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1.
BJA Educ ; 24(5): 155-163, 2024 May.
Article in English | MEDLINE | ID: mdl-38646450
3.
Clin Neurol Neurosurg ; 233: 107928, 2023 10.
Article in English | MEDLINE | ID: mdl-37573681

ABSTRACT

OBJECTIVE: Central nervous system (CNS) manifestations of hematologic malignancies are uncommon and often have a poor prognosis. As hematologic neoplasms are typically chemotherapy- and radiotherapy-sensitive, surgical resection is usually not indicated; thus, opportunities for in-depth characterization of CNS hematologic tumors are limited. Here, we report four cases of rare intracranial hematologic tumors requiring surgical intervention, allowing for histopathologic and genomic characterization. METHODS: The clinical course, genetic perturbations, and histopathological features are described for a case of 1) primary marginal zone B-cell lymphoma of the dura as well as cases of brain metastases of 2) cutaneous T-cell lymphoma, 3) acute myeloid leukemia/myeloid sarcoma, and 4) multiple myeloma. Targeted DNA sequencing, fluorescence in situ hybridization, cytogenetic analysis, flow cytometry and immunohistochemical staining were used to assess the lesions. RESULT: Molecular and histopathological characterizations of four unusual presentations of hematolymphoid diseases involving the CNS are presented. Genetic abnormalities were identified in each lesion, including chromosomal aberrations and single nucleotide variants resulting in missense or nonsense mutations in oncogenes. CONCLUSIONS: Our case series provides insight into unique pathological phenotypes of hematologic neoplasms with atypical CNS involvement. We offer targets for future studies by identifying potentially pathogenic genetic variants in these lesions, as the full implications of the novel molecular abnormalities described remain unclear.


Subject(s)
Brain Neoplasms , Central Nervous System Neoplasms , Hematologic Neoplasms , Lymphoma, B-Cell, Marginal Zone , Multiple Myeloma , Humans , In Situ Hybridization, Fluorescence , Hematologic Neoplasms/genetics , Lymphoma, B-Cell, Marginal Zone/genetics , Lymphoma, B-Cell, Marginal Zone/pathology , Brain Neoplasms/genetics
4.
Nat Aging ; 3(9): 1144-1166, 2023 09.
Article in English | MEDLINE | ID: mdl-37563227

ABSTRACT

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.


Subject(s)
DNA Methylation , Epigenesis, Genetic , Humans , Mice , Animals , DNA Methylation/genetics , Aging/genetics , Longevity/genetics , Mammals/genetics
5.
Acta Neurochir (Wien) ; 164(10): 2563-2572, 2022 10.
Article in English | MEDLINE | ID: mdl-35867183

ABSTRACT

BACKGROUND: Treatments for symptomatic or unstable basilar invagination (BI) include posterior decompression, distraction/fusion, trans-nasal or trans-oral anterior decompression, and combined techniques, with the need for occipitocervical fusion based on the degree of craniocervical instability. Variations of the far lateral transcondylar approach are described in limited case series for BI, but have not been widely applied. METHODS: A single-institution, retrospective review of consecutive patients undergoing a far lateral transcondylar approach for odontoidectomy (± resection of the inferior clivus) followed by occipitocervical fusion over a 6-year period (1/1/2016 to 12/31/2021) is performed. Detailed technical notes are combined with images from cadaveric dissections and patient surgeries to illustrate our technique using a lateral retroauricular incision. RESULTS: Nine patients were identified (3 males, 6 females; mean age 40.2 ± 19.6 years). All patients had congenital or acquired BI causing neurologic deficits. There were no major neurologic or wound-healing complications. 9/9 patients (100%) experienced improvement in preoperative symptoms. CONCLUSIONS: The far lateral transcondylar approach provides a direct corridor for ventral brainstem decompression in patients with symptomatic BI. A comprehensive knowledge of craniovertebral junction anatomy is critical to the safe performance of this surgery, especially when using a lateral retroauricular incision.


Subject(s)
Platybasia , Spinal Fusion , Adult , Decompression, Surgical , Female , Humans , Male , Middle Aged , Nose/surgery , Platybasia/complications , Platybasia/surgery , Retrospective Studies , Spinal Fusion/methods , Young Adult
7.
Disabil Health J ; 15(3): 101317, 2022 07.
Article in English | MEDLINE | ID: mdl-35410777

ABSTRACT

BACKGROUND: Achieving equitable medical care for people with disabilities is a complex challenge with emphasis often placed on the need for improved physician knowledge and cultural competence. Physical medicine and rehabilitation (PM&R) is a specialty dedicated to maximizing patient function, where a focus on working with and learning from patients with complex disabilities informs physician training and patient care. OBJECTIVE: The purpose of this study was to assess barriers to equitable care in PM&R clinics through a structural checklist and semi-structured interviews with clinic staff and physicians. METHODS: We used qualitative analysis with a grounded theory approach to develop a unified explanation of how existing clinic processes and provider attitudes affect equitable access to medical care. RESULTS: We found physicians comfortable with and respectful of patient differences who described leveraging unpaid time and creativity to navigate structural, resource, and awareness barriers. Staff and physicians described current barriers as negatively affecting quality of care, clinic efficiency, and, in some cases, patient and staff safety. CONCLUSION: Our results suggest that high levels of physician disability-related knowledge and cultural competence may be insufficient to the challenge of achieving equitable care.


Subject(s)
Disabled Persons , Physicians , Cultural Competency , Humans
8.
Anaesthesia ; 77(3): 277-285, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34530496

ABSTRACT

We used the Hospital Episodes Statistics database to investigate unwarranted variation in the rates Trusts discharged children the same day after scheduled tonsillectomy and associations with adverse postoperative outcomes. We included children aged 2-18 years who underwent tonsillectomy between 1 April 2014 and 31 March 2019. We stratified analyses by category of Trust, non-specialist or specialist, defined as without or with paediatric critical care facilities, respectively. We adjusted analyses for age, sex, year of surgery and aspects of presentation and procedure type. Of 101,180 children who underwent tonsillectomy at non-specialist Trusts, 62,926 (62%) were discharged the same day, compared with 24,138/48,755 (50%) at specialist Trusts. The adjusted proportion of children discharged the same day as tonsillectomy ranged from 5% to 100% at non-specialist Trusts and 9% to 88% at specialist Trusts. Same-day discharge was not independently associated with an increased rate of 30-day emergency re-admission at non-specialist Trusts but was associated with a modest rate increase at specialist Trusts; adjusted probability 8.0% vs 7.7%, odds ratio (95%CI) 1.14 (1.05-1.24). Rates of adverse postoperative outcomes were similar for Trusts that discharged >70% children the same day as tonsillectomy compared with Trusts that discharged <50% children the same day, for both non-specialist and specialist Trust categories. We found no consistent evidence that day-case tonsillectomy is associated with poorer outcomes. All Trusts, but particularly specialist centres, should explore reasons for low day-case rates and should aim for rates >70%.


Subject(s)
Ambulatory Surgical Procedures/trends , Patient Discharge/trends , Patient Safety , State Medicine/trends , Tonsillectomy/trends , Adolescent , Ambulatory Surgical Procedures/standards , Child , Child, Preschool , England/epidemiology , Female , Humans , Male , Patient Discharge/standards , Patient Safety/standards , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , State Medicine/standards , Tonsillectomy/standards , Treatment Outcome
9.
Neuroscience ; 479: 70-90, 2021 12 15.
Article in English | MEDLINE | ID: mdl-34648866

ABSTRACT

Deficiency in peroxisome proliferator-activated receptor gamma coactivator 1-alpha. (PGC-1α) expression or function is implicated in numerous neurological and psychiatric disorders. PGC-1α is required for the expression of genes involved in synchronous neurotransmitter release, axonal integrity, and metabolism, especially in parvalbumin-positive interneurons. As a transcriptional coactivator, PGC-1α requires transcription factors to specify cell-type-specific gene programs; while much is known about these factors in peripheral tissues, it is unclear if PGC-1α utilizes these same factors in neurons. Here, we identified putative transcription factors controlling PGC-1α-dependent gene expression in the brain using bioinformatics and then validated the role of the top candidate in a knockout mouse model. We transcriptionally profiled cells overexpressing PGC-1α and searched for over-represented binding motifs in the promoters of upregulated genes. Binding sites of the estrogen-related receptor (ERR) family of transcription factors were enriched, and blockade of ERRα attenuated PGC-1α-mediated induction of mitochondrial and synaptic genes in cell culture. Localization in the mouse brain revealed enrichment of ERRα expression in parvalbumin-expressing neurons with tight correlation of expression with PGC-1α across brain regions. In ERRα null mice, PGC-1α-dependent genes were reduced in multiple regions, including neocortex, hippocampus, and cerebellum, though not to the extent observed in PGC-1α null mice. Behavioral assessment revealed ambulatory hyperactivity in response to amphetamine and impairments in sensorimotor gating without the overt motor impairment characteristic of PGC-1α null mice. These data suggest that ERRα is required for normal levels of expression of PGC-1α-dependent genes in neurons but that additional factors may be involved in their regulation.


Subject(s)
Brain , Receptors, Estrogen , Animals , Brain/metabolism , Gene Expression , Gene Expression Regulation , Mice , Mice, Knockout , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Transcription Factors , ERRalpha Estrogen-Related Receptor
10.
Vet Microbiol ; 259: 109155, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34197977

ABSTRACT

Turkey coronavirus (TCoV) can cause a highly contagious enteric disease in turkeys with severe economic losses in the global turkey industry. To date, no commercial vaccines are available for control of the disease. In the present study, we isolated a field strain (NC1743) of TCoV and evaluated its pathogenicity in specific-pathogen-free (SPF) turkey poults to establish a TCoV disease model. The results showed that the TCoV NC1743 isolate was pathogenic to turkey poults with a minimal infectious dose at 106 EID50/bird. About 50 % of one-day-old SPF turkeys infected with the virus's minimal infectious dose exhibited typical enteric disease signs and lesions from 6 days post-infection (dpi) to the end of the experiment (21 dpi). In contrast, fewer than 20 % of older turkeys (1- or 2-week-old) infected with the same amount of TCoV displayed enteric disease signs, which disappeared after 15-18 dpi. Although all infected turkeys, regardless of age, shed TCoV, the older turkeys shed less virus than the younger birds, and 50 % of the 2-week-old birds even cleared the virus at 21 dpi. Furthermore, the viral infection caused day-old turkeys more body-weight-gain reduction than older birds. The overall data demonstrated that the TCoV NC1743 isolate is a highly pathogenic strain and younger turkeys are more susceptible to TCoV infection than older birds. Thus, one-day-old turkeys infected with the minimal infectious dose of TCoV NC1743 could be used as a TCoV disease model to study the disease pathogenesis, and the TCoV NC1743 strain could be used as a challenge virus to evaluate a vaccine protective efficacy.


Subject(s)
Coronavirus Infections/veterinary , Coronavirus, Turkey/pathogenicity , Poultry Diseases/prevention & control , Turkeys/virology , Animals , Antibodies, Viral/blood , Coronavirus Infections/blood , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Coronavirus, Turkey/classification , Disease Models, Animal , Poultry Diseases/blood , Poultry Diseases/virology , Specific Pathogen-Free Organisms
11.
Antimicrob Agents Chemother ; 65(8): e0029021, 2021 07 16.
Article in English | MEDLINE | ID: mdl-34031051

ABSTRACT

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (i.v.) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg body weight (maximum, 372 mg) isavuconazonium sulfate either i.v. or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric i.v. and oral data plus i.v. data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration-time curve at steady state (AUCSS) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUCSS range, 60 to 233 µg · h/ml) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).


Subject(s)
Invasive Fungal Infections , Triazoles , Administration, Oral , Adolescent , Child , Child, Preschool , Humans , Infant , Invasive Fungal Infections/drug therapy , Nitriles/therapeutic use , Pyridines/adverse effects , Triazoles/therapeutic use
12.
Br J Surg ; 108(9): 1112-1119, 2021 09 27.
Article in English | MEDLINE | ID: mdl-33990837

ABSTRACT

BACKGROUND: A minimum volume threshold of at least six procedures per annum per surgeon has been set in UK and European guidelines for adrenal surgery. The aim of this study was to investigate outcomes for adrenal surgery in England relative to annual surgeon and hospital trust volume. METHODS: Data were extracted from the Hospital Episodes Statistics database for England. A 6-year period (January 2013 to December 2018 inclusive) for all adult admissions for unilateral adrenal surgery was used. The primary outcome measure was an emergency readmission within 30 days of discharge following surgery. Procedures were categorized as open or minimally invasive surgery for analysis. Multilevel modelling was used to adjust for hierarchy and potential confounders. RESULTS: Data for 4189 adrenalectomies were identified. Only one third of surgeons (who operated on just over a half of all patients) performed at least six procedures in the year prior to the index procedure. For open surgery, emergency readmission rates fell significantly from 15.2 to 6.4 per cent for surgeons and from 13.2 to 6.1 per cent for trusts between the lowest- and highest-volume categories. Significant, but less dramatic falls were also seen for minimally invasive surgery. CONCLUSION: A volume-outcome effect was identified for adrenal surgery in England. Minimum volume thresholds should be set, although these may need to be more ambitious than the current threshold if outcomes are to be optimized. LAY SUMMARY: Surgery for disease of the adrenal gland can be complex. In many cases the skill and experience of the surgeon and the wider surgical team is thought to be important in determining the success of the procedure. The relative rarity of adrenal surgery means that there is little evidence to support this view. This study looked at outcomes for all 4189 patients who underwent adrenal surgery in England over a 6-year period. There was evidence that outcomes were better for patents when the surgeon and hospital trust had performed a larger number of adrenal surgery procedures in the year prior to the procedure. This was, however, dependent on which patient outcomes were studied and the type of procedure. These findings will inform the ongoing debate as to whether adrenal surgery in England should only be performed in regional centres by experienced teams.


Surgery for disease of the adrenal gland can be complex. In many cases the skill and experience of the surgeon and the wider surgical team is thought to be important in determining the success of the procedure. The relative rarity of adrenal surgery means that there is little evidence to support this view. This study looked at outcomes for all 4189 patients who underwent adrenal surgery in England over a 6-year period. There was evidence that outcomes were better for patents when the surgeon and hospital trust had performed a larger number of adrenal surgery procedures in the year prior to the procedure. This was, however, dependent on which patient outcomes were studied and the type of procedure. These findings will inform the ongoing debate as to whether adrenal surgery in England should only be performed in regional centres by experienced teams.


Subject(s)
Adrenalectomy/statistics & numerical data , Hospitals, High-Volume/statistics & numerical data , Outcome Assessment, Health Care/statistics & numerical data , Surgeons/statistics & numerical data , Databases, Factual , England , Female , Humans , Length of Stay/statistics & numerical data , Male , Middle Aged , Retrospective Studies
13.
Surg Neurol Int ; 12: 107, 2021.
Article in English | MEDLINE | ID: mdl-33880212

ABSTRACT

BACKGROUND: Approaches to subcortical lesions have traditionally been limited by the morbidity of white matter dissection and fixed blade retraction required to reach these targets. Visualization of deep surgical fields with a traditional operating microscope is also poor. Coordinated use of intra-operative image guidance, a tubular retractor (BrainPath®, Nico Corp, Indianapolis, Indiana), a high-definition exoscope (Vitom®, Karl Storz Endoscopy America, Inc, El Segundo, California), and a low-profile resection device (Myriad®, Nico Corp) facilitates atraumatic access to and resection of subcortical lesions including primary brain tumors, brain metastases, and intracerebral hemorrhages.[1] Use of pre-planned transsulcal and parafascicular trajectories based on magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can further mitigate damage to white matter tracts with this technique. CASE DESCRIPTION: We herein present details of the transsulcal parafascicular BrainPath®-assisted approach to subcortical lesions and demonstrate the utility of this technique using two patient examples: a spontaneous deep left posterior temporal lobe hematoma in a 41-year-old male and a left hippocampal glioblastoma in a 54-year-old female. Key steps include selection of appropriate patients with non-skull base subcortical lesions, preoperative trajectory and tube depth planning based on MRI (including diffusion-weighted imaging and DTI), patient positioning and operating room setup to facilitate pre-planned trajectories and surgeon ergonomics, and use of low-profile instruments with a two-handed surgical technique. CONCLUSION: Given recent data demonstrating the utility of this approach for hematoma evacuation and a likely increased future usage of this technique,[2] surgeon familiarity with the above steps will be of increasing importance.

14.
Res Involv Engagem ; 7(1): 18, 2021 Mar 20.
Article in English | MEDLINE | ID: mdl-33743827

ABSTRACT

BACKGROUND: Collaborative working between academic institutions and those who provide health and social care has been identified as integral in order to produce acceptable, relevant, and timely research, and for outputs to be useful and practical to implement. The ExCHANGE Collaboration aims to bring together researchers and people working, living in and visiting care homes to build capacity, share and mobilise knowledge, and identify key areas for future research. This paper describes an embedded, formative, realist and theory-driven evaluation which aims to gather information about how successful the ExCHANGE Collaboration is perceived to be in achieving its aims. An existing realist programme theory from the literature - Closer Collaboration - will be supplemented by two substantive theories: Co-production and Knowledge Brokering. This will result in an initial programme theory which will be tested by this formative evaluation to refine understanding of how the ExCHANGE Collaboration works. METHODS: The evaluation will employ mixed qualitative methods, including: analysis of documents such as feedback forms, Knowledge Broker journal/diary, event attendance records, risk and issues logs and other relevant paperwork gathered as part of project delivery; observations of events/activities; and interviews with care home providers and staff, care home residents, residents' family members, and researchers who are involved in the project (both project design/delivery, and also attendance or involvement in project activities/events). Framework Analysis will be used to interpret the data collected; analysis will be strategic, by focusing on particular key areas of importance in the developing theory of how the ExCHANGE Collaboration might achieve change. RESULTS: The results of this study are expected to be published in 2022. DISCUSSION: This evaluation will investigate how successful the ExCHANGE Collaboration is perceived to be in achieving its aims, in what way, in which contexts, and how this may differ for those involved. It will do this by testing an initial programme theory about how the collaboration works, for whom, under which circumstances, and in what way. Findings will be shared through written publication, an end of project learning event for those involved/interested in the project, and a lay summary to be made publically available.

15.
Oper Neurosurg (Hagerstown) ; 20(6): E410-E416, 2021 05 13.
Article in English | MEDLINE | ID: mdl-33647963

ABSTRACT

BACKGROUND: An enlarged suprameatal tubercle (SMT) can obscure visualization of the trigeminal nerve and require removal during microvascular decompression (MVD) surgery, especially when the superior petrosal vein (SPV) complex is preserved. OBJECTIVE: To define the incidence and important variables affecting the need for SMT removal with an SPV-sparing trigeminal nerve MVD. METHODS: Retrospective single-institution review identified patients who underwent a first-time, SPV-sparing MVD for trigeminal neuralgia (TGN) over a 26-mo period. SMT length (SMT-L), SMT width (SMT-W), and peri-trigeminal cerebellopontine cisternal thickness (CT) were measured from axial high-resolution magnetic resonance images. Need for SMT removal and use of endoscopic assistance was recorded. Data were analyzed using unpaired t-tests, and receiver operating characteristic (ROC)/area under the curve testing. RESULTS: A total of 43 MVD surgeries for TGN on 42 patients (mean age 52.7 ± 14.4 yr) were analyzed. Mean SMT-L, SMT-W, and CT were 9.8 ± 1.6, 2.0 ± 0.8, and 4.2 ± 1.5 mm, respectively. SMT removal via drilling was required in 4/43 cases (9.3%). Endoscopic assistance was used in 3 cases (2 SMT removed and 1 SMT preserved). SMT-W was the biggest predictor of the need for SMT removal on ROC analysis (area under the curve 0.97, 0.92-1.0 95% CI). The combined thresholds of SMT-W ≥ 3.2 mm and CT ≤ 3.5 mm demonstrated 100% sensitive and 100% specificity for the need to remove the SMT on optimal cutoff analysis. CONCLUSION: SMT drilling is necessary in nearly 10% of SPV-sparing MVDs for TGN. The combination of SMT width and cerebellopontine cistern thickness is predictive of the need for SMT removal.


Subject(s)
Cerebral Veins , Microvascular Decompression Surgery , Trigeminal Neuralgia , Adult , Aged , Cerebral Veins/surgery , Humans , Middle Aged , Retrospective Studies , Trigeminal Nerve/diagnostic imaging , Trigeminal Nerve/surgery , Trigeminal Neuralgia/diagnostic imaging , Trigeminal Neuralgia/surgery
16.
Biotechnol Lett ; 43(3): 729-743, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33459952

ABSTRACT

OBJECTIVE: Changes in the partitioning of dissolved inorganic (DIC) and glucose were elucidated by utilising 13C labelled DIC or glucose, and quantifying the biochemical profile of mixotrophic, heterotrophic and photoautotrophic cultures of the microalga Tetraselmis suecica. RESULTS: Mixotrophic cultivation increases microalgal productivity and changes their biochemical profile, due to an alteration in the partitioning of carbon within the cell. When cultured mixotrophically and heterotrophically, there is enhanced incorporation of carbon into shorter chain saturated fatty acids and non-lipid biomass, compared to photoautotrophic cultivation. Autotrophic culture results in increased total fatty acid content of cultures (4.19% dry weight compared to 2.13%) and shifts the fatty acid profile in favour of long-chain unsaturated fatty acids, such as 18:2 n-(9,12), compared to mixotrophic culture. Quantifying the changes in partitioning between DIC and glucose facilitates tailoring of the biochemical profile to develop "designer" algae. CONCLUSIONS: There is a condition specific shift in carbon partitioning into different fatty acid and biochemical fractions in T. suecica, with more inorganic carbon partitioned into 18:2 n-(9,12) in photoautotrophic rather than mixotrophic cultures.


Subject(s)
Autotrophic Processes/physiology , Carbon/metabolism , Chlorophyta , Glucose/metabolism , Heterotrophic Processes/physiology , Biomass , Chlorophyta/metabolism , Chlorophyta/physiology , Fatty Acids/metabolism
17.
Anaesthesia ; 76(9): 1245-1258, 2021 Sep.
Article in English | MEDLINE | ID: mdl-33421029

ABSTRACT

Septic shock is a leading cause of death and morbidity worldwide. The cornerstones of management include prompt identification of sepsis, early initiation of antibiotic therapy, adequate fluid resuscitation and organ support. Over the past two decades, there have been considerable improvements in our understanding of the pathophysiology of sepsis and the host response, including regulation of inflammation, endothelial disruption and impaired immunity. This has offered opportunities for innovative adjunctive treatments such as vitamin C, corticosteroids and beta-blockers. Some of these approaches have shown promising results in early phase trials in humans, while others, such as corticosteroids, have been tested in large, international, multicentre randomised controlled trials. Contemporary guidelines make a weak recommendation for the use of corticosteroids to reduce mortality in sepsis and septic shock. Vitamin C, despite showing initial promise in observational studies, has so far not been shown to be clinically effective in randomised trials. Beta-blocker therapy may have beneficial cardiac and non-cardiac effects in septic shock, but there is currently insufficient evidence to recommend their use for this condition. The results of ongoing randomised trials are awaited. Crucial to reducing heterogeneity in the trials of new sepsis treatments will be the concept of enrichment, which refers to the purposive selection of patients with clinical and biological characteristics that are likely to be responsive to the intervention being tested.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Adrenergic beta-Antagonists/therapeutic use , Anti-Bacterial Agents/therapeutic use , Ascorbic Acid/therapeutic use , Fluid Therapy/methods , Shock, Septic/therapy , Combined Modality Therapy , Humans , Shock, Septic/drug therapy
18.
J Intellect Disabil Res ; 65(4): 306-319, 2021 04.
Article in English | MEDLINE | ID: mdl-33506597

ABSTRACT

BACKGROUND: Parents of children with developmental or intellectual disabilities tend to report greater use of coercive parenting practices relative to parents of typically developing children, increasing the risk of adverse child outcomes. However, to date, there is limited research exploring the role and relative contribution of modifiable and nonmodifiable risk factors in parents of children with a disability. The present study aimed to explore the role of various modifiable and nonmodifiable parenting, family and sociodemographic factors associated with the use of coercive parenting practices in parents of children with a disability. METHODS: Caregivers (N = 1392) enrolled in the Mental Health of Young People with Developmental Disabilities (MHYPeDD) programme in Australia completed a cross-sectional survey about their parenting and their child aged 2-12 years with a disability. Measures covered a range of domains including relevant demographic and family background, use of coercive parenting practices, intensity of child behavioural difficulties and questions relating to parent and family functioning such as parental self-efficacy, adjustment difficulties and quality of family relationships. RESULTS: Parents of older children, those who were younger at the birth of their child, and parents who were co-parenting or working reported more use of coercive parenting practices. Greater intensity of child difficulties, poorer parental self-efficacy and parent-child relationships, and more parental adjustment difficulties were also significantly associated with more use of coercive parenting. Examination of the relative contribution of variables revealed parent-child relationship was a key contributing factor, followed by intensity of child behaviour problems, parent adjustment and parent confidence. CONCLUSIONS: These findings highlight a range of factors that should be targeted and modified through upstream prevention programmes and further inform our understanding of how coercive practices may be influenced through targeted parenting interventions.


Subject(s)
Developmental Disabilities , Parenting , Adolescent , Child , Cross-Sectional Studies , Developmental Disabilities/epidemiology , Humans , Parents , Risk Factors , Sociodemographic Factors
19.
Pediatr Transplant ; 24(8): e13807, 2020 12.
Article in English | MEDLINE | ID: mdl-32777150

ABSTRACT

BACKGROUND: Cryptosporidium enteritis can be devastating in the immunocompromised host. In pediatric liver transplant recipients, infection may be complicated by prolonged carriage of the parasite, rejection, and biliary tree damage and fibrosis. Herein, we report on six patients and their long-term outcomes following cryptosporidiosis. METHODS: We reviewed all cases of cryptosporidiosis in a pediatric liver transplant population over a 17-year period at a single center. Six patients with infection were identified, and their outcomes were analyzed. RESULTS: Infection was associated with significant diarrhea and dehydration in all cases, and led to hospitalization in one-half of patients. Four of the six patients developed biopsy-proven rejection following infection, with three of those patients developing rejection that was recalcitrant to intravenous steroid treatment. Additionally, three patients developed biliary tree abnormalities with similarity to sclerosing cholangitis. In one patient, those biliary changes led to repeated need for biliary drain placement and advancing fibrotic liver allograft changes. CONCLUSIONS: Cryptosporidiosis in pediatric liver transplant recipients may lead to significant complications, including recalcitrant episodes of rejection and detrimental biliary tree changes. We advocate for increased awareness of this cause of diarrheal disease and the allograft injuries that may accompany infection.


Subject(s)
Cryptosporidiosis/complications , Immunocompromised Host , Liver Transplantation , Adolescent , Biliary Tract Diseases/parasitology , Child , Child, Preschool , Diarrhea/parasitology , Female , Graft Rejection/parasitology , Humans , Male
20.
Br J Oral Maxillofac Surg ; 58(9): 1151-1157, 2020 11.
Article in English | MEDLINE | ID: mdl-32800609

ABSTRACT

When patients attend the emergency department with facial fractures that require surgery and are immediately admitted, surgery can be delayed as theatre time is prioritised for other more urgent patients. One solution is to send the patient home and admit them as an elective patient at a later date. The aim of this study was to investigate the outcomes of patients admitted directly and those seen as elective patients following fracture of the mandible or zygomatic complex. Data were taken from the hospital episodes statistics (HES) dataset for 2011-2018, and all hospital admissions for mandibular and zygomatic complex fractures within the National Health Service (NHS) in England were extracted. Patients were categorised as those admitted on attendance at the emergency department and given definitive treatment during the admission, and those not admitted on attendance at the emergency department but discharged home and seen as elective admissions within 30 days of attendance. Data were available for 39 606 patients. For both types of fracture there was substantial variation between NHS trusts in the proportion of patients admitted electively and the proportion admitted directly as emergencies. Elective admission was independently associated with shorter overall stay and lower emergency readmission rates. We found no evidence that delays to definitive surgery through elective admission had a negative impact on emergency readmission rates. Patients admitted electively had a significantly shorter hospital stay.


Subject(s)
Elective Surgical Procedures , State Medicine , Emergency Service, Hospital , England , Humans , Length of Stay , Mandible
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