Efficacy of Epidural Blood Patching or Surgery in Spontaneous Intracranial Hypotension: A Systematic Review and Evidence Map.

BACKGROUND: Spontaneous intracranial hypotension is an important cause of treatable secondary headaches. Evidence on the efficacy of epidural blood patching and surgery for spontaneous intracranial hypotension has not been synthesized. PURPOSE: Our aim was to identify evidence clusters and knowledge gaps in the efficacy of treatments for spontaneous intracranial hypotension to prioritize future research. DATA SOURCES: We searched published English language articles on MEDLINE (Ovid), the Web of Science (Clarivate), and EMBASE (Elsevier) from inception until October 29, 2021. STUDY SELECTION: We reviewed experimental, observational, and systematic review studies assessing the efficacy of epidural blood patching or surgery in spontaneous intracranial hypotension. DATA ANALYSIS: One author performed data extraction, and a second verified it. Disagreements were resolved by consensus or adjudicated by a third author. DATA SYNTHESIS: One hundred thirty-nine studies were included (median, 14 participants; range, 3-298 participants). Most articles were published in the past decade. Most assessed epidural blood patching outcomes. No studies met level 1 evidence. Most were retrospective cohort or case series (92.1%, n = 128). A few compared the efficacy of different treatments (10.8%, n = 15). Most used objective methods for the diagnosis of spontaneous intracranial hypotension (62.3%, n = 86); however, 37.7% (n = 52) did not clearly meet the International Classification of Headache Disorders-3 criteria. CSF leak type was unclear in 77.7% (n = 108). Nearly all reported patient symptoms using unvalidated measures (84.9%, n = 118). Outcomes were rarely collected at uniform prespecified time points. LIMITATIONS: The investigation did not include transvenous embolization of CSF-to-venous fistulas. CONCLUSIONS: Evidence gaps demonstrate a need for prospective study designs, clinical trials, and comparative studies. We recommend using the International Classification of Headache Disorders-3 diagnostic criteria, explicit reporting of CSF leak subtype, inclusion of key procedural details, and using objective validated outcome measures collected at uniform time points.

Patient experiences with a phone-based cardiovascular risk reduction intervention: Are there differences between women and men?

OBJECTIVES: To explore gender-based differences in experiences with a telehealth-delivered intervention for reduction of cardiovascular risk. METHODS: We conducted 23 semi-structured qualitative interviews by telephone with 11 women and 12 men who received a 12-month, pharmacist-delivered, telephone-based medication and behavioral management intervention. We used content analysis to identify themes. RESULTS: We identified three common themes for both men and women: ease and convenience of phone support, preference for proactive outreach, and need for trust building in the context of telehealth. While both genders appreciated the social support from the intervention pharmacist, women voiced appreciation for accountability whereas men generally spoke about encouragement. CONCLUSIONS: Rapport building may differ between telehealth and in-person healthcare visits; our work highlights how men and women's experiences can differ with telehealth care and which can inform the development of future, purposeful rapport building activities to strengthen the clinician-patient interaction. PRACTICE IMPLICATIONS: Clinicians should seek opportunities to provide frequent and routine support for patients with chronic disease. Telehealth interventions may benefit from gender-specific tailoring of social support.

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity.

Despite investment in toxicogenomics, nonclinical safety studies are still used to predict clinical liabilities for new drug candidates. Network-based approaches for genomic analysis help overcome challenges with whole-genome transcriptional profiling using limited numbers of treatments for phenotypes of interest. Herein, we apply co-expression network analysis to safety assessment using rat liver gene expression data to define 415 modules, exhibiting unique transcriptional control, organized in a visual representation of the transcriptome (the 'TXG-MAP'). Accounting for the overall transcriptional activity resulting from treatment, we explain mechanisms of toxicity and predict distinct toxicity phenotypes using module associations. We demonstrate that early network responses complement traditional histology-based assessment in predicting outcomes for longer studies and identify a novel mechanism of hepatotoxicity involving endoplasmic reticulum stress and Nrf2 activation. Module-based molecular subtypes of cholestatic injury derived using rat translate to human. Moreover, compared to gene-level analysis alone, combining module and gene-level analysis performed in sequence identifies significantly more phenotype-gene associations, including established and novel biomarkers of liver injury.

Improving vasomotor symptoms; psychological symptoms; and health-related quality of life in peri- or post-menopausal women through yoga: An umbrella systematic review and meta-analysis.

OBJECTIVES: Vasomotor symptoms (VMS), commonly reported during menopausal transition, negatively affect psychological health and health-related quality of life (HRQoL). While hormone therapy is an effective treatment, its use is limited by concerns about possible harms. Thus, many women with VMS seek nonhormonal, nonpharmacologic treatment options. However, evidence to guide clinical recommendations is inconclusive. This study reviewed the effectiveness of yoga, tai chi and qigong on vasomotor, psychological symptoms, and HRQoL in peri- or post-menopausal women. DESIGN: MEDLINE, Cochrane Database of Systematic Reviews, EMBASE, CINAHL and the Allied and Complementary Medicine Database were searched. Researchers identified systematic reviews (SR) or RCTs that evaluated yoga, tai chi, or qigong for vasomotor, psychological symptoms, and health-related quality of life (HRQoL) in peri- or post-menopausal women. Data were abstracted on study design, participants, interventions and outcomes. Risk of bias (ROB) was assessed and updated meta-analyses were performed. RESULTS: We identified one high-quality SR (5 RCTs, 582 participants) and 3 new RCTs (345 participants) published after the SR evaluating yoga for vasomotor, psychological symptoms, and HRQoL; no studies evaluated tai chi or qigong. Updated meta-analyses indicate that, compared to controls, yoga reduced VMS (5 trials, standardized mean difference (SMD) -0.27, 95% CI -0.49 to -0.05) and psychological symptoms (6 trials, SDM -0.32; 95% CI -0.47 to -0.17). Effects on quality of life were reported infrequently. Key limitations are that adverse effects were rarely reported and outcome measures lacked standardization. CONCLUSIONS: Results from this meta-analysis suggest that yoga may be a useful therapy to manage bothersome vasomotor and psychological symptoms.

Use of mindfulness, meditation and relaxation to treat vasomotor symptoms.

Postmenopausal women with bothersome vasomotor symptoms (VMS) often seek alternatives to hormone-based treatment due to medication risks or personal preference. We sought to identify the effects of meditation, mindfulness, hypnosis and relaxation on VMS and health-related quality of life in perimenopausal and postmenopausal women. To do this, we conducted an umbrella review supplemented by new randomized, controlled trials (RCTs) published since the most recent good-quality systematic review for eligible interventions. We searched MEDLINE and the Cochrane Database of Systematic Reviews, PubMed, EMBASE, CINAHL and the Allied and Complementary Medicine Databases. We identified five systematic reviews and six new RCTs that met eligibility criteria. In a new meta-analysis examining four RCTs comparing paced respiration with a control group, we found that paced respiration is not associated with a statistically significant decrease in VMS frequency (standardized mean difference (SMD) 0.04, 95% confidence interval (CI) -0.73 to 0.82, I2 = 56.6%, three trials) or severity (SMD 0.06, 95% CI -0.69 to 0.80; I2 = 65.1%, three trials). There was not sufficient new information to conduct meta-analyses that examined the effect of mindfulness or hypnosis on our outcomes of interest. No effect on VMS or quality of life was found between various relaxation or mindfulness interventions.

Data-driven analysis approach for biomarker discovery using molecular-profiling technologies.

High-throughput molecular-profiling technologies provide rapid, efficient and systematic approaches to search for biomarkers. Supervised learning algorithms are naturally suited to analyse a large amount of data generated using these technologies in biomarker discovery efforts. The study demonstrates with two examples a data-driven analysis approach to analysis of large complicated datasets collected in high-throughput technologies in the context of biomarker discovery. The approach consists of two analytic steps: an initial unsupervised analysis to obtain accurate knowledge about sample clustering, followed by a second supervised analysis to identify a small set of putative biomarkers for further experimental characterization. By comparing the most widely applied clustering algorithms using a leukaemia DNA microarray dataset, it was established that principal component analysis-assisted projections of samples from a high-dimensional molecular feature space into a few low dimensional subspaces provides a more effective and accurate way to explore visually and identify data structures that confirm intended experimental effects based on expected group membership. A supervised analysis method, shrunken centroid algorithm, was chosen to take knowledge of sample clustering gained or confirmed by the first step of the analysis to identify a small set of molecules as candidate biomarkers for further experimentation. The approach was applied to two molecular-profiling studies. In the first study, PCA-assisted analysis of DNA microarray data revealed that discrete data structures exist in rat liver gene expression and correlated with blood clinical chemistry and liver pathological damage in response to a chemical toxicant diethylhexylphthalate, a peroxisome-proliferator-activator receptor agonist. Sixteen genes were then identified by shrunken centroid algorithm as the best candidate biomarkers for liver damage. Functional annotations of these genes revealed roles in acute phase response, lipid and fatty acid metabolism and they are functionally relevant to the observed toxicities. In the second study, 26 urine ions identified from a GC/MS spectrum, two of which were glucose fragment ions included as positive controls, showed robust changes with the development of diabetes in Zucker diabetic fatty rats. Further experiments are needed to define their chemical identities and establish functional relevancy to disease development.

Expression of the monocytic differentiation/activation factor P48 in Mycoplasma species.

P48 is a 48 kd monocytic differentiation/activation factor previously purified from the conditioned medium of the Reh human pre-B cell leukemia line. It induces differentiation of HL-60 promyelocytic leukemia cells along the monocytic pathway and production of IL1, TNF-alpha and IL6 in human monocytes and monocytic cell lines. Recently our laboratory isolated cDNA clones for P48 from Reh cells and genomic clones from Mycoplasma fermentans DNA and showed that P48 is a M. fermentans gene product. In this paper we report the analysis of P48 expression at the DNA, mRNA and protein levels in different Mycoplasma species. Polymerase Chain Reaction (PCR) analysis of extracted DNA using P48-specific oligonucleotide primers revealed P48 sequences in M. fermentans but not M. hominis, M. iowae, M. genitalium or M. capricolum. Southern analysis of Mycoplasma DNAs revealed hybridizing bands in M. fermentans and M. capricolum under low stringency, but only in M. fermentans under high stringency. Consistent with this, Northern blot studies revealed a single hybridizing transcript in M. fermentans but not in other Mycoplasma species tested. However, Western blot studies with anti-P48 antibodies revealed P48 antigenic material in M. fermentans, as well as M. hominis and M. iowae. These studies demonstrate that the gene for P48 is derived from M. fermentans or a closely related species and is absent in these other species tested. However, the P48 protein exhibits shared antigenic determinants among several Mycoplasma species which presently are of unknown function or significance. P48 is a Mycoplasma -derived immunomodulatory molecule which may be important in Mycoplasma pathophysiology and may be useful in understanding human haematopoietic differentiation and the control of cytokine biosynthesis.

Hematopoietic differentiation activity of a recombinant human interleukin-6 (IL-6) isoform resulting from alternatively spliced deletion of the second exon.

We have previously identified and cloned an alternatively spliced form of human interleukin-6 mRNA lacking exon II, which encodes amino acid residues known to be important in gp130-mediated signal transduction pathways. We expressed and purified the recombinant protein (rIL6-alt) resulting from this alternatively spliced mRNA and now report the initial characterization of its biologic activities with comparison to full length IL6 (rIL6-full). rIL6-alt was found to have 10(4) to 10(5) fold less activity in proliferation assays with 7TD1 murine plasmacytoma cells and did not competitively inhibit the stimulatory activity of rIL6-full. In addition, like rIL6-full, rIL6-alt had antiproliferative activity toward M1 murine myeloblast cells and was 10-200-fold less active than rIL6-full. In contrast, in assays with human HL60 promyelocytic leukemia cells, rIL6-alt had greater antiproliferative activity than rIL6-full and more strongly upregulated phagocytosis as well as surface expression of the differentiation antigen CD11b. rIL6-full and rIL6-alt upregulated the level of lysozyme mRNA in HL60 cells approximately equally. These findings suggest that IL6-alt, which lacks amino acid residues encoded by the second exon of the gene, is not a natural inhibitor of IL6-full but may be relatively tissue specific and may play a role in modulation of hematopoietic cell growth and differentiation.

cDNA and genomic cloning and expression of the P48 monocytic differentiation/activation factor, a Mycoplasma fermentans gene product.

P48 is a 48 kDa monocytic differentiation/activation factor previously purified from the conditioned medium of the Reh human pre-B cell leukaemia cell line. It induces growth arrest and differentiation of HL-60 human promyelocytic leukaemia cells along the monocytic pathway and the production of the cytokines interleukin 1, tumour necrosis factor-alpha and interleukin 6 in human monocytes and monocytic cell lines. The cDNA for P48 was cloned from Reh cellular RNA using 3' reverse amplification of cDNA ends. Southern blot probing with P48 cDNA revealed hybridization with DNA from Reh and Molt-4 cells, but not with DNA from human peripheral blood mononuclear cells. Subsequent studies using PCR and Southern analysis revealed P48 sequences in DNA isolated from Mycoplasma fermentans but not M. hominis, M.iowae, M.synoviae or M.lypophilum. Although initial studies using Mycoplasma culture and hybridization techniques had failed to reveal Mycoplasma infection in our Reh and Molt-4 cell lines, subsequent PCR studies using Mycoplasma genus-specific rRNA primrs revealed Mycoplasma sequences in these cell lines. Using the P48 cDNA probe, we isolated a genomic clone from M. fermentans DNA which was found to be 98.5% identical with the P48 cDNA clone, and the deduced amino acid sequence agreed with N-terminal microsequencing data for P48 protein purified from the Reh cell line conditioned medium. The 5' end of the gene has a number of consensus sequences characteristic of prokaryotic genes, and the deduced amino acid sequence has a number of features suggesting that P48 is a lipoprotein. The P48 cDNA was expressed in pMAL in Escherichia coli, and the 60 kDa expressed fusion protein was found to react with anti-P48 antibodies on Western blots. This is consistent with a pMAL fusion protein representing the sum of the 42 kDa maltose-binding protein and 18 kDa of P48 recombinant protein, suggesting that native P48 has significant post-translational modification. Consistent with this, Northern blot studies revealed a single 1 kb transcript. The recombinant fusion protein was found to possess anti-proliferative activity against HL-60 cells, and antibodies against recombinant P48 were found to block the biological activity of native P48 isolated from conditioned medium. These studies demonstrate that P48, a molecule with immunomodulatory and haematopoietic differentiation activities, is derived from M. fermentans or a closely related species. P48 may be important in the pathophysiology of Mycoplasma infections and may be useful in dissecting the mechanisms involved in mammalian haematopoietic cell differentiation, immune function and cytokine biosynthesis.

Detection and analysis of an alternatively spliced isoform of interleukin-6 mRNA in peripheral blood mononuclear cells.

Oligonucleotide primers for human interleukin-6 (IL-6) that bracketed the entire coding region of the gene were used in reverse transciptase-polymerase chain reaction (RT-PCR) studies to examine lL-6 expression in peripheral blood mononuclear cells (PBMC). In addition to the predicted 0.64-kb RT-PCR product, a second 0.45-kb product was observed. Cloning and dideoxy sequence analysis of this product revealed evidence for an alternatively spliced lL-6 transcript lacking exon II. Further RT-PCR analysis using forward primers ending at or one base before the exon I donor splice site again yielded both products. Additional primers were designed and successfully used to selectively distinguish the two forms of IL-6 transcript. Both transcripts were prominent in peripheral blood monocytes and lymphocytes, whereas only the 0.64-kb, full-length transcript was prominent in the lL-6-producing 5637 (human bladder carcinoma) cell line. Northern analysis revealed, in addition to the predominant 1.3-kb transcript, several minor transcripts at 1.9 to 4.8 kb that hybridized with the alternatively spliced cDNA probe but not with an exon II probe. Western analysis revealed lL-6 polypeptides of predicted size (26 to 29 kD) in culture medium from PBMC, while showing an immunoreactive band at 17 kD in cell lysates. These findings suggest the existence of an alternatively spliced form of lL-6 mRNA, which would encode for a polypeptide missing the gp130 interactive (signal-transducing) domain contained in exon II while retaining the lL-6 receptor (p80) domain. Such a molecule could in theory function as a natural antagonist of lL-6, as it would be expected to bind to the IL-6 receptor but not lead to signal transduction.

The effects of prenatal and perinatal complications on development at one year of age.

35 variables descriptive of birth and obstetric complications, prematurity, maternal discomfort, and demographic status were studied for a sample of 322 infants. Factor analyses of these variables resulted in 7 major factors that were used to predict developmental status at 1 year of age for 233 of the subjects. Factors identified as "prematurity," "delivery and related variables," "ethnicity," and "complications" made significant independent contributions to Cattell DQ at 1 year. When Cattell DQs were corrected for the effects of gestational age, only delivery and related variables remained critical, confirming the importance of this factor for later development.

Toward a modification of the indices of neonatal prematurity.

In a study of 233 infants, traditional indices of neonatal prematurity were excessively high for predicting developmental lag at 1 yr., and alternative cut-off scores were suggested. Prematurity indices were especially important for infants with below-average development.

Some aspects of a theory of community mental health.

A theoretical position is developed relating the likelihood of an individual's becoming disabled to his pattern of interaction in the community. It is postulated that a system of reciprocation exists among the people with whom an individual interacts. This reciprocation may provide emotional support and services in times of stress, thus helping the individual to ward off disability. Characteristics of networks within which such reciprocation systems may exist, and some measurement problems, are discussed.