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OBJECTIVES: ANA-associated RMDs (ANA-RMDs-SLE, pSS, scleroderma, inflammatory myositis, mixed connective tissue disease (MCTD) and undifferentiated connective tissue disease) are a disease spectrum with overlapping clinical and immunological features. Musculoskeletal inflammation is common and impactful across ANA-RMDs. We evaluated musculoskeletal inflammation (ANA-arthritis) prevalence in a multi-disease ANA-RMD study, assessed its clinical impact across ANA-RMD diagnoses, proposed new basket groupings of patients and evaluated immunological profiles in legacy and new basket contexts. METHODS: An observational study enrolled ANA-RMD patients. Demographic variables, comorbidities, therapies, disease activity instruments (BILAG, SLEDAI, ESSDAI, physician-VAS), patient-reported outcomes (SF36, FACIT-Fatigue, EQ5D, ICECAP-A, WPAI, patient-VAS) and biomarker profile (6 gene expression scores, flow cytometry, autoantibody profile) were analysed. Reclustering utilized Gaussian Mixture Modelling (GMM). Clinical and immune features of new and legacy clusters were compared. RESULTS: Inflammatory MSK symptoms were prevalent across ANA-RMDs, in 213/294 patients. In ANA-arthritis patients, most variables did not differ between diagnoses, excluding EQ5D-5L index and mobility domains (lower in MCTD/pSS, both p< 0.05). Fibromyalgia and osteoarthritis prevalence were similar across diagnoses. Therapy use differed significantly, biologic use being greatest in SLE (p< 0.05).GMM yielded two multi-disease clusters; High-MSK disease activity (n = 89) and Low-MSK disease activity (n = 124). High-MSK disease activity contained all patients with active joint swelling and had significantly higher prednisolone usage, PGA and Sm/RNP/SmRNP/Chromatin positivity, Tetherin-MFI and Interferon Score-A activity; with numerically lower fibromyalgia and osteoarthritis prevalence. CONCLUSION: We define ANA-Arthritis, a more clinically and immunologically homogeneous population than existing RMDs for trials, and a more prevalent population for therapies in the clinic.
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OBJECTIVE: To examine the impact of increased body mass index (BMI) on (1) tracheotomy timing and (2) short-term surgical complications requiring a return to the operating room and 30-day mortality utilizing data from the Multi-Institutional Study on Tracheotomy (MIST). METHODS: A retrospective analysis of patients from the MIST database who underwent surgical or percutaneous tracheotomy between 2013 and 2016 at eight institutions was completed. Unadjusted and adjusted logistic regression analyses were used to assess the impact of obesity on tracheotomy timing and complications. RESULTS: Among the 3369 patients who underwent tracheotomy, 41.0% were obese and 21.6% were morbidly obese. BMI was associated with higher rates of prolonged intubation prior to tracheotomy accounting for comorbidities, indication for tracheotomy, institution, and type of tracheostomy (p = 0.001). Morbidly obese patients (BMI ≥35 kg/m2) experienced a longer duration of intubation compared with patients with a normal BMI (median days intubated [IQR 25%-75%]: 11.0 days [7-17 days] versus 9.0 days [5-14 days]; p < 0.001) but did not have statistically higher rates of return to the operating room within 30 days (p = 0.12) or mortality (p = 0.90) on multivariable analysis. This same finding of prolonged intubation was not seen in overweight, nonobese patients when compared with normal BMI patients (median days intubated [IQR 25%-75%]: 10.0 days [6-15 days] versus 10.0 days [6-15 days]; p = 0.36). CONCLUSION: BMI was associated with increased duration of intubation prior to tracheotomy. Although morbidly obese patients had a longer duration of intubation, there were no differences in return to the operating room or mortality within 30 days. LEVEL OF EVIDENCE: III Laryngoscope, 2024.
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Treatment of giant cell arteritis (GCA) aims initially to prevent acute visual loss, and subsequently to optimise long-term quality of life. Initial prevention of acute visual loss in GCA is well-standardised with high-dose glucocorticoid therapy but in the longer term optimising quality of life requires tailoring of treatment to the individual. The licensing of the IL-6 receptor inhibitor tocilizumab combined with advances in vascular imaging have resulted in many changes to diagnostic and therapeutic practice. Firstly, GCA is a systemic disease that may involve multiple vascular territories and present in diverse ways. Broadening of the "spectrum" of what is called GCA has been crystallised in the 2022 GCA classification criteria. Secondly, the vascular inflammation of GCA frequently co-exists with the extracapsular musculoskeletal inflammation of the related disease, polymyalgia rheumatica (PMR). Thirdly, GCA care must often be delivered across multiple specialities and healthcare organisations requiring effective interprofessional communication. Fourthly, both GCA and PMR may follow a chronic or multiphasic disease course; long-term management must be tailored to the individual patient's needs. In this article we focus on some areas of current rheumatology practice that ophthalmologists need to be aware of, including comprehensive assessment of extra-ocular symptoms, physical signs and laboratory markers; advanced imaging techniques; and implications for multi-speciality collaboration.
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Arteritis de Células Gigantes , Arteritis de Células Gigantes/diagnóstico , Humanos , Polimialgia Reumática/diagnóstico , Glucocorticoides/uso terapéutico , Reumatología , Calidad de Vida , Anticuerpos Monoclonales HumanizadosRESUMEN
BACKGROUND: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus. METHODS: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak. FINDINGS: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. INTERPRETATION: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms. FUNDING: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.
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Autoanticuerpos , Autoinmunidad , COVID-19 , Helicasa Inducida por Interferón IFIH1 , Enfermedades Pulmonares Intersticiales , SARS-CoV-2 , Humanos , COVID-19/inmunología , Helicasa Inducida por Interferón IFIH1/genética , Helicasa Inducida por Interferón IFIH1/inmunología , Enfermedades Pulmonares Intersticiales/inmunología , Enfermedades Pulmonares Intersticiales/genética , SARS-CoV-2/inmunología , Masculino , Femenino , Persona de Mediana Edad , Autoanticuerpos/inmunología , Anciano , Estudios Retrospectivos , Pandemias , Dermatomiositis/inmunología , Dermatomiositis/genética , AdultoRESUMEN
We report the direct and accurate spectroscopic quantification of the inverted singlet-triplet gap in 1,3,4,6,9b-pentaazaphenalene. This measurement is achieved by directly probing the lowest singlet and triplet states via high-resolution cryogenic anion photoelectron spectroscopy. The assignment of the first excited singlet state is confirmed by visible absorption spectroscopy in an argon matrix at 20 K. Our measurements yield an inverted singlet-triplet gap with ΔEST= -0.047(7) eV. The accurate quantification of the singlet-triplet gap presented here allows for direct evaluation of various computational electronic structure methods and highlights the critical importance of the proper description of the double excitation character of these electronic states. Overall, this study validates the idea that despite Hund's multiplicity rule, useful organic chromophores can have inherently inverted singlet-triplet gaps.
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BACKGROUND: Developmental coordination disorder (DCD) affects movement coordination, but little is known about how the condition impacts the behaviours of car drivers and pedestrians. AIMS: This study examined the self-reported driving and pedestrian behaviours of adults with Developmental Coordination Disorder (DCD). METHODS AND PROCEDURES: One hundred and twenty-eight participants (62 adults with DCD vs. 66 TD adults) responded to an online survey asking them about their perceptions of confidence and self-reported driving and pedestrian behaviours in the real-world. OUTCOMES AND RESULTS: Results suggested that adults with DCD felt less confident and reported more lapses in attention (e.g., forgetting where their car was parked) and errors (e.g., failing to check their mirrors prior to a manoeuvre) when driving compared to typically developed (TD) adults. Adults with DCD also reported feeling less confident and reported less adherence to road traffic laws (e.g., not waiting for a green crossing signal before crossing the road) when walking as pedestrians. CONCLUSIONS AND IMPLICATIONS: These results offer some much-needed insight into the behaviours of those with DCD outside of the laboratory environment and underline the need for research investigating the driving and pedestrian behaviours of individuals with DCD in 'real-world' contexts.
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Conducción de Automóvil , Trastornos de la Destreza Motora , Peatones , Autoinforme , Humanos , Adulto , Femenino , Masculino , Conducción de Automóvil/psicología , Peatones/psicología , Trastornos de la Destreza Motora/psicología , Trastornos de la Destreza Motora/fisiopatología , Adulto Joven , Persona de Mediana Edad , Caminata , Atención/fisiología , Adolescente , Encuestas y CuestionariosRESUMEN
Introduction: Empathic behaviors are driven by the ability to understand the emotional states of others along with the motivation to improve it. Evidence points towards forms of empathy, like targeted helping, in many species including rats. There are several variables that may modulate targeted helping, including sex, sensory modalities, and activity of multiple neural substrates. Methods: Using a model of social contact-independent targeted helping, we first tested whether sex differences exist in helping behavior. Next, we explored sex differences in sensory and affective signaling, including direct visualization and an analysis of ultrasonic vocalizations made between animal pairs. Finally, we examined the neural activity in males and females of multiple regions of interest across time. Here, we aim to examine any behavioral differences in our lab's social contact independent targeted helping task between males and females. Results and Discussion: These findings are the first to intimate that, like other prosocial behaviors, males and females may exhibit similar social-independent targeted helping behavior, but the underlying sensory communication in males and females may differ. In addition, this is the first set of experiments that explore the neural correlates of social-independent targeted helping in both males and females. These results lay the groundwork for future studies to explore the similarities and differences that drive targeted helping in both sexes.
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Broad-band ultraviolet photolysis (λ > 200 nm) of (cyanomethylene)cyclopropane (5) in an argon matrix at 20 K generates 1-cyano-2-methylenecyclopropane (7), a previously unknown compound. This product was initially identified by comparison of its infrared spectrum to that predicted by an anharmonic MP2/6-311+G(2d,p) calculation. This assignment was unambiguously confirmed by the synthesis of 1-cyano-2-methylenecyclopropane (7) and observation of its authentic infrared spectrum, which proved identical to that of the observed photoproduct. We investigated the singlet and triplet potential energy surfaces associated with this isomerization process using density functional theory and multireference calculations. The observed rearrangement of compound 5 to compound 7 is computed to be endothermic (3.3 kcal/mol). We were unable to observe the reverse reaction (7 â 5) under the photochemical conditions.
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The gas-phase rotational spectrum of 1-cyano-2-methylenecyclopropane (C1, C5H5N), an isomer of pyridine, is presented for the first time, covering the range from 235 to 500 GHz. Over 3600 a-, b-, and c-type transitions for the ground vibrational state have been assigned, measured, and least-squares fit to partial-octic A- and S-reduced distorted-rotor Hamiltonians with low statistical uncertainty (σfit = 42 kHz). Transitions for the two lowest-energy fundamental states (ν27 and ν26) and the lowest-energy overtone (2ν27) have been similarly measured, assigned, and least-squares fit to single-state Hamiltonians. Computed vibration-rotation interaction constants (B0-Bv) using the B3LYP and MP2 levels of theory are compared with the corresponding experimental values. Based upon our preliminary analysis, the next few vibrationally excited states form one or more complex polyads of interacting states via Coriolis and anharmonic coupling. The spectroscopic constants and transition frequencies presented here form the foundation for both future laboratory spectroscopy and astronomical searches for 1-cyano-2-methylenecyclopropane.
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Background: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5 + -DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 senses single-stranded RNA and is a key pattern recognition receptor for the SARS-CoV-2 virus. Methods: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018-December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5 + -DM outbreak. Results: Sixty new anti-MDA5+, but not other MSAs surged between 2020-2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. Few (8/60) had a prior history of COVID-19, whereas 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. Conclusions: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms.
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Importance: Tracheotomies are frequently performed by nonotolaryngology services. The factors that determine which specialty performs the procedure are not defined in the literature but may be influenced by tracheotomy approach (open vs percutaneous) and other clinicodemographic factors. Objective: To evaluate demographic and clinical characteristics associated with tracheotomies performed by otolaryngologists compared with other specialists and to differentiate those factors from factors associated with use of open vs percutaneous tracheotomy. Design, Setting, and Participants: This multicenter, retrospective cohort study included patients aged 18 years or older who underwent a tracheotomy for cardiopulmonary failure at 1 of 8 US academic institutions between January 1, 2013, and December 31, 2016. Data were analyzed from September 2022 to July 2023. Exposure: Tracheotomy. Main Outcomes and Measures: The primary outcome was factors associated with an otolaryngologist performing tracheotomy. The secondary outcome was factors associated with use of the open tracheotomy technique. Results: A total of 2929 patients (mean [SD] age, 57.2 [17.2] years; 1751 [59.8%] male) who received a tracheotomy for cardiopulmonary failure (652 [22.3%] performed by otolaryngologists and 2277 [77.7%] by another service) were analyzed. Although 1664 of all tracheotomies (56.8%) were performed by an open approach, only 602 open tracheotomies (36.2%) were performed by otolaryngologists. Most tracheotomies performed by otolaryngologists (602 of 652 [92.3%]) used the open technique. Multivariable regression analysis revealed that self-reported Black race (odds ratio [OR], 1.89; 95% CI, 1.52-2.35), history of neck surgery (OR, 2.71; 95% CI, 2.06-3.57), antiplatelet and/or anticoagulation therapy (OR, 1.74; 95% CI, 1.29-2.36), and morbid obesity (OR, 1.54; 95% CI, 1.24-1.92) were associated with greater odds of an otolaryngologist performing tracheotomy. In contrast, history of neck surgery (OR, 1.36; 95% CI, 0.96-1.92), antiplatelet and/or anticoagulation therapy (OR, 0.80; 95% CI, 0.56-1.14), and morbid obesity (OR, 0.94; 95% CI, 0.74-1.19) were not associated with undergoing open tracheotomy when performed by any service, and Black race (OR, 0.56; 95% CI, 0.44-0.71) was associated with lesser odds of an open approach being used. Age-adjusted Charlson Comorbidity Index score greater than 4 was associated with greater odds of both an otolaryngologist performing tracheotomy (OR, 1.26; 95% CI, 1.03-1.53) and use of the open tracheotomy technique (OR, 1.48, 95% CI, 1.21-1.82). Conclusions and Relevance: In this study, otolaryngologists were significantly more likely than other specialists to perform a tracheotomy for patients with history of neck surgery, morbid obesity, and ongoing anticoagulation therapy. These findings suggest that patients undergoing tracheotomy performed by an otolaryngologist are more likely to present with complex and challenging clinical characteristics.
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Obesidad Mórbida , Otolaringología , Humanos , Masculino , Persona de Mediana Edad , Femenino , Traqueotomía , Otorrinolaringólogos , Estudios Retrospectivos , AnticoagulantesRESUMEN
We investigate the underlying assumptions and limits of applicability of several documented models for outbreaks of airborne disease inside buildings by showing how they may each be regarded as special cases of a system of equations which combines quanta conservation and compartmental epidemiological modelling. We investigate the behaviour of this system analytically, gaining insight to its behaviour at large time. We then investigate the characteristic timescales of an indoor outbreak, showing how the dilution rate of the space, and the quanta generation rate, incubation rate and removal rate associated with the illness may be used to predict the evolution of an outbreak over time, and may also be used to predict the relative performances of other indoor airborne outbreak models. The model is compared to a more commonly used model, in which it is assumed the environmental concentration of infectious aerosols adheres to a quasi-steady-state, so that the the dimensionless quanta concentration is equal to the the infectious fraction. The model presented here is shown to approach this limit exponentially to within an interval defined by the incubation and removal rates. This may be used to predict the maximum extent to which a case will deviate from the quasi steady state condition.
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Contaminación del Aire Interior , Enfermedades Transmisibles , Humanos , Modelos Epidemiológicos , Enfermedades Transmisibles/epidemiología , Brotes de EnfermedadesRESUMEN
Return to methamphetamine (meth) use is part of an overarching addictive disorder hallmarked by cognitive sequela and cortical dysfunction in individuals who use meth chronically. In rats, long access meth self-administration produces object recognition memory deficits due to drug-induced plasticity within the perirhinal cortex (PRH). PRH projections are numerous and include the medial prefrontal cortex (mPFC). To evaluate the role of the PRH-mPFC reciprocal circuit in novel object recognition memory, a rgAAV encoding GFP-tagged Cre recombinase was infused into the PRH or the mPFC and rats were tested for recognition memory. On test day, one group explored both familiar and novel objects. A second group explored only familiar objects. GFP and Fos expression were visualized in the mPFC or PRH. During exploration, PRH neurons receiving input from the mPFC were equally activated by exploration of novel and familiar objects. In contrast, PRH neurons that provide input to the mPFC were disproportionately activated by novel objects. Further, the percent of Fos + cells in the PRH positively correlated with recognition memory. As such, the flow of communication appears to be from the PRH to the mPFC. In agreement with this proposed directionality, chemogenetic inhibition of the PRH-mPFC circuit impaired object recognition memory, whereas chemogenetic activation in animals with a history of long access meth self-administration reversed the meth-induced recognition memory deficit. This finding informs future work aimed at understanding the role of the PRH, mPFC, and their connectivity in meth associated memory deficits. These data suggest a more complex circuitry governing recognition memory than previously indicated with anatomical or lesion studies.
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Metanfetamina , Ratas , Animales , Reconocimiento en Psicología , Trastornos de la Memoria/metabolismo , Corteza Prefrontal/metabolismo , Percepción VisualRESUMEN
Choroid plexus insufficiency or glymphatic stasis are often classified as prequels to harmful accretion of toxic proteins in neurodegenerative disease. Cognitive decline and disordered neuronal signaling subsequently become cardinal features of Alzheimer's disease (AD), typically progressing with amyloid-ß and tau protein accumulation. For Parkinson's disease (PD), α-synuclein deposits and dopamine depletion are linked to impaired movement, resting tremor, and rigidity. Importantly, both diagnoses feature hyperinflammation and intrathecal cytokine changes. Thus far, numerous clinical trials have produced nothing effective for AD or PD, yet the anti-inflammatory and regenerative potential of autologous platelet-rich plasma (PRP) remains largely unexamined in this context. Our report explores a proposed Phase I study on intrathecal condensed plasma growth factors processed from thrombin-activated PRP as monotherapy for AD or PD. The concept gains support from related work where cytokines of platelet origin successfully lowered inflammation, corrected background fibrosis, deactivated abnormal cells, and recovered local tissue function-all desirable outcomes in AD and PD. While PRP-mediated effects on membrane potentials, cellular signaling, electrolyte balance, and water clearance are less well characterized, experimental data suggest these pathways could likewise influence glymphatic drainage to ameliorate proteinopathies. As a well-tolerated 'orthobiologic' with no hypersensitivity risk, intrathecal PRP and its derivatives bring advantages over synthetic pharmaceuticals. If age-associated neuroinflammation in AD and PD is an upstream event inciting or contributing to neural disruption, then dampening local oxidative stress by a patient's own platelet cytokines (successful in other contexts) could offer therapeutic relevance to these neurodegenerative conditions as well.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Enfermedad de Alzheimer/terapia , Antiinflamatorios/uso terapéutico , Enfermedad Crónica , Citocinas/metabolismo , Enfermedades Neurodegenerativas/terapia , Enfermedad de Parkinson/tratamiento farmacológico , Trombina/uso terapéutico , Ensayos Clínicos Fase I como AsuntoRESUMEN
Neuroendocrine tumors (NETs) of duodenal origin are an unusual subset among all NETs, comprising only about 3% of this neoplasm class. In general, NETs are characterized by overexpression of somatostatin receptors and carry an excellent prognosis with early diagnosis and intervention. Chromogranin A (CgA), a protein originating in secretory vesicles of neurons and endocrine cells, has gained wide usage in NET diagnosis and surveillance. Lanreotide is a synthetic octapeptide somatostatin analog with potent anti-proliferative action which has been approved by the FDA (U.S.) and EMA (E.U.) for NET treatment. It is known for its inhibitory effects on growth hormone, serotonin, CgA, and other markers. Here we describe a 56yr-old female with functional NET of duodenal origin, where serum CgA was successfully reduced from 3636 to <100 ng/mL after multidose lanreotide within five months. Of note, no metastatic spread was identified on positron emission tomography/computed tomography with 64Cu-labeled somatostatin analog tracer. Surgical resection of distal antrum, pylorus, and proximal duodenum was completed without complication. Histology revealed well-differentiated tumor cells with characteristic neuroendocrine features and clear surgical margins; low proliferation index (2%) was noted on Ki-67 staining. While select laboratory and imaging modalities are available for diagnosis and monitoring of duodenal NET, this is the first reported therapeutic use of lanreotide in this NET setting. The observed serum chromogranin A attenuation, even before surgery, supports its effectiveness in management of primary nonmetastatic duodenal NET after resection.
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Neoplasias Duodenales , Tumores Neuroendocrinos , Femenino , Humanos , Cromogranina A/sangre , Cromogranina A/metabolismo , Neoplasias Duodenales/diagnóstico por imagen , Neoplasias Duodenales/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/metabolismo , Receptores de Somatostatina , Somatostatina/uso terapéutico , Persona de Mediana EdadRESUMEN
Platelet-rich plasma (PRP) is an 'orthobiologic' with recognized roles in plastic surgery, musculoskeletal disorders, dentistry, dermatology, and more recently, 'ovarian rejuvenation'. Intraovarian PRP involves a complex secretome discharged after platelet activation, comprising multiple cytokine mediators delivered surgically to older or inactive ovarian tissue. Loss of oocyte meiotic fidelity and impaired fertilization accompanying advanced maternal age are already managed by IVF, but only with eggs provided by younger donors. However, if the observed effect of rectifying embryo ploidy error can be proven beyond case reports and small series, activated PRP (or its condensed plasma cytokines) would deliver a welcome therapeutic disruption that is difficult to overstate. Because shortcomings in ovarian function are presently addressed mainly by pharmacological approaches (i.e., via recombinant gonadotropins, GnRH analogs, or luteal support), autologous PRP would represent an unusual departure from these interventions. Given the diversity of platelet cargo proteins, the target response of intraovarian PRP is probably not confined to oocytes or follicles. For example, PRP manipulates signal networks driving improved perfusion, HOX regulation, N-glycan post-translational modification, adjustment of voltage-gated ion channels, telomere stabilization, optimization of SIRT3, and ribosome and mitochondria recovery in older oocytes. While multichannel signals operating on various pathways are not unique to reproductive biology, in intraovarian PRP this feature has received little study and may help explain why its standardization has been difficult. Against this background, our report examines the research themes considered most likely to shape clinical practice.
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No major breakthroughs have entered mainstream clinical fertility practice since egg donation and intracytoplasmic sperm injection decades ago, and oocyte deficits secondary to advanced age continue as the main manifestation of diminished ovarian reserve. In the meantime, several unproven IVF 'accessories' have emerged including so-called ovarian rejuvenation which entails placing fresh autologous platelet-rich plasma (PRP) directly into ovarian tissue. Among cellular responses attributed to this intervention are reduced oxidative stress, slowed apoptosis and improved metabolism. Besides having an impact on the existing follicle pool, platelet growth factors might also facilitate de novo oocyte recruitment by specified gene upregulation targeting uncommitted ovarian stem cells. Given that disordered activity at the mechanistic target of rapamycin (mTOR) has been shown to exacerbate or accelerate ovarian aging, PRP-discharged plasma cytokines combined with mTOR suppression by pulsed/cyclic rapamycin represents a novel fusion technique to enhance ovarian function. While beneficial effects have already been observed experimentally in oocytes and embryos with mTOR inhibition alone, this proposal is the first to discuss intraovarian platelet cytokines followed by low-dose, phased rapamycin. For refractory cases, this investigational, tailored approach could amplify or sustain ovarian capacity sufficient to permit retrieval of competent oocytes via distinct but complementary pathways-thus reducing dependency on oocyte donation.
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The millimeter-wave rotational spectrum of ketene (H2C=C=O) has been collected and analyzed from 130 to 750 GHz, providing highly precise spectroscopic constants from a sextic, S-reduced Hamiltonian in the Ir representation. The chemical synthesis of deuteriated samples allowed spectroscopic measurements of five previously unstudied ketene isotopologues. Combined with previous work, these data provide a new, highly precise, and accurate semi-experimental (reSE) structure for ketene from 32 independent moments of inertia. This reSE structure was determined with the experimental rotational constants of each available isotopologue, together with computed vibration-rotation interaction and electron-mass distribution corrections from coupled-cluster calculations with single, double, and perturbative triple excitations [CCSD(T)/cc-pCVTZ]. The 2σ uncertainties of the reSE parameters are ≤0.0007 Å and 0.014° for the bond distances and angle, respectively. Only S-reduced spectroscopic constants were used in the structure determination due to a breakdown in the A-reduction of the Hamiltonian for the highly prolate ketene species. All four reSE structural parameters agree with the "best theoretical estimate" (BTE) values, which are derived from a high-level computed re structure [CCSD(T)/cc-pCV6Z] with corrections for the use of a finite basis set, the incomplete treatment of electron correlation, relativistic effects, and the diagonal Born-Oppenheimer breakdown. In each case, the computed value of the geometric parameter lies within the statistical experimental uncertainty (2σ) of the corresponding semi-experimental coordinate. The discrepancies between the BTE structure and the reSE structure are 0.0003, 0.0000, and 0.0004 Å for rC-C, rC-H, and rC-O, respectively, and 0.009° for θC-C-H.
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Etilenos , Teoría Cuántica , Análisis Espectral , CetonasRESUMEN
Background: Recurrent in-frame insertions within exon 20 causing duplication of amino acids Tyrosine-Valine-Methionine-Alanine (YVMA) represent 80% of all HER2 alterations in non-small cell lung cancer (NSCLC). HER2 tyrosine kinase inhibitors (TKI), anti-HER2 monoclonal antibodies and HER2 directed antibody-drug conjugates have been evaluated in patients with HER2 mutated NSCLC. Limited data are available regarding the activity of these agents in exon 19 alterations. Osimertinib, a 3rd generation EGFR-TKI, has been found in pre-clinical studies to decrease growth of NSCLC with HER2 exon 19 aberrations. Case Description: A 68-year-old female with a past medical history of type 2 diabetes and minimal smoking was diagnosed with stage IV NSCLC. Next generation sequencing on tumor tissue demonstrated an ERBB2 exon 19 c.2262_2264delinsTCC, p.(L755P) mutation. After five lines of treatment that included chemotherapy, chemoimmunotherapy and investigational agents the patient's disease was progressing. At this time her functional status remained good, therefore clinical trials were explored however, none were available. Based on findings from pre-clinical studies, the patient was commenced on osimertinib 80 mg OD and achieved a partial response (PR) according to RESIST criteria both intra- and extracranially. Conclusions: This is the first report to our knowledge to demonstrate activity of osimertinib in a patient with NSCLC harboring HER2 exon 19, p.L755P mutation resulting in intra- and extracranial response. In the future, osimertinib could become a targeted treatment for patients harboring exon19 ERBB2 point mutations.
RESUMEN
Relapse to drug seeking involves transient synaptic remodelling that occurs in response to drug-associated cues. This remodelling includes activation of matrix metalloproteinases (MMPs) to initiate catalytic signalling in the extracellular matrix in the nucleus accumbens core (NAcore). We hypothesized that MMP activity would be increased in the NAcore during cue-induced methamphetamine (meth) seeking in a rat model of meth use and relapse. Male and female rats had indwelling jugular catheters and bilateral intracranial cannula targeting the NAcore surgically implanted. Following recovery, rats underwent meth or saline self-administration (6 h/day for 15 days) in which active lever responding was paired with a light + tone stimulus complex, followed by home cage abstinence. Testing occurred after 7 or 30 days of abstinence. On test day, rats were microinjected with a fluorescein isothiocyanate (FITC)-quenched gelatin substrate that fluoresces following cleavage by MMP-2,9, allowing for the quantification of gelatinase activity during cued-relapse testing. MMP-2,9 activity was significantly increased in the NAcore by meth cues presentation after 7 and 30 days of abstinence, indicating that remodelling by MMPs occurs during presentation of meth associated cues. Surprisingly, although cue-induced seeking increased between Days 7 and 30, MMP-2,9 activity did not increase. These findings indicate that although MMP activation is elicited during meth cue-induced seeking, MMP activation did not parallel the meth seeking that occurs during extended drug abstinence.