G3PDH, rDNA, and actin genes but not for the histone genes. Developmental decreases in methylation were noted for the delta-crystallin and actin genes in chicken kidney between embryo and adult. Since most of the sequences examined were housekeeping genes, transcriptional differences are apparently not a necessary accompaniment to changes in DNA methylation at the CpG sites examined. The only exception is sperm DNA where the delta-crystallin, beta-tubulin, and actin genes are highly methylated and almost certainly not transcribed. However the G3PDH genes are no more highly methylated in sperm than in other somatic tissues. Many sequences homologous to the rDNA and histone probes used are unmethylated in all tissues examined including sperm, but a methylated rDNA subfraction is more heavily methylated in sperm than in other tissues. We speculate as to the significance of these differences in sperm DNA methylation in the light of possible requirements for early gene activation and the probable deleterious mutagenic effects of heavy methylation within coding sequences.

Cytoplasmic RNA sequences complementary to cloned chick delta-crystallin cDNA show size heterogeneity.

Double-stranded complementary DNA (cDNA) sequences were prepared from day-old chick lens total polysomal RNA and inserted into the unique PstI restriction site of the plasmid pBR322. Colonies containing sequences complementary to abundant lens poly(A)-containing RNA sequences were identified by using lens 32P-labelled cDNA. Some of these clones have been characterized as containing delta-crystallin mRNA coding sequences by genomic DNA blot hybridization and RNA blot hybridizations. Hybridization of labelled DNA from such clones to RNA blots detected four size classes of delta-crystallin RNA sequences, although Southern blots indicated that there are probably only two delta-crystallin genes.

Clinical testing of the radiosensitiser Ro-07-0582. III. Response of tumours.

The nitro-imidazole Ro-07-0582, a known radiosensitiser of hypoxic cells in animals, was administered orally to seven patients with metastatic tumour, before irradiation. The delay imposed on the growth of tumour treated in this way was compared to that of tumour in the same patient treated with radiation alone. Two patients died before any assessment of response could be made. Qualitative evidence from a further three patients suggested some enhancement of radiation effect in two patients but not in the third. Quantitative evidence was obtained from the remaining two patients. In one, a patient with multiple pulmonary metastases from a carcinoma of the breast, no enhancement was shown. In the other, a patient in whom 21 subcutaneous metastases from a carcinoms of the cervix of the uterus were measured, an enhancement ratio of 1-2 was found. This agrees with the value from the same patient's skin when rendered artificially hypoxic, as reported previously. The conditions under which quantitative information may best be obtained in this type of trial are described and various factors affecting the interpretation of results are discussed. Ro-07-0582 has thus been shown to have a radiosensitising effect in man and may therefore prove of value in radiotherapy.

Induction of RNA polymerase synthesis in Escherichia coli.

Studies on the rate of synthesis of the beta and beta' subunits of RNA polymerase in haploid strains of Escherichia coli K12 containing poorly-suppressed rif degrees am mutations provide conclusive evidence that synthesis of at least these two subunits is regulated.