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2.
Nat Commun ; 15(1): 5006, 2024 Jun 12.
Article En | MEDLINE | ID: mdl-38866738

Body mass results from a complex interplay between genetics and environment. Previous studies of the genetic contribution to body mass have excluded repetitive regions due to the technical limitations of platforms used for population scale studies. Here we apply genome-wide approaches, identifying an association between adult body mass and the copy number (CN) of 47S-ribosomal DNA (rDNA). rDNA codes for the 18 S, 5.8 S and 28 S ribosomal RNA (rRNA) components of the ribosome. In mammals, there are hundreds of copies of these genes. Inter-individual variation in the rDNA CN has not previously been associated with a mammalian phenotype. Here, we show that rDNA CN variation associates with post-pubertal growth rate in rats and body mass index in adult humans. rDNA CN is not associated with rRNA transcription rates in adult tissues, suggesting the mechanistic link occurs earlier in development. This aligns with the observation that the association emerges by early adulthood.


Body Mass Index , DNA Copy Number Variations , DNA, Ribosomal , Animals , Humans , DNA, Ribosomal/genetics , Male , Rats , Female , Adult , Mammals/genetics , RNA, Ribosomal/genetics , RNA, Ribosomal/metabolism
4.
J Orthop ; 53: 147-149, 2024 Jul.
Article En | MEDLINE | ID: mdl-38601891

Introduction: Previously published studies have hypothesized that total hip arthroplasty (THA) requires the surgeon to expend more energy that total knee arthroplasty (TKA). However, techniques for performing these procedures have evolved. Therefore, we sought to compare if primary THA had increased energy expenditure compared to primary TKA. Methods: We prospectively recorded the heart rate, respiratory rate, minute ventilation, cadence, and energy expenditure of a single fellowship-trained arthroplasty surgeon while performing primary THA and TKA on 372 patients. Patient demographics and operative records were reviewed to evaluate differences in the physical demands of each surgical case. Age (64.3 versus 65.9 years, p = 0.1) and gender (54.8% versus 51.0% female, p = 0.5) were similar between THA and TKA, but TKAs had a higher body mass index (31.1 versus 28.7 kg/m2, p < 0.001). Chi-square and independent-samples t-tests were used to compare cohorts. Significance was set at p < 0.05. Results: THA tended to have 1.1 times longer operative time than TKA (102.2 versus 88.9 min, p < 0.001). THA had a statistically higher heart rate compared to TKA, although this is unlikely to be clinically significant (82.5 versus 80.7 beats/minute, p < 0.001). Respiratory Rate was 1.1 times higher (15.9 versus 14.9 respirations/minute, p < 0.001) and minute ventilation was 1.2 times higher (19.6 versus 16.9 L/min, p < 0.001) when performing THA. Cadence was 1.5 times higher when performing TKA (4.2 versus 2.8 steps/minute, p < 0.001). THA had a 1.2 times higher energy expenditure/patient (378.8 versus 312.0 Calories/patient, p < 0.001) and a 1.1 times higher energy expenditure/minute (3.7 versus 3.5 Calories/minute, p = 0.01) compared to TKA. Discussion: THA is associated with longer operative time and increased energy expenditure per compared to TKA. Despite THA and TKA procedures becoming more efficient, arthroplasty surgery continues to have heavy physical burden on the surgeon. Further research is needed to understand ways to decrease surgeon energy expenditure and promote career longevity.

5.
iScience ; 27(4): 109601, 2024 Apr 19.
Article En | MEDLINE | ID: mdl-38623341

Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.

6.
J Invest Dermatol ; 2024 Apr 04.
Article En | MEDLINE | ID: mdl-38582370

The evolution of primary melanoma to lymph node and distant metastasis is incompletely understood. We examined the genomic diversity in melanoma progression in matched primary melanomas and lymph node and distant metastases from 17 patients. FISH analysis revealed cancer cell fractions with monotonic copy number alterations, including PHIP gain and PTEN loss, in the metastatic cascade. By contrast, the cancer cell fraction with copy number alterations for BPTF and MITF was reduced in lymph node metastases but increased in distant metastases. Separately, the cancer cell fraction with NCOA3 copy number alteration was comparable between primary tumors and lymph node metastases yet increased in distant metastases. These results suggest enrichment of the phosphoinositide 3-kinase and MITF pathways in the transition through the metastatic cascade. By contrast, next-generation sequencing analysis did not identify a consistent pattern of changes in variant allele frequency while revealing several intriguing findings, including decreased variant allele frequency in distant metastases and distinct drivers in lymph node versus distant metastases. These results provide evidence that distant melanoma metastasis does not always emanate from lymph node metastasis. These results enhance our understanding of clonal patterns of melanoma metastasis, with possible implications for targeted therapy and metastasis competency.

7.
Neuromuscul Disord ; 38: 51-57, 2024 May.
Article En | MEDLINE | ID: mdl-38626662

Azathioprine is recommended as the first-line steroid-sparing immunosuppressive agent for myasthenia gravis. Mycophenolate and methotrexate are often considered as second-line choices despite widespread consensus on their efficacy. We aimed to gather real-world data comparing the tolerability and reasons for discontinuation for these agents, by performing a national United Kingdom survey of side effects and reasons for discontinuation of immunosuppressants in myasthenia gravis. Of 235 patients, 166 had taken azathioprine, 102 mycophenolate, and 40 methotrexate. The most common side effects for each agent were liver dysfunction for azathioprine (23 %), diarrhoea for mycophenolate (14 %), and fatigue for methotrexate (18 %). Women were generally more likely to experience side effects of immunosuppressants. Azathioprine was significantly more likely to be discontinued than mycophenolate and methotrexate due to side effects. There was no significant difference in treatment cessation due to lack of efficacy. This study highlights the significant side-effect burden of treatment for myasthenia gravis. Mechanisms to reduce azathioprine toxicity should be utilised, however mycophenolate and methotrexate appear to be good treatment choices if teratogenicity is not a concern. Women are disadvantaged due to higher frequency of side effects and considerations around pregnancy and breastfeeding. Treatments with improved tolerability are needed.


Azathioprine , Immunosuppressive Agents , Methotrexate , Myasthenia Gravis , Mycophenolic Acid , Humans , Myasthenia Gravis/drug therapy , Methotrexate/therapeutic use , Methotrexate/adverse effects , Female , Mycophenolic Acid/adverse effects , Mycophenolic Acid/therapeutic use , Azathioprine/adverse effects , Azathioprine/therapeutic use , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Adult , Aged , United Kingdom
8.
Emerg Infect Dis ; 30(13): S17-S20, 2024 04.
Article En | MEDLINE | ID: mdl-38561633

The large COVID-19 outbreaks in prisons in the Washington (USA) State Department of Corrections (WADOC) system during 2020 highlighted the need for a new public health approach to prevent and control COVID-19 transmission in the system's 12 facilities. WADOC and the Washington State Department of Health (WADOH) responded by strengthening partnerships through dedicated corrections-focused public health staff, improving cross-agency outbreak response coordination, implementing and developing corrections-specific public health guidance, and establishing collaborative data systems. The preexisting partnerships and trust between WADOC and WADOH, strengthened during the COVID-19 response, laid the foundation for a collaborative response during late 2021 to the largest tuberculosis outbreak in Washington State in the past 20 years. We describe challenges of a multiagency collaboration during 2 outbreak responses, as well as approaches to address those challenges, and share lessons learned for future communicable disease outbreak responses in correctional settings.


COVID-19 , Tuberculosis , Humans , COVID-19/epidemiology , COVID-19/prevention & control , Public Health , Prisons , Washington/epidemiology , Pandemics/prevention & control , Disease Outbreaks/prevention & control , Tuberculosis/epidemiology , Tuberculosis/prevention & control
9.
Zookeys ; 1192: 111-140, 2024.
Article En | MEDLINE | ID: mdl-38425443

The hyperdiverse geometrid genus Eois Hübner, estimated to encompass more than 1,000 species, is among the most species-rich genera in all of Lepidoptera. While the genus has attracted considerable attention from ecologists and evolutionary biologists in recent decades, limited progress has been made on its alpha taxonomy. This contribution focuses on the Olivacea clade, whose monophyly has been recognized previously through molecular analyses. We attempt to define the clade from a morphological perspective and recognize the following species based on morphology and genomic data: E.olivacea (Felder & Rogenhofer); E.pseudolivacea Doan, sp. nov.; E.auruda (Dognin), stat. rev.; E.beebei (Fletcher, 1952), stat. rev.; E.boliviensis (Dognin), stat. rev.; and E.parumsimii Doan, sp. nov. Descriptions and illustrations of the immature stages of E.pseudolivacea reared from Piper (Piperaceae) in Ecuador are provided.

10.
Mol Cancer Ther ; 23(6): 823-835, 2024 Jun 04.
Article En | MEDLINE | ID: mdl-38442920

Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate cancer patient derived-tumor xenograft (PDTX) models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi). Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using whole-exome sequencing. PDTX 3D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular-targeted therapies. CDK4/6i's were combined with AKTi's to assess synergistic antitumor response to prove our hypothesis that blockade of AKT overcomes drug resistance to CDK4/6i. This combination was evaluated in PDTX three-dimensional (3D) spheroids and in vivo experiments with responses measured by tumor volumes, PSA, and Ga-68 PSMA-11 PET-CT imaging. We demonstrated CDK4/6i's with AKTi's possess synergistic antitumor activity in three mCRPC PDTX models. These models have multiple unique pathogenic and deleterious genomic alterations with resistance to single-agent CDK4/6i's. Despite this, combination therapy with AKTi's was able to overcome resistance mechanisms. The IHC and Western blot analysis confirmed on target effects, whereas tumor volume, serum PSA ELISA, and radionuclide imaging demonstrated response to therapy with statistically significant SUV differences seen with Ga-68 PSMA-11 PET-CT. These preclinical data demonstrating antitumor synergy by overcoming single-agent CDK 4/6i as well as AKTi drug resistance provide the rational for a clinical trial combining a CDK4/6i with an AKTi in patients with mCRPC whose tumor expresses wild-type retinoblastoma 1.


Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Prostatic Neoplasms, Castration-Resistant , Protein Kinase Inhibitors , Proto-Oncogene Proteins c-akt , Xenograft Model Antitumor Assays , Humans , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Male , Animals , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Mice , Proto-Oncogene Proteins c-akt/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Neoplasm Metastasis , Cell Line, Tumor , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use
11.
Crit Care Med ; 52(4): 596-606, 2024 04 01.
Article En | MEDLINE | ID: mdl-38483219

OBJECTIVES: We hypothesized that the immunosuppressive effects associated with antibiotics, sedatives, and catecholamines amplify sepsis-associated immune suppression through mitochondrial dysfunction, and there is a cumulative effect when used in combination. We thus sought to determine the impact of the exemplar drugs ciprofloxacin, propofol, and norepinephrine, used alone and in combination, at clinically relevant concentrations, on the ex vivo functionality of peripheral blood mononuclear cells (PBMCs) drawn from healthy, infected, and septic individuals. DESIGN: In vitro/ex vivo investigation. SETTING: University laboratory. SUBJECTS: Healthy volunteers, infected (nonseptic) patients in the emergency department, and septic ICU patients. INTERVENTIONS: PBMCs were isolated from these subjects and treated with ciprofloxacin (100 µg/mL), propofol (50 µg/mL), norepinephrine (10 µg/mL), or all three drugs combined, with and without lipopolysaccharide (100 ng/mL) for 6 or 24 hours. Comparison was made between study groups and against untreated cells. Measurements were made of cell viability, cytokine production, phagocytosis, human leukocyte antigen-DR (HLA-DR) status, mitochondrial membrane potential, mitochondrial reactive oxygen species production, and oxygen consumption. Gene expression in immune and metabolic pathways was investigated in PBMCs sampled from healthy volunteers coincubated with septic serum. MEASUREMENTS AND RESULTS: Coincubation with each of the drugs reduced cytokine production and phagocytosis in PBMCs isolated from septic patients, and healthy volunteers coincubated with septic serum. No effect was seen on HLA-DR surface expression. No cumulative effects were seen with the drug combination. Sepsis-induced changes in gene expression and mitochondrial functionality were not further affected by addition of any of the drugs. CONCLUSION: Drugs commonly used in critical care lead to significant immune dysfunction ex vivo and enhance sepsis-associated immunosuppression. Further studies are required to identify underlying mechanisms and potential impact on patient outcomes.


Propofol , Sepsis , Humans , Catecholamines , Hypnotics and Sedatives/pharmacology , Anti-Bacterial Agents , Leukocytes, Mononuclear , Norepinephrine , Immunosuppression Therapy , Ciprofloxacin , HLA-DR Antigens , Cytokines
12.
Sci Total Environ ; 927: 171958, 2024 Jun 01.
Article En | MEDLINE | ID: mdl-38547970

There is a need to understand what makes certain targeted measures for in-river phosphorus load reduction more effective than others. Therefore, this paper investigates multiple development scenarios in a small lowland polluted river draining an urban area (The Cut, Bracknell, UK), using an advection-dispersion model (ADModel-P). A comparative analysis is presented whereby changes in concentrations and fluxes of soluble reactive phosphorus (SRP) and organic phosphorus (OP) have been attributed to specific transformations (mineralization, sedimentation, resuspension, adsorption-desorption, and algal uptake) and correlated to controlling factors. Under present day conditions the river stretch is a net source of SRP (10.4 % increase in mean concentration) implying a release of previously accumulated material. Scenarios with the greatest impact are those based on managed reduction of phosphorus load in sources (e.g., 20 % increase in afforestation causes an in-river SRP and OP reduction of 1.3 % to 12.6 %) followed by scenarios involving changes in water temperature (e.g., 1 °C decrease leads to in-river SRP reduction around 3.1 %). Measures involving increased river residence time show the lowest effects (e.g., 16 % decrease in velocity results in under 0.02 % in-river SRP and OP reduction). For better understanding downstream persistence of phosphorus pollution and the effectiveness of mitigation measures the research demonstrates the importance of establishing when and where reaches are net adsorbers or desorbers, and whether sedimentation or resuspension is important.

13.
PLoS One ; 19(2): e0298390, 2024.
Article En | MEDLINE | ID: mdl-38416747

Although highly conserved in structure and function, many (patho)physiological processes of the mammary gland vary drastically between mammals, with mechanisms regulating these differences not well understood. Large mammals display variable lactation strategies and mammary cancer incidence, however, research into these variations is often limited to in vitro analysis due to logistical limitations. Validating a model with functional mammary xenografts from cryopreserved tissue fragments would allow for in vivo comparative analysis of mammary glands from large and/or rare mammals and would improve our understanding of postnatal development, lactation, and premalignancy across mammals. To this end, we generated functional mammary xenografts using mammary tissue fragments containing mammary stroma and parenchyma isolated via an antibody-independent approach from healthy, nulliparous equine and canine donor tissues to study these species in vivo. Cryopreserved mammary tissue fragments were xenotransplanted into de-epithelialized fat pads of immunodeficient mice and resulting xenografts were structurally and functionally assessed. Preimplantation of mammary stromal fibroblasts was performed to promote ductal morphogenesis. Xenografts recapitulated mammary lobule architecture and contained donor-derived stromal components. Mammatropic hormone stimulation resulted in (i) upregulation of lactation-associated genes, (ii) altered proliferation index, and (iii) morphological changes, indicating functionality. Preimplantation of mammary stromal fibroblasts did not promote ductal morphogenesis. This model presents the opportunity to study novel mechanisms regulating unique lactation strategies and mammary cancer induction in vivo. Due to the universal applicability of this approach, this model serves as proof-of-concept for developing mammary xenografts for in vivo analysis of virtually any mammals, including large and rare mammals.


Breast Neoplasms , Mammary Glands, Human , Humans , Female , Mice , Animals , Horses , Dogs , Transplantation, Heterologous , Mammary Glands, Animal/pathology , Lactation/physiology , Mammals , Breast Neoplasms/pathology
15.
Appl Ergon ; 117: 104227, 2024 May.
Article En | MEDLINE | ID: mdl-38290318

Increasing chair recline during seated computer work may reduce the load placed on the upper trapezius (UT), a common location of pain for those with idiopathic chronic neck pain. This study determined the effect of increasing chair recline on UT stiffness and muscle activity during computer work in people with and without idiopathic chronic neck pain. Surface electromyography and ultrasound shear wave elastography were collected from three subdivisions of the UT in 15 individuals with idiopathic chronic neck pain and 15 sex-matched healthy controls. Participants sat in a standardized computer-work setup while chair recline (0°, 25°, 45°) and head and neck position (self-selected, neutral, flexed) were systematically adjusted and maintained for 2.5-min intervals. Repeated-measures ANOVAs were completed for each sex, muscle, and data type, with group (chronic neck pain, control), chair recline (0°,25°,45°), head and neck position (self-selected, flexed, neutral), and side of collected data (dominant, non-dominant) as fixed factors. Men with idiopathic chronic neck pain demonstrated greater UT stiffness in the cranial subdivision when compared to healthy men. Additionally, the 25° and 45° recline levels increased the stiffness of men's dominant UT compared to men's non-dominant UT. Women's UT was more affected by head and neck position, and a neutral head and neck position resulted in lower UT activation, but higher UT stiffness for the cranial subdivision and midway between C-7 and the acromion process. Overall, our findings suggest that the commonly suggested neutral position may not be a beneficial prompt when positioning someone during seated computer work.


Neck Pain , Superficial Back Muscles , Male , Humans , Female , Sitting Position , Head , Electromyography/methods , Neck Muscles/physiology
16.
J Clin Gastroenterol ; 2024 Jan 15.
Article En | MEDLINE | ID: mdl-38227842

OBJECTIVE: The aims of this study are to determine the functional luminal imaging probe's (FLIP) diagnostic utility by comparing FLIP measurements with results from other esophageal evaluation standards. BACKGROUND: The FLIP is an esophageal evaluation technique performed at the time of endoscopy. Few studies have evaluated FLIP diagnostic capabilities compared with the established testing techniques, including high-resolution manometry (HRIM), time barium esophagram (TBE), and 24-hour impedance-pH monitoring. PATIENTS AND METHODS: A retrospective review was performed for 413 preintervention patients who underwent FLIP testing during endoscopy. Data from HRIM, 24-hour pH monitoring, and TBE were compared. RESULTS: Abnormal Distensibility Index (DI) was associated with abnormal integrated relaxation pressure (IRP; P = 0.003). Average DI was higher in patients with abnormal IRP (>15 mm Hg) when a hiatal hernia was present (P = 0.025). The total agreement between correlated diagnoses from FLIP and HRIM was 33.5%. DI was not associated with acid exposure time on pH monitoring. Agreement between FLIP and TBE was 49% with a sensitivity of 98.1% and a specificity of 36.5%. A 60 mL distension had a significantly lower detection rate than 40 mL and 50 mL for active peristalsis and was unaffected by pressure (P < 0.05). CONCLUSIONS: FLIP as an adjunct to HRIM is supported by strong metric correlation. FLIP was not correlated to pH monitoring findings, suggesting FLIP is not useful in reflux assessment. The agreement between FLIP and TBE was lower than in previous studies. Hiatal hernia impacted the normality between DI and IRP, not between FLIP and TBE. We suggest analyzing peristaltic patterns on panometry at all fill volumes to optimize detection.

17.
Am J Obstet Gynecol ; 230(3): 279-294.e2, 2024 Mar.
Article En | MEDLINE | ID: mdl-38168908

Pelvic floor disorders after childbirth have distressing lifelong consequences for women, requiring more than 300,000 women to have surgery annually. This represents approximately 10% of the 3 million women who give birth vaginally each year. Vaginal birth is the largest modifiable risk factor for prolapse, the pelvic floor disorder most strongly associated with birth, and is an important contributor to stress incontinence. These disorders require 10 times as many operations as anal sphincter injuries. Imaging shows that injuries of the levator ani muscle, perineal body, and membrane occur in up to 19% of primiparous women. During birth, the levator muscle and birth canal tissues must stretch to more than 3 times their original length; it is this overstretching that is responsible for the muscle tear visible on imaging rather than compression or neuropathy. The injury is present in 55% of women with prolapse later in life, with an odds ratio of 7.3, compared with women with normal support. In addition, levator damage can affect other aspects of hiatal closure, such as the perineal body and membrane. These injuries are associated with an enlarged urogenital hiatus, now known as antedate prolapse, and with prolapse surgery failure. Risk factors for levator injury are multifactorial and include forceps delivery, occiput posterior birth, older maternal age, long second stage of labor, and birthweight of >4000 g. Delivery with a vacuum device is associated with reduced levator damage. Other steps that might logically reduce injuries include manual rotation from occiput posterior to occiput anterior, slow gradual delivery, perineal massage or compresses, and early induction of labor, but these require study to document protection. In addition, teaching women to avoid pushing against a contracted levator muscle would likely decrease injury risk by decreasing tension on the vulnerable muscle origin. Providing care for women who have experienced difficult deliveries can be enhanced with early recognition, physical therapy, and attention to recovery. It is only right that women be made aware of these risks during pregnancy. Educating women on the long-term pelvic floor sequelae of childbirth should be performed antenatally so that they can be empowered to make informed decisions about management decisions during labor.


Pelvic Floor Disorders , Pelvic Floor , Pregnancy , Female , Humans , Pelvic Floor/injuries , Delivery, Obstetric/adverse effects , Anal Canal/injuries , Pelvic Floor Disorders/etiology , Pelvic Floor Disorders/prevention & control , Prolapse
18.
Int Urogynecol J ; 35(2): 441-449, 2024 Feb.
Article En | MEDLINE | ID: mdl-38206338

INTRODUCTION: Urogenital hiatus enlargement is a critical factor associated with prolapse and operative failure. This study of the perineal complex was performed to understand how interactions among its three structures: the levator ani, perineal membrane, and perineal body-united by the vaginal fascia-work to maintain urogenital hiatus closure. METHODS: Magnetic resonance images from 30 healthy nulliparous women with 3D reconstruction of selected subjects were used to establish overall geometry. Connection points and lines of action were based on perineal dissection in 10 female cadavers (aged 22-86 years), cross sections of 4 female cadavers (aged 14-35 years), and histological sections (cadavers aged 16 and 21 years). RESULTS: The perineal membrane originates laterally from the ventral two thirds of the ischiopubic rami and attaches medially to the perineal body and vaginal wall. The levator ani attaches to the perineal membrane's cranial surface, vaginal fascia, and the perineal body. The levator line of action in 3D reconstruction is oriented so that the levator pulls the medial perineal membrane cranio-ventrally. In cadavers, simulated levator contraction and relaxation along this vector changes the length of the membrane and the antero-posterior diameter of the urogenital hiatus. Loss of the connection of the left and right perineal membranes through the perineal body results in diastasis of the levator and a widened hiatus, as well as a downward rotation of the perineal membrane. CONCLUSION: Interconnections involving the levator ani muscles, perineal membrane, perineal body, and vaginal fascia form the perineal complex surrounding the urogenital hiatus in an arrangement that maintains hiatal closure.


Pelvic Floor , Perineum , Female , Humans , Fascia , Cadaver , Hypertrophy
19.
Brain ; 147(5): 1887-1898, 2024 May 03.
Article En | MEDLINE | ID: mdl-38193360

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson's coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I-V ß = -1.06, P < 0.001; lobules VI-VII ß = -0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion.


Age of Onset , Replication Protein C , Humans , Male , Female , Replication Protein C/genetics , Adult , DNA Repeat Expansion/genetics , Middle Aged , Young Adult , Adolescent , Child , Phenotype , Severity of Illness Index , Child, Preschool , Disease Progression
20.
J Thorac Cardiovasc Surg ; 167(2): 517-525.e2, 2024 Feb.
Article En | MEDLINE | ID: mdl-37236600

OBJECTIVES: The need for routine chest radiography following chest tube removal after elective pulmonary resection may be unnecessary in most patients. The purpose of this study was to determine the safety of eliminating routine chest radiography in these patients. METHODS: Patients who underwent elective pulmonary resection, excluding pneumonectomy, for benign or malignant indications between 2007 and 2013 were reviewed. Patients with in-hospital mortality or without routine follow-up were excluded. During this interval, our practice transitioned from ordering routine chest radiography after chest tube removal and at the first postoperative clinic visit to obtaining imaging based on symptomatology. The primary outcome was changes in management from results of chest radiography obtained routinely versus for symptoms. Characteristics and outcomes were compared using the Student t test and chi-square analyses. RESULTS: A total of 322 patients met inclusion criteria. Ninety-three patients underwent a routine same-day post-pull chest radiography, and 229 patients did not. Thirty-three patients (14.4%) in the nonroutine chest radiography cohort received imaging for symptoms, in whom 8 (24.2%) resulted in management changes. Only 3.2% of routine post-pull chest radiography resulted in management changes versus 3.5% of unplanned chest radiography with no adverse outcomes (P = .905). At outpatient postoperative follow-up, 146 patients received routine chest radiography; none resulted in a change in management. Of the 176 patients who did not have planned chest radiography at follow-up, 12 (6.8%) underwent chest radiography for symptoms. Two of these patients required readmission and chest tube reinsertion. CONCLUSIONS: Reserving imaging for patients with symptoms after chest tube removal and follow-up after elective lung resections resulted in a higher percentage of meaningful changes in clinical management.


Chest Tubes , Pneumothorax , Humans , Chest Tubes/adverse effects , Thoracostomy/adverse effects , Follow-Up Studies , Radiography , Lung , Radiography, Thoracic , Retrospective Studies , Pneumothorax/etiology
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