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Article ; Online: Implications for the colorectal surgeon following the 100 000 Genomes Project.

McDermott, Frank D / Newton, Katy / Beggs, Andrew D / Clark, Susan K

Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland

2021 Volume 23, Issue 5, Page(s) 1049–1058

Abstract: Aim: The 100 000 Genomes Project was completed in 2019 with the objective of integrating genomic medicine into routine National Health Service (NHS) clinical pathways. This project and genomic research will revolutionize the way we practice colorectal ... ...

Abstract	Aim: The 100 000 Genomes Project was completed in 2019 with the objective of integrating genomic medicine into routine National Health Service (NHS) clinical pathways. This project and genomic research will revolutionize the way we practice colorectal surgery in the 21st century. This paper aims to provide an overview of genomic medicine and its implications for the colorectal surgeon. Results: Within NHS England, consolidation has created seven regional Genomic Laboratory Hubs. DNA from solid tumours, including colorectal cancers, will be assessed using 500-gene panels, results will be fed back to Genome Tumour Advisory Boards. Identifying variants from biopsies earlier in the clinical pathway may alter surgical and other treatment options for patients. However, there is an important distinction between somatic variants within a tumour biopsy and germline variants that may suggest a heritable condition such as Lynch syndrome. Novel drugs, for example immunotherapy, will increase treatment options including downstaging cancers and changing the surgical approach. The use of circulating tumour DNA (liquid biopsies) will have applications in diagnosis, treatment and surveillance of cancer. There are many exciting potential future applications of this technology for offering personalized medicine that will require multidisciplinary working and the colorectal community. Conclusion: There are many challenges but also exciting opportunities to embed new 'omic' technologies and innovation into 21st century colorectal surgery. The next phase for the colorectal community is how we engage with this change, with questions around training, identification of genomic multidisciplinary team (MDT) champions and how we collaborate with the core members of the MDT, clinical geneticists and national genomic testing.
MeSH term(s)	Colorectal Neoplasms/genetics ; Colorectal Neoplasms/surgery ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Genomics ; Humans ; Precision Medicine ; State Medicine ; Surgeons
Language	English
Publishing date	2021-02-09
Publishing country	England
Document type	Journal Article
ZDB-ID	1440017-0
ISSN	1463-1318 ; 1462-8910
ISSN (online)	1463-1318
ISSN	1462-8910
DOI	10.1111/codi.15539
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Article ; Online: Postoperative Packing of Perianal Abscess Cavities (PPAC2): randomized clinical trial.

Newton, Katy / Dumville, Jo / Briggs, Michelle / Law, Jennifer / Martin, Julia / Pearce, Lyndsay / Kirwan, Cliona / Pinkney, Thomas / Needham, Alexander / Jackson, Richard / Winn, Simon / McCulloch, Haley / Hill, James

The British journal of surgery

2022 Volume 109, Issue 10, Page(s) 951–957

Abstract: Background: Perianal abscess is common. Traditionally, postoperative perianal abscess cavities are managed with internal wound packing, a practice not supported by evidence. The aim of this randomized clinical trial (RCT) was to assess if non-packing is ...

Abstract	Background: Perianal abscess is common. Traditionally, postoperative perianal abscess cavities are managed with internal wound packing, a practice not supported by evidence. The aim of this randomized clinical trial (RCT) was to assess if non-packing is less painful and if it is associated with adverse outcomes. Methods: The Postoperative Packing of Perianal Abscess Cavities (PPAC2) trial was a multicentre, RCT (two-group parallel design) of adult participants admitted to an NHS hospital for incision and drainage of a primary perianal abscess. Participants were randomized 1:1 (via an online system) to receive continued postoperative wound packing or non-packing. Blinded data were collected via symptom diaries, telephone, and clinics over 6 months. The objective was to determine whether non-packing of perianal abscess cavities is less painful than packing, without an increase in perianal fistula or abscess recurrence. The primary outcome was pain (mean maximum pain score on a 100-point visual analogue scale). Results: Between February 2018 and March 2020, 433 participants (mean age 42 years) were randomized across 50 sites. Two hundred and thirteen participants allocated to packing reported higher pain scores than 220 allocated to non-packing (38.2 versus 28.2, mean difference 9.9; P < 0.0001). The occurrence of fistula-in-ano was low in both groups: 32/213 (15 per cent) in the packing group and 24/220 (11 per cent) in the non-packing group (OR 0.69, 95 per cent c.i. 0.39 to 1.22; P = 0.20). The proportion of patients with abscess recurrence was also low: 13/223 (6 per cent) in the non-packing group and 7/213 (3 per cent) in the packing group (OR 1.85, 95 per cent c.i. 0.72 to 4.73; P = 0.20). Conclusion: Avoiding abscess cavity packing is less painful without a negative morbidity risk. Registration number: ISRCTN93273484 (https://www.isrctn.com/ISRCTN93273484). Registration number: NCT03315169 (http://clinicaltrials.gov).
MeSH term(s)	Abscess/surgery ; Adult ; Anus Diseases/surgery ; Bandages ; Drainage ; Humans ; Pain ; Rectal Fistula/surgery ; Treatment Outcome
Language	English
Publishing date	2022-09-09
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial
ZDB-ID	2985-3
ISSN	1365-2168 ; 0263-1202 ; 0007-1323 ; 1355-7688
ISSN (online)	1365-2168
ISSN	0263-1202 ; 0007-1323 ; 1355-7688
DOI	10.1093/bjs/znac225
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Article ; Online: Negative pressure wound therapy for open traumatic wounds.

Iheozor-Ejiofor, Zipporah / Newton, Katy / Dumville, Jo C / Costa, Matthew L / Norman, Gill / Bruce, Julie

The Cochrane database of systematic reviews

2018 Volume 7, Page(s) CD012522

Abstract: Background: Traumatic wounds (wounds caused by injury) range from abrasions and minor skin incisions or tears, to wounds with extensive tissue damage or loss as well as damage to bone and internal organs. Two key types of traumatic wounds considered in ... ...

Abstract	Background: Traumatic wounds (wounds caused by injury) range from abrasions and minor skin incisions or tears, to wounds with extensive tissue damage or loss as well as damage to bone and internal organs. Two key types of traumatic wounds considered in this review are those that damage soft tissue only and those that involve a broken bone, that is, open fractures. In some cases these wounds are left open and negative pressure wound therapy (NPWT) is used as a treatment. This medical device involves the application of a wound dressing through which negative pressure is applied and tissue fluid drawn away from the area. The treatment aims to support wound management, to prepare wounds for further surgery, to reduce the risk of infection and potentially to reduce time to healing (with or without surgical intervention). There are no systematic reviews assessing the effectiveness of NPWT for traumatic wounds. Objectives: To assess the effects of NPWT for treating open traumatic wounds in people managed in any care setting. Search methods: In June 2018 we searched the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. Selection criteria: Published and unpublished randomised controlled trials that used NPWT for open traumatic wounds involving either open fractures or soft tissue wounds. Wound healing, wound infection and adverse events were our primary outcomes. Data collection and analysis: Two review authors independently selected eligible studies, extracted data, carried out a 'Risk of bias' assessment and rated the certainty of the evidence. Data were presented and analysed separately for open fracture wounds and other open traumatic wounds (not involving a broken bone). Main results: Seven RCTs (1377 participants recruited) met the inclusion criteria of this review. Study sample sizes ranged from 40 to 586 participants. One study had three arms, which were all included in the review. Six studies compared NPWT at 125 mmHg with standard care: one of these studies did not report any relevant outcome data. One further study compared NPWT at 75 mmHg with standard care and NPWT 125mmHg with NPWT 75 mmHg.Open fracture wounds (four studies all comparing NPWT 125 mmHg with standard care)One study (460 participants) comparing NPWT 125 mmHg with standard care reported the proportions of wounds healed in each arm. At six weeks there was no clear difference between groups in the number of participants with a healed, open fracture wound: risk ratio (RR) 1.01 (95% confidence interval (CI) 0.81 to 1.27); moderate-certainty evidence, downgraded for imprecision.We pooled data on wound infection from four studies (596 participants). Follow-up varied between studies but was approximately 30 days. On average, it is uncertain whether NPWT at 125 mmHg reduces the risk of wound infection compared with standard care (RR 0.48, 95% CI 0.20 to 1.13; I Authors' conclusions: There is moderate-certainty evidence for no clear difference between NPWT and standard care on the proportion of wounds healed at six weeks for open fracture wounds. There is moderate-certainty evidence that NPWT is not a cost-effective treatment for open fracture wounds. Moderate-certainty evidence means that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. It is uncertain whether there is a difference in risk of wound infection, adverse events, time to closure or coverage surgery, pain or health-related quality of life between NPWT and standard care for any type of open traumatic wound.
MeSH term(s)	Fractures, Open/therapy ; Humans ; Negative-Pressure Wound Therapy/methods ; Quality of Life ; Quality-Adjusted Life Years ; Randomized Controlled Trials as Topic ; Soft Tissue Injuries/therapy ; Wound Healing ; Wound Infection/prevention & control
Language	English
Publishing date	2018-07-03
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Review ; Systematic Review
ISSN	1469-493X
ISSN (online)	1469-493X
DOI	10.1002/14651858.CD012522.pub2
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Article ; Online: Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers.

Evans, D Gareth / Lalloo, Fiona / Ryan, Neil Aj / Bowers, Naomi / Green, Kate / Woodward, Emma R / Clancy, Tara / Bolton, James / McVey, Rhona J / Wallace, Andrew J / Newton, Katy / Hill, James / McMahon, Raymond / Crosbie, Emma J

Journal of medical genetics

2021 Volume 59, Issue 4, Page(s) 328–334

Abstract: Background: Testing cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was to evaluate tumour dMMR and the ... ...

Abstract	Background: Testing cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was to evaluate tumour dMMR and the prevalence of Lynch syndrome in patients referred to the Manchester Centre for Genomic Medicine, which serves a population of 5.6 million. Methods: Tumour testing used IHC for MMR proteins with targeted Results: In total, 3694 index tumours were tested by IHC (2204 colorectal cancers (CRCs), 739 endometrial cancers (ECs) and 761 other), of which 672/3694 (18.2%) had protein loss, including 348 (9.4%) with MLH1 loss. MLH1 loss was significantly higher for 739 ECs (15%) vs 2204 CRCs (10%) (p=0.0003) and was explained entirely by higher rates of somatic Conclusions: Reflex testing of EC/CRC leads to uncertain diagnoses in many individuals with dMMR following IHC but without germline pathogenic variants or
MeSH term(s)	Brain Neoplasms ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/pathology ; DNA Methylation/genetics ; DNA Mismatch Repair/genetics ; Endometrial Neoplasms/diagnosis ; Endometrial Neoplasms/genetics ; Endometrial Neoplasms/pathology ; Female ; Germ-Line Mutation/genetics ; Humans ; Mismatch Repair Endonuclease PMS2/genetics ; MutL Protein Homolog 1/genetics ; MutS Homolog 2 Protein/genetics ; Neoplastic Syndromes, Hereditary ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism
Chemical Substances	Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Mismatch Repair Endonuclease PMS2 (EC 3.6.1.3) ; MutL Protein Homolog 1 (EC 3.6.1.3) ; MutS Homolog 2 Protein (EC 3.6.1.3)
Language	English
Publishing date	2021-01-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmedgenet-2020-107542
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Article ; Online: Successful isolation and expansion of CMV-reactive T cells from G-CSF mobilized donors that retain a strong cytotoxic effector function.

Samuel, Edward R / Newton, Katy / Mackinnon, Stephen / Lowdell, Mark W

British journal of haematology

2013 Volume 160, Issue 1, Page(s) 87–100

Abstract: Cytomegalovirus (CMV) infections post-haematopoietic stem cell transplantation (HSCT) can be effectively controlled through the adoptive transfer of donor-derived CMV-specific T cells (CMV-T). Current strategies involve a second leukapheresis collection ... ...

Abstract	Cytomegalovirus (CMV) infections post-haematopoietic stem cell transplantation (HSCT) can be effectively controlled through the adoptive transfer of donor-derived CMV-specific T cells (CMV-T). Current strategies involve a second leukapheresis collection from the original donor to manufacture CMV-T, which is often not possible in the unrelated donor setting. To overcome these limitations we have investigated the use of a small aliquot of the original granulocyte-colony stimulating factor (G-CSF) mobilized HSCT graft to manufacture CMV-T. We explored the T cell response to CMVpp65 peptide stimulation in G-CSF mobilized peripheral blood mononuclear cells (PBMC) and subsequently examined isolation of CMV-T based on the activation markers CD154 and CD25. CD25(+) enriched CMV-T from G-CSF mobilized PBMC contained a higher proportion of FoxP3 expression than non-mobilized PBMC and showed superior suppression of T cell proliferation. Expanded CMV-T enriched through CD154 were CD4(+) and CD8(+) , demonstrated a high specificity for CMV, secreted cytotoxic effector molecules and lysed CMVpp65 peptide-loaded phytohaemagglutinin-stimulated blasts. These data provide the first known evidence that CMV-T can be effectively manufactured from G-CSF mobilized PBMC and that they share the same characteristics as CMV-T isolated in an identical manner from conventional non-mobilized PBMC. This provides a novel strategy for adoptive immunotherapy that abrogates the need for successive donation.
MeSH term(s)	Cytokines/biosynthesis ; Cytokines/immunology ; Cytomegalovirus/immunology ; Cytomegalovirus Infections/immunology ; Epitopes, T-Lymphocyte/immunology ; Flow Cytometry ; Granulocyte Colony-Stimulating Factor/pharmacology ; Hematopoietic Stem Cell Mobilization/methods ; Humans ; Immunotherapy, Adoptive ; Leukocytes, Mononuclear/cytology ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/immunology ; Phosphoproteins/pharmacology ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; Viral Matrix Proteins/pharmacology
Chemical Substances	Cytokines ; Epitopes, T-Lymphocyte ; Phosphoproteins ; Viral Matrix Proteins ; cytomegalovirus matrix protein 65kDa ; Granulocyte Colony-Stimulating Factor (143011-72-7)
Language	English
Publishing date	2013-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.12082
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Article ; Online: Isolation of highly suppressive CD25+FoxP3+ T regulatory cells from G-CSF-mobilized donors with retention of cytotoxic anti-viral CTLs: application for multi-functional immunotherapy post stem cell transplantation.

Samuel, Edward R / Beloki, Lorea / Newton, Katy / Mackinnon, Stephen / Lowdell, Mark W

PloS one

2014 Volume 9, Issue 1, Page(s) e85911

Abstract: Previous studies have demonstrated the effective control of cytomegalovirus (CMV) infections post haematopoietic stem cell transplant through the adoptive transfer of donor derived CMV-specific T cells (CMV-T). Strategies for manufacturing CMV ... ...

Abstract	Previous studies have demonstrated the effective control of cytomegalovirus (CMV) infections post haematopoietic stem cell transplant through the adoptive transfer of donor derived CMV-specific T cells (CMV-T). Strategies for manufacturing CMV immunotherapies has involved a second leukapheresis or blood draw from the donor, which in the unrelated donor setting is not always possible. We have investigated the feasibility of using an aliquot of the original G-CSF-mobilized graft as a starting material for manufacture of CMV-T and examined the activation marker CD25 as a targeted approach for identification and isolation following CMVpp65 peptide stimulation. CD25+ cells isolated from G-CSF-mobilized apheresis revealed a significant increase in the proportion of FoxP3 expression when compared with conventional non-mobilized CD25+ cells and showed a superior suppressive capacity in a T cell proliferation assay, demonstrating the emergence of a population of Tregs not present in non-mobilized apheresis collections. The expansion of CD25+ CMV-T in short-term culture resulted in a mixed population of CD4+ and CD8+ T cells with CMV-specificity that secreted cytotoxic effector molecules and lysed CMVpp65 peptide-loaded phytohaemagglutinin-stimulated blasts. Furthermore CD25 expanded cells retained their suppressive capacity but did not maintain FoxP3 expression or secrete IL-10. In summary our data indicates that CD25 enrichment post CMV stimulation in G-CSF-mobilized PBMCs results in the simultaneous generation of both a functional population of anti-viral T cells and Tregs thus illustrating a potential single therapeutic strategy for the treatment of both GvHD and CMV reactivation following allogeneic haematopoietic stem cell transplantation. The use of G-CSF-mobilized cells as a starting material for cell therapy manufacture represents a feasible approach to alleviating the many problems incurred with successive donations and procurement of cells from unrelated donors. This approach may therefore simplify the clinical application of adoptive immunotherapy and broaden the approach for manufacturing multi-functional T cells.
MeSH term(s)	Cell Proliferation/drug effects ; Cell Separation ; Cytokines/metabolism ; Cytomegalovirus/drug effects ; Forkhead Transcription Factors/metabolism ; Granulocyte Colony-Stimulating Factor/pharmacology ; Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cell Transplantation ; Humans ; Immunomagnetic Separation ; Immunotherapy ; Interleukin-2 Receptor alpha Subunit/metabolism ; Phosphoproteins/metabolism ; Species Specificity ; T-Lymphocytes, Cytotoxic/cytology ; T-Lymphocytes, Cytotoxic/drug effects ; T-Lymphocytes, Cytotoxic/metabolism ; Tissue Donors ; Transplantation, Autologous ; Viral Matrix Proteins/metabolism
Chemical Substances	Cytokines ; FOXP3 protein, human ; Forkhead Transcription Factors ; Interleukin-2 Receptor alpha Subunit ; Phosphoproteins ; Viral Matrix Proteins ; cytomegalovirus matrix protein 65kDa ; Granulocyte Colony-Stimulating Factor (143011-72-7)
Language	English
Publishing date	2014-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0085911
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Article ; Online: Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: a cohort study.

Harkness, Elaine F / Barrow, Emma / Newton, Katy / Green, Kate / Clancy, Tara / Lalloo, Fiona / Hill, James / Evans, D Gareth

Journal of medical genetics

2015 Volume 52, Issue 8, Page(s) 553–556

Abstract: Introduction: Lynch syndrome is known to cause an increased risk of malignancies, including bowel and endometrial cancers. However, the risk of breast cancer associated with mutations in the mismatch repair (MMR) genes that cause Lynch syndrome is still ...

Abstract	Introduction: Lynch syndrome is known to cause an increased risk of malignancies, including bowel and endometrial cancers. However, the risk of breast cancer associated with mutations in the mismatch repair (MMR) genes that cause Lynch syndrome is still unclear. Materials and methods: This study assesses the cumulative risk of breast cancer in 106 MLH1 and 118 MSH2 families. Families were referred on the basis of clinical criteria. Pedigree information was obtained, and tumour immunohistochemistry and microsatellite testing performed. Appropriate patients underwent sequencing and multiple ligation dependent probe amplification of all relevant exons of the MMR genes. Kaplan-Meier analysis of cumulative lifetime risk of breast cancer was made combining proven mutation carriers and their first-degree female relatives. Results: After allocation of mutation status, the cumulative risk of breast cancer to 70 years in MLH1 carriers was 18.6% (95% CI 11.3 to 25.9)). This is significantly higher than the cumulative risk for MSH2 which was 11.2% (95% CI 1.4 to 21.0) to age 70 years (p=0.014). The UK population risk is 7.5%-8% at the age of 70 years. Prospective analysis identified six breast cancers in 1120 years of follow-up with an OR of 3.41 (95% CI 1.53 to 7.59). Discussions: Female MLH1 carriers would appear to be at moderate risk of breast cancer and should be considered for breast screening at ages earlier than national screening programmes.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adolescent ; Adult ; Aged ; Breast Neoplasms/complications ; Breast Neoplasms/epidemiology ; Breast Neoplasms/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/complications ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Female ; Genetic Association Studies ; Heterozygote ; Humans ; Incidence ; Kaplan-Meier Estimate ; Microsatellite Repeats ; Middle Aged ; MutL Protein Homolog 1 ; Nuclear Proteins/genetics ; Pedigree ; Risk Assessment
Chemical Substances	Adaptor Proteins, Signal Transducing ; MLH1 protein, human ; Nuclear Proteins ; MutL Protein Homolog 1 (EC 3.6.1.3)
Language	English
Publishing date	2015-08
Publishing country	England
Document type	Journal Article
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmedgenet-2015-103216
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Article ; Online: Internal dressings for healing perianal abscess cavities.

Smith, Stella R / Newton, Katy / Smith, Jennifer A / Dumville, Jo C / Iheozor-Ejiofor, Zipporah / Pearce, Lyndsay E / Barrow, Paul J / Hancock, Laura / Hill, James

The Cochrane database of systematic reviews

2016 , Issue 8, Page(s) CD011193

Abstract: Background: A perianal abscess is a collection of pus under the skin, around the anus. It usually occurs due to an infection of an anal gland. In the UK, the annual incidence is 40 per 100,000 of the adult population, and the standard treatment is ... ...

Abstract	Background: A perianal abscess is a collection of pus under the skin, around the anus. It usually occurs due to an infection of an anal gland. In the UK, the annual incidence is 40 per 100,000 of the adult population, and the standard treatment is admission to hospital for incision and drainage under general anaesthetic. Following drainage of the pus, an internal dressing (pack) is placed into the cavity to stop bleeding. Common practice is for community nursing teams to change the pack regularly until the cavity heals. Some practitioners in the USA and Australia make a small stab incision under local anaesthetic and place a catheter into the cavity which drains into an external dressing. It is removed when it stops draining. Elsewhere in the USA, simple drainage is performed in an outpatient setting under local anaesthetic. Objectives: To assess the effects of internal dressings in healing wound cavities resulting from drainage of perianal abscesses. Search methods: In May 2016 we searched: The Cochrane Wounds Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE and EBSCO CINAHL Plus. We also searched clinical trial registries to identify ongoing and unpublished studies, and searched reference lists of relevant reports to identify additional studies. We did not restrict studies with respect to language, date of publication, or study setting. Selection criteria: Published or unpublished randomised controlled trials (RCTs) comparing any type of internal dressing (packing) used in the post-operative management of perianal abscess cavities with alternative treatments or different types of internal dressing. Data collection and analysis: Two review authors independently performed study selection, risk of bias assessment, and data extraction. Main results: We included two studies, with a total of 64 randomised participants (50 and 14 participants) aged 18 years or over, with a perianal abscess. In both studies, participants were enrolled on the first post-operative day and randomised to continued packing by community district nursing teams or to no packing. Participants in the non-packing group managed their own wounds in the community and used absorbant dressings to cover the area. Fortnightly follow-up was undertaken until the cavity closed and the skin re-epithelialised, which constituted healing. For non-attenders, telephone follow-up was conducted.Both studies were at high risk of bias due to risk of attrition, performance and detection bias.It was not possible to pool the two studies for the outcome of time to healing. It is unclear whether continued post-operative packing of the cavity of perianal abscesses affects time to complete healing. One study reported a mean time to wound healing of 26.8 days (95% confidence interval (CI) 22.7 to 30.7) in the packing group and 19.5 days (95% CI 13.6 to 25.4) in the non-packing group (it was not clear if all participants healed). We re-analysed the data and found no clear difference in the time to healing (7.30 days longer in the packing group, 95% CI -2.24 to 16.84; 14 participants). This was assessed as very low quality evidence (downgraded three levels for very serious imprecision and serious risk of bias). The second study reported a median time to complete wound healing of 24.5 days (range 10 to 150 days) in the packing group and 21 days (range 8 to 90 days) in the non-packed group. There was insufficient information to be able to recreate the analysis and the original analysis was inappropriate (did not account for censoring). This second study also provided very low quality evidence (downgraded four levels for serious risk of bias, serious indirectness and very serious imprecision).There was very low quality evidence (downgraded for risk of bias, indirectness and imprecision) of no difference in wound pain scores at the initial dressing change. Both studies also reported patients' retrospective judgement of wound pain over the preceding two weeks (visual analogue scale, VAS) as lower for the non-packed group (2; both studies) compared with the packed group (0; both studies); (very low quality evidence) but we have been unable to reproduce these analyses as no variance data were published.There was no clear evidence of a difference in the number of post-operative fistulae detected between the packed and non-packed groups (risk ratio (RR) 2.31, 95% CIs 0.56 to 9.45, I(2) = 0%) (very low quality evidence downgraded three levels for very serious imprecision and serious risk of bias).There was no clear evidence of a difference in the number of abscess recurrences between the packed and non-packed groups over the variable follow-up periods (RR 0.72, 95% CI 0.22 to 2.37, I(2) = 0%) (very low quality evidence downgraded three levels for serious risk of bias and very serious imprecision).No study reported participant health-related quality of life/health status, incontinence rates, time to return to work or normal function, resource use in terms of number of dressing changes or visits to a nurse, or change in wound size. Authors' conclusions: It is unclear whether using internal dressings (packing) for the healing of perianal abscess cavities influences time to healing, wound pain, development of fistulae, abscess recurrence or other outcomes. Despite this absence of evidence, the practice of packing abscess cavities is commonplace. Given the lack of high quality evidence, decisions to pack may be based on local practices or patient preferences. Further clinical research is needed to assess the effects and patient experience of packing.
MeSH term(s)	Abscess/surgery ; Anus Diseases/etiology ; Anus Diseases/therapy ; Bandages ; Drainage ; Humans ; Postoperative Complications/therapy ; Randomized Controlled Trials as Topic ; Rectal Fistula/etiology ; Rectal Fistula/therapy ; Self Care ; Time Factors ; Wound Healing
Keywords	covid19
Language	English
Publishing date	2016-08-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review ; Systematic Review
ISSN	1469-493X
ISSN (online)	1469-493X
DOI	10.1002/14651858.CD011193.pub2
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Article ; Online: Manufacture of GMP-compliant functional adenovirus-specific T-cell therapy for treatment of post-transplant infectious complications.

Horlock, Claire / Skulte, Amanda / Mitra, Arindam / Stansfield, Alka / Bhandari, Shristi / Ip, Winnie / Qasim, Waseem / Lowdell, Mark W / Patel, Shreenal / Friedetzky, Anke / Purbhoo, Marco A / Newton, Katy

Cytotherapy

2016 Volume 18, Issue 9, Page(s) 1209–1218

Abstract: Background aims: In pediatric patients, adenovirus (ADV) reactivation after allogeneic hematopoietic stem cell transplantation (allo HSCT) is a major cause of morbidity and mortality. For patients who do not respond to antiviral drug therapy, a new ... ...

Abstract	Background aims: In pediatric patients, adenovirus (ADV) reactivation after allogeneic hematopoietic stem cell transplantation (allo HSCT) is a major cause of morbidity and mortality. For patients who do not respond to antiviral drug therapy, a new treatment approach using ADV-specific T cells can present a promising alternative. Here we describe the clinical scale Good Manufacturing Practice (GMP)-compliant manufacture and characterization of 40 ADV-specific T-cell products, Cytovir ADV, which are currently being tested in a multi-center phase I/IIa clinical trial. This process requires minimal intervention, is high yield, and results in a pure T-cell product that is functional. Methods: Mononuclear cells (2 × 10(7)) were cultured in a closed system in the presence of GMP-grade ADV peptide pool and cytokines for 10 days. On day 10, the T-cell product was harvested, washed in a closed system, counted and assessed for purity and potency. Additional characterization was carried out where cell numbers allowed. Results: Thirty-eight of 40 products (95%) met all release criteria. Median purity of the cell product was 88.3% CD3+ cells with a median yield of 2.9 × 10(7) CD3+ cells. Potency analyses showed a median ADV-specific interferon (IFN)γ response of 5.9% of CD3+ and 2345 IFNγ spot-forming cells/million. CD4 and CD8 T cells were capable of proliferating in response to ADV (63.3 and 56.3%, respectively). These virus-specific T cells (VST) were heterogenous, containing both effector memory and central memory T cells. In an exemplar patient with ADV viremia treated in the open ASPIRE trial, ADV-specific T-cell response was detected by IFNγ enzyme-linked immunospot from 13 days post-infusion. ADV DNA levels declined following cellular therapy and were below level of detection from day 64 post-infusion onward. Conclusions: The clinical-scale GMP-compliant One Touch manufacturing system is feasible and yields functional ADV-specific T cells at clinically relevant doses.
MeSH term(s)	Adenoviridae/pathogenicity ; Adenoviridae/physiology ; Adenoviridae Infections/therapy ; Cell Culture Techniques/methods ; Cell Culture Techniques/standards ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Immunophenotyping ; Immunotherapy/methods ; T-Lymphocytes/cytology ; T-Lymphocytes/virology
Language	English
Publishing date	2016-07-14
Publishing country	England
Document type	Clinical Trial ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2039821-9
ISSN	1477-2566 ; 1465-3249
ISSN (online)	1477-2566
ISSN	1465-3249
DOI	10.1016/j.jcyt.2016.06.009
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Article: Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers.

Nistala, Kiran / Moncrieffe, Halima / Newton, Katy R / Varsani, Hemlata / Hunter, Patricia / Wedderburn, Lucy R

Arthritis and rheumatism

2008 Volume 58, Issue 3, Page(s) 875–887

Abstract: Objective: To identify interleukin-17 (IL-17)-producing T cells from patients with juvenile idiopathic arthritis (JIA), and investigate their cytokine production, migratory capacity, and relationship to Treg cells at sites of inflammation, as well as to ...

Abstract	Objective: To identify interleukin-17 (IL-17)-producing T cells from patients with juvenile idiopathic arthritis (JIA), and investigate their cytokine production, migratory capacity, and relationship to Treg cells at sites of inflammation, as well as to test the hypothesis that IL-17+ T cell numbers correlate with clinical phenotype in childhood arthritis. Methods: Flow cytometry was used to analyze the phenotype, cytokine production, and chemokine receptor expression of IL-17-producing T cells in peripheral blood and synovial fluid mononuclear cells from 36 children with JIA, in parallel with analysis of forkhead box P3 (FoxP3)-positive Treg cells. Migration of IL-17+ T cells toward CCL20 was assessed by a Transwell assay. Synovial tissue was analyzed by immunohistochemistry for IL-17 and IL-22. Results: IL-17+ T cells were enriched in the joints of children with JIA as compared with the blood of JIA patients (P = 0.0001) and controls (P = 0.018) and were demonstrated in synovial tissue. IL-17+ T cell numbers were higher in patients with extended oligoarthritis, the more severe subtype of JIA, as compared with patients with persistent oligoarthritis, the milder subtype (P = 0.046). Within the joint, there was an inverse relationship between IL-17+ T cells and FoxP3+ Treg cells (r = 0.61, P = 0.016). IL-17+,CD4+ T cells were uniformly CCR6+ and migrated toward CCL20, but synovial IL-17+ T cells had variable CCR4 expression. A proportion of IL-17+ synovial T cells produced IL-22 and interferon-gamma. Conclusion: This study is the first to define the frequency and characteristics of "Th17" cells in JIA. We suggest that these highly proinflammatory cells contribute to joint pathology, as indicated by relationships with clinical phenotypes, and that the balance between IL-17+ T cells and Treg cells may be critical to outcome.
MeSH term(s)	Adolescent ; Adult ; Arthritis, Juvenile/metabolism ; Arthritis, Juvenile/pathology ; Case-Control Studies ; Cell Movement/drug effects ; Chemokine CCL20/pharmacology ; Child ; Female ; Forkhead Transcription Factors/metabolism ; Humans ; Interferon-gamma/metabolism ; Interleukin-17/metabolism ; Interleukin-4/metabolism ; Interleukins/metabolism ; Joints/metabolism ; Joints/pathology ; Macrophage Inflammatory Proteins/pharmacology ; Male ; Phenotype ; Receptors, CCR4/metabolism ; Synovial Fluid/cytology ; T-Lymphocytes/metabolism ; T-Lymphocytes/pathology ; T-Lymphocytes, Regulatory/metabolism ; T-Lymphocytes, Regulatory/pathology ; Interleukin-22
Chemical Substances	CCL20 protein, human ; CCR4 protein, human ; Chemokine CCL20 ; FOXP3 protein, human ; Forkhead Transcription Factors ; Interleukin-17 ; Interleukins ; Macrophage Inflammatory Proteins ; Receptors, CCR4 ; Interleukin-4 (207137-56-2) ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2008-02-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	127294-9
ISSN	1529-0131 ; 0004-3591 ; 2326-5191
ISSN (online)	1529-0131
ISSN	0004-3591 ; 2326-5191
DOI	10.1002/art.23291
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Zs.A 24: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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