Towards standard setting for patient-reported outcomes in the NHS homeopathic hospitals

We report findings from a pilot data collection study within a programme of quality assurance, improvement and development across all five homeopathic hospitals in the UK National Health Service (NHS).<p></p> <b>Aims</b> (1) To pilot the collection of clinical data in the homeopathic hospital outpatient setting, recording patient-reported outcome since first appointment; (2) to sample the range of medical complaints that secondary-care doctors treat using homeopathy, and thus identify the nature and complexity of complaints most frequently treated nationally; (3) to present a cross section of outcome scores by appointment number, including that for the most frequently treated medical complaints; (4) to explore approaches to standard setting for homeopathic practice outcome in patients treated at the homeopathic hospitals.<p></p> <b>Methods</b> A total of 51 medical practitioners took part in data collection over a 4-week period. Consecutive patient appointments were recorded under the headings: (1) date of first appointment in the current series; (2) appointment number; (3) age of patient; (4) sex of patient; (5) main medical complaint being treated; (6) whether other main medical complaint(s); (7) patient-reported change in health, using Outcome Related to Impact on Daily Living (ORIDL) and its derivative, the ORIDL Profile Score (ORIDL-PS; range, –4 to +4, where a score ≤−2 or ≥+2 indicates an effect on the quality of a patient's daily life); (8) receipt of other complementary medicine for their main medical complaint.<p></p> <b>Results</b> The distribution of patient age was bimodal: main peak, 49 years; secondary peak, 6 years. Male:female ratio was 1:3.5. Data were recorded on a total of 1797 individual patients: 195 first appointments, 1602 follow-ups (FUs). Size of clinical service and proportion of patients who attended more than six visits varied between hospitals. A total of 235 different medical complaints were reported. The 30 most commonly treated complaints were (in decreasing order of frequency): eczema; chronic fatigue syndrome (CFS); menopausal disorder; osteoarthritis; depression; breast cancer; rheumatoid arthritis; asthma; anxiety; irritable bowel syndrome; multiple sclerosis; psoriasis; allergy (unspecified); fibromyalgia; migraine; premenstrual syndrome; chronic rhinitis; headache; vitiligo; seasonal allergic rhinitis; chronic intractable pain; insomnia; ulcerative colitis; acne; psoriatic arthropathy; urticaria; ovarian cancer; attention-deficit hyperactivity disorder (ADHD); epilepsy; sinusitis. The proportion of patients with important co-morbidity was higher in those seen after visit 6 (56.9%) compared with those seen up to and including that point (40.7%; P < 0.001). The proportion of FU patients reporting ORIDL-PS ≥ +2 (improvement affecting daily living) increased overall with appointment number: 34.5% of patients at visit 2 and 59.3% of patients at visit 6, for example. Amongst the four most frequently treated complaints, the proportion of patients that reported ORIDL-PS ≥ +2 at visit numbers greater than 6 varied between 59.3% (CFS) and 73.3% (menopausal disorder).<p></p> <b>Conclusions</b> We have successfully piloted a process of national clinical data collection using patient-reported outcome in homeopathic hospital outpatients, identifying a wide range and complexity of medical complaints treated in that setting. After a series of homeopathy appointments, a high proportion of patients, often representing “effectiveness gaps” for conventional medical treatment, reported improvement in health affecting their daily living. These pilot findings are informing our developing programme of standard setting for homeopathic care in the hospital outpatient context

Infantile hypertrophic pyloric stenosis in patients with esophageal atresia

Background: Patients born with esophageal atresia (EA) have a higher incidence of infantile hypertrophic pyloric stenosis (IHPS), suggestive of a relationship. A shared etiology makes sense from a developmental perspective as both affected structures are foregut derived. A genetic component has been described for both conditions as single entities and EA and IHPS are variable components in several monogenetic syndromes. We hypothesized that defects disturbing foregut morphogenesis are responsible for this combination of malformations. Methods: We investigated the genetic variation of 15 patients with both EA and IHPS with unaffected parents using exome sequencing and SNP array-based genotyping, and compared the results to mouse transcriptome data of the developing foregut. Results: We did not identify putatively deleterious de novo mutations or recessive variants. However, we detected rare inherited variants in EA or IHPS disease genes or in genes important in foregut morphogenesis, expressed at the proper developmental time-points. Two pathways were significantly enriched (p < 1 × 10−5): proliferation and differentiation of smooth muscle cells and self-renewal of satellite cells. Conclusions: None of our findings could fully explain the combination of abnormalities on its own, which makes complex inheritance the most plausible genetic explanation, most likely in combination with mechanical and/or environmental factors. As we did not find one defining monogenetic cause for the EA/IHPS phenotype, the impact of the corrective surgery could should be further investigated

Aberrant microRNA expression and its implications for uveal melanoma metastasis

Uveal melanoma (UM) is the most frequently found primary intra-ocular tumor in adults. It is a highly aggressive cancer that causes metastasis-related mortality in up to half of the patients. Many independent studies have reported somatic genetic changes associated with high metastatic risk, such as monosomy of chromosome 3 and mutations in BAP1. Still, the mechanisms that drive metastatic spread are largely unknown

Generation of 3 human induced pluripotent stem cell lines LUMCi005-A, B and C from a Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch type patient

Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch type (HCHWA-D) is an autosomal dominant hereditary disease caused by a point mutation in exon 17 of the APP gene. We generated human induced pluripotent stem cells (hiPSCs) from a symptomatic HCHWA-D patient by using non-integrating Sendai virus (SeV). The newly generated hiPSCs express all pluripotency markers, have a normal karyotype, carry the Dutch mutation, can differentiate in the three germ layers in vitro and are SeV free

Generation of genetically matched hiPSC lines from two mosaic facioscapulohumeral dystrophy type 1 patients

Facioscapulohumeral dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array on chromosome 4q resulting in sporadic misexpression of the transcription factor DUX4 in skeletal muscle tissue. In ~4% of families, de novo D4Z4 contractions occur after fertilization resulting in somatic mosaicism with control and FSHD1 cell populations present within the same patient. Reprogramming of mosaic fibroblasts from two FSHD1 patients into human induced pluripotent stem cells (hiPSCs) generated genetically matched control and FSHD1 hiPSC lines. All hiPSC lines contained a normal karyotype, expressed pluripotency genes and differentiated into cells from the three germ layers

Myeloid cell tet methylcytosine dioxygenase 2 does not affect the host response during gram-negative bacterial pneumonia and sepsis

Tet methylcytosine dioxygenase 2 (Tet2) is an important enzyme in the demethylation of DNA. Recent evidence has indicated a role for Tet2 in the regulation of macrophage activation by lipopolysaccharide (LPS) and mice with a myeloid cell Tet2 deficiency showed enhanced lung inflammation upon local LPS administration. However, mice with a global Tet2 deficiency showed reduced systemic inflammation during abdominal sepsis. Here, we sought to determine the role of myeloid cell Tet2 in the host response during gram-negative bacterial pneumonia. To this end we infected myeloid cell specific Tet2 deficient and control mice with two common gram-negative respiratory pathogens via the airways: Pseudomonas aeruginosa (PAK, causing acute infection that remains confined in the lungs) or Klebsiella pneumoniae (causing a gradually evolving pneumonia with subsequent dissemination and sepsis) and compared bacterial loads and host response parameters between mouse strains. Bone marrow derived macrophages from myeloid Tet2 deficient mice released more interleukin-6 than control macrophages upon stimulation with PAK or K. pneumoniae. However, bacterial loads did not differ between mouse strains upon infection with viable PAK or K. pneumoniae, and neither did cytokine levels or neutrophil recruitment. In addition, in the K. pneumoniae pneumosepsis model myeloid Tet2 deficiency did not affect systemic inflammation or organ injury. Together these data strongly argue against a role for myeloid cell Tet2 in the host response during gram-negative bacterial pneumonia and pneumosepsis

Distance bounding under different assumptions

Distance-bounding protocols were introduced in 1993 as a countermeasure to relay attacks, in which an adversary fraudulently forwards the communication between a verifier and a distant prover. In the more than 40 different protocols that followed, assumptions were taken on the structure of distance-bounding protocols and their threat models. In this paper, we survey works disrupting these assumptions, and discuss the remaining challenges

Mast cells impair host defense during murine Streptococcus pneumoniae pneumonia

Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia. Mast cells (MCs) are located mainly at the host-environment interface where they function as sentinels. Our goal was to study the role of MCs during pneumonia caused by S. pneumoniae. Lung tissue of patients who had died from pneumococcal pneumonia or a nonpulmonary cause was stained for MCs and tryptase. Wild-type (WT) and MC-deficient (Kit(W-sh/W-sh)) mice were observed or sacrificed after induction of pneumonia by intranasal inoculation of S. pneumoniae. In separate experiments, WT mice were treated with doxantrazole or cromoglycate, which are MC stabilizing agents. The constitutive presence of tryptase-positive MCs was reduced in affected lungs from pneumonia patients. Kit(W-sh/W-sh) mice showed a prolonged survival during the first few days after median lethal dose (LD)100 and LD50 infection, while overall mortality did not differ from that in WT mice. Relative to WT mice, Kit(W-sh/W-sh) mice showed reduced bacterial counts with less bacterial dissemination to distant organs and less inflammation. Neither doxantrazole nor cromoglycate influenced antibacterial defense or inflammatory responses after airway infection with S. pneumoniae. MCs exhibit an unfavorable role in host defense during pneumococcal pneumonia by a mechanism independent of degranulatio

High-volume and High-intensity Functional Training in Patients with Multiple Sclerosis: A Pilot Study on Feasibility and Functional Capacity

OBJECTIVE: To evaluate the feasibility of a high-volume and high-intensity functional training programme in patients with multiple sclerosis (MS), and to explore whether functional capacity improves. A further objective was to explore changes in muscle strength and aerobic capacity. METHODS: This pilot study comprised a 12-week intervention, with an 8-week follow-up period. The intervention consisted of 3 weekly 3-h training sessions, comprising functional resistance-, endurance-, and skills training. Feasibility (questionnaire), functional capacity (Timed Up and Go Test, 10-Meter Walk Test, and 6-Minute Walk Test), aerobic capacity (cardiopulmonary exercise test) and muscle strength (1 repetition maximum (RM) leg press) were evaluated. RESULTS: Seven patients completed the study. Patients attended a mean of 93% of the training sessions. One adverse event was reported, which was not related to the training programme. Patients scored positive or very positive on 86% of the feasibility aspects and scored an overall grade of 8.9 on a scale of 1-10 regarding satisfaction with the training programme. Functional capacity, aerobic capacity, and muscle strength seemed to be improved after the training programme, but the improvements were not always sustained. CONCLUSION: This new high-volume and high-intensity functional training programme appeared to be feasible in patients with MS, and may improve their functional capacity, aerobic capacity and muscle strength. A large-scale controlled trial over a longer period of time is required to evaluate the added value of the training programme

Bronchial epithelial DNA methyltransferase 3b dampens pulmonary immune responses during Pseudomonas aeruginosa infection.

DNA methyltransferase (Dnmt)3b mediates de novo DNA methylation and modulation of Dnmt3b in respiratory epithelial cells has been shown to affect the expression of multiple genes. Respiratory epithelial cells provide a first line of defense against pulmonary pathogens and play a crucial role in the immune response during pneumonia caused by Pseudomonas (P.) aeruginosa, a gram-negative bacterium that expresses flagellin as an important virulence factor. We here sought to determine the role of Dntm3b in respiratory epithelial cells in immune responses elicited by P. aeruginosa. DNMT3B expression was reduced in human bronchial epithelial (BEAS-2B) cells as well as in primary human and mouse bronchial epithelial cells grown in air liquid interface upon exposure to P. aeruginosa (PAK). Dnmt3b deficient human bronchial epithelial (BEAS-2B) cells produced more CXCL1, CXCL8 and CCL20 than control cells when stimulated with PAK, flagellin-deficient PAK (PAKflic) or flagellin. Dnmt3b deficiency reduced DNA methylation at exon 1 of CXCL1 and enhanced NF-ĸB p65 binding to the CXCL1 promoter. Mice with bronchial epithelial Dntm3b deficiency showed increased Cxcl1 mRNA expression in bronchial epithelium and CXCL1 protein release in the airways during pneumonia caused by PAK, which was associated with enhanced neutrophil recruitment and accelerated bacterial clearance; bronchial epithelial Dnmt3b deficiency did not modify responses during pneumonia caused by PAKflic or Klebsiella pneumoniae (an un-flagellated gram-negative bacterium). Dnmt3b deficiency in type II alveolar epithelial cells did not affect mouse pulmonary defense against PAK infection. These results suggest that bronchial epithelial Dnmt3b impairs host defense during Pseudomonas induced pneumonia, at least in part, by dampening mucosal responses to flagellin