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1.
Blood Adv ; 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39226456

RESUMEN

Cancer associated fibroblasts (CAF) arising from bone marrow-derived mesenchymal stromal cells (MSC) are prominent in B-precursor acute lymphoblastic leukaemia (B-ALL). We have previously shown that CAF formation is triggered by exposure to reactive oxygen species-inducing chemotherapy and that CAF support chemoresistance by donating mitochondria to the cancer cells, through tunnelling nanotubes. In the present study, we show that exposure of MSC to ALL cell lines, patient-derived xenografts and primary cells or their conditioned media can also trigger CAF formation. Using bulk RNA sequencing in cell lines, we show that the MSC to CAF transition is accompanied by a robust interferon pathway response and we have validated this finding in primary cells. Using confocal microscopy and flow cytometry, we identify the take-up of leukaemia cell-derived mitochondrial dsRNA by MSC as a proximate trigger for the MSC to CAF transition. We show that inhibition of dsRNA formation in ALL cells by treatment with low-dose ethidium or the mitochondrial transcription inhibitor IMT1 or degradation of dsRNA in conditioned media by 100°C exposure ablates the ability of the ALL conditioned media to stimulate MSC to CAF transition. Our data reveal a novel and previously undescribed mechanism by which cancer cells induce a CAF phenotype in stromal cells, showing how B-ALL cells can directly induce the previously described niche-mediated protection within the bone marrow.

2.
Virus Evol ; 10(1): veae001, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38486802

RESUMEN

Mutagenic antiviral drugs have shown promise against multiple viruses, but concerns have been raised about whether their use might promote the emergence of new and harmful viral variants. Recently, genetic signatures associated with molnupiravir use have been identified in the global SARS-COV-2 population. Here, we examine the consequences of using favipiravir and molnupiravir to treat SARS-CoV-2 infection in a hamster model, comparing viral genome sequence data collected from (1) untreated hamsters, and (2) from hamsters receiving effective and suboptimal doses of treatment. We identify a broadly linear relationship between drug dose and the extent of variation in treated viral populations, with a high proportion of this variation being composed of variants at frequencies of less than 1 per cent, below typical thresholds for variant calling. Treatment with an effective dose of antiviral drug was associated with a gain of between 7 and 10 variants per viral genome relative to drug-free controls: even after a short period of treatment a population founded by a transmitted virus could contain multiple sequence differences to that of the original host. Treatment with a suboptimal dose of drug showed intermediate gains of variants. No dose-dependent signal was identified in the numbers of single-nucleotide variants reaching frequencies in excess of 5 per cent. We did not find evidence to support the emergence of drug resistance or of novel immune phenotypes. Our study suggests that where onward transmission occurs, a short period of treatment with mutagenic drugs may be sufficient to generate a significant increase in the number of viral variants transmitted.

3.
Nat Commun ; 15(1): 1652, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38396069

RESUMEN

Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031.


Asunto(s)
COVID-19 , Citidina/análogos & derivados , Hidroxilaminas , SARS-CoV-2 , Adulto , Humanos , SARS-CoV-2/genética , Pacientes Ambulatorios , Formación de Anticuerpos , Anticuerpos Antivirales , Antivirales/uso terapéutico
4.
Braz. j. anesth ; 74(1): 744268, 2024. tab, graf
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1557223

RESUMEN

Abstract Background and objectives: Chronic shoulder pain is a frequent cause of suffering and impaired quality of life. Treatment includes non-pharmacological and pharmacological therapies, and interventional procedures such as suprascapular nerve blocks and radiofrequency. This prospective study aims to evaluate the efficacy of ultrasound-guided pulsed radiofrequency of suprascapular nerve for chronic shoulder pain in a clinical setting. Methods: Therapeutic efficacy was evaluated through pain intensity using numeric pain rating scale at baseline, immediately, 3, and 6 months after, and patient's motor function improvement. The secondary outcome was patient satisfaction. Results: A total of 34 patients were enrolled and all patients presented a reduction in the numeric pain rating scale immediately after treatment. Pain reduction from baseline to 6 months after the procedure was 34.4% and 36.9% static and dynamic, respectively. The median percentage reduction was statistically significant immediately, 3 and 6 months after. There was also an improvement in range of motion, 39.6% in abduction, 24.1% in flexion, and 29.5% in extension. Ninety percent of patients reported patient's global impression of change superior to six. Conclusion: This study concludes that ultrasound-guided pulsed radiofrequency of suprascapular nerve reduces pain intensity for at least 6 months, accompanied by improvement of motor function and higher levels of patients' satisfaction. Therefore, this technique represents a valid analgesic approach to chronic shoulder pain.

5.
J Perioper Pract ; : 17504589231193553, 2023 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-37886901

RESUMEN

BACKGROUND: Post-extubation negative pressure pulmonary oedema is a rare, potentially life-threatening complication associated with general anaesthesia. Chest radiography is used as a diagnostic tool, but it implies a non-negligible radiation exposure, a very important consideration, especially for the paediatric population. However, lung ultrasound can overcome this problem and can be used to detect postoperative pulmonary complications. CASE REPORT: A 16-year-old male was scheduled for tympanoplasty. General anaesthesia was conducted, and after extubation, the patient developed a laryngospasm. On arrival at the post-anaesthetic care unit, the patient started to cough, a pink frothy sputum and hypoxemia were noticed, and auscultation revealed crepitations. A bedside lung ultrasound showed more than three B-lines per intercostal window, suggesting an alveolar-interstitial syndrome. DISCUSSION: With this case report, we would like to raise awareness to this clinical entity and demonstrate bedside ultrasound has an important role in the diagnostic and therapeutic assessment during the perioperative period.

6.
J Clin Immunol ; 43(6): 1083-1092, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37148422

RESUMEN

PURPOSE: COVID-19 infection in immunodeficient individuals can result in chronically poor health, persistent or relapsing SARS-CoV-2 PCR positivity, and long-term infectious potential. While clinical trials have demonstrated promising outcomes using anti-SARS-CoV-2 medicines in immunocompetent hosts, their ability to achieve sustained viral clearance in immunodeficient patients remains unknown. We therefore aimed to study long-term virological outcomes in patients treated at our centre. METHODS: We followed up immunocompromised inpatients treated with casirivimab-imdevimab (Ronapreve) between September and December 2021, and immunocompromised patients who received sotrovimab, molnupiravir, nirmatrelvir/ritonavir (Paxlovid), or no treatment from December 2021 to March 2022. Nasopharyngeal swab and sputum samples were obtained either in hospital or in the community until sustained viral clearance, defined as 3 consecutive negative PCR samples, was achieved. Positive samples were sequenced and analysed for mutations of interest. RESULTS: We observed sustained viral clearance in 71 of 103 patients, none of whom died. Of the 32/103 patients where sustained clearance was not confirmed, 6 died (between 2 and 34 days from treatment). Notably, we observed 25 cases of sputum positivity despite negative nasopharyngeal swab samples, as well as recurrence of SARS-CoV-2 positivity following a negative sample in 12 cases. Patients were then divided into those who cleared within 28 days and those with PCR positivity beyond 28 days. We noted lower B cell counts in the group with persistent PCR positivity (mean (SD) 0.06 (0.10) ×109/L vs 0.22 (0.28) ×109/L, p = 0.015) as well as lower IgA (median (IQR) 0.00 (0.00-0.15) g/L vs 0.40 (0.00-0.95) g/L, p = 0.001) and IgM (median (IQR) 0.05 (0.00-0.28) g/L vs 0.35 (0.10-1.10) g/L, p = 0.005). No differences were seen in CD4+ or CD8+ T cell counts. Antiviral treatment did not impact risk of persistent PCR positivity. CONCLUSION: Persistent SARS-CoV-2 PCR positivity is common among immunodeficient individuals, especially those with antibody deficiencies, regardless of anti-viral treatment. Peripheral B cell count and serum IgA and IgM levels are predictors of viral persistence.


Asunto(s)
COVID-19 , Síndromes de Inmunodeficiencia , Humanos , COVID-19/diagnóstico , SARS-CoV-2 , Antivirales/uso terapéutico , Reacción en Cadena de la Polimerasa , Inmunoglobulina A , Inmunoglobulina M , Prueba de COVID-19
7.
Braz. J. Anesth. (Impr.) ; 73(2): 220-222, March-Apr. 2023. graf
Artículo en Inglés | LILACS | ID: biblio-1439601

RESUMEN

Abstract Burning mouth syndrome is a poorly understood entity for which current treatment modalities fail to provide effective relieve. Branches of the maxillary and mandibular nerves are responsible for the innervation of the affected area. These are also the nerves involved in trigeminal neuralgia, an entity where sphenopalatine block has proved to be effective. We present a case of a patient with burning mouth syndrome in whom a bilateral sphenopalatine ganglion block was successfully performed for pain treatment. It is an easy and safe technique that can be a valuable treatment option for these patients, although more studies are needed.


Asunto(s)
Humanos , Neuralgia del Trigémino/etiología , Neuralgia del Trigémino/terapia , Síndrome de Boca Ardiente/complicaciones , Síndrome de Boca Ardiente/terapia , Bloqueo del Ganglio Esfenopalatino/métodos , Resultado del Tratamiento , Manejo del Dolor
8.
Nature ; 617(7961): 564-573, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36996872

RESUMEN

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.


Asunto(s)
Infecciones por Adenovirus Humanos , Genómica , Hepatitis , Niño , Humanos , Enfermedad Aguda/epidemiología , Infecciones por Adenovirus Humanos/epidemiología , Infecciones por Adenovirus Humanos/inmunología , Infecciones por Adenovirus Humanos/virología , Linfocitos B/inmunología , Perfilación de la Expresión Génica , Hepatitis/epidemiología , Hepatitis/inmunología , Hepatitis/virología , Inmunohistoquímica , Hígado/inmunología , Hígado/virología , Proteómica , Linfocitos T/inmunología
9.
Blood Purif ; 52(4): 366-372, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36702111

RESUMEN

INTRODUCTION: Exit-site infection (ESi) prevention is a key factor in lowering the risk of peritonitis. This study aimed to evaluate the associations between exit-site (ES) care protocols and the annual incidence rates of ESi and peritonitis in Portugal. METHODS: We performed a national survey using two questionnaires: one about the incidence of catheter-related infections and the other characterizing patients' education and ES care protocols. RESULTS: In 2017 and 2018, 14 Portuguese units followed 764 and 689 patients. ESi incidence rate was 0.41 episodes/year, and the peritonitis incidence rate was 0.37. All units monitor catheter-related infections on a yearly basis, use antibiotic prophylaxis at the time of catheter placement, and treat nasal carriage of S. aureus, although with different approaches. Screening for nasal carriage of S. aureus is performed by 12 units, and daily topical antibiotic cream is recommended by 6 out of 14 of the units. We did not find statistical differences in ESi/peritonitis, comparing these practices. The rate of ESis was lower with nonocclusive dressing immediately after catheter insertion, bathing without ES dressing, with the use of colostomy bags in beach baths and was higher with the use of bath sponge. The peritonitis rate was lower with bathing without ES dressing and if shaving of the external cuff was performed in the presence of chronic ESi. CONCLUSIONS: We found potential proceedings associated with ESi and peritonitis. A regular national audit of peritoneal dialysis units is an important tool for clarifying the best procedures for reduction of catheter-related infections.


Asunto(s)
Infecciones Relacionadas con Catéteres , Diálisis Peritoneal , Peritonitis , Humanos , Mupirocina , Portugal , Infecciones Relacionadas con Catéteres/etiología , Staphylococcus aureus , Catéteres de Permanencia/efectos adversos , Administración Tópica , Diálisis Renal/efectos adversos , Antibacterianos , Diálisis Peritoneal/efectos adversos , Peritonitis/etiología
10.
Pain Physician ; 25(4): E641-E647, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35793188

RESUMEN

BACKGROUND: Chronic neuropathic pain is a disabling condition that affects quality of life. Despite recommendations and guidelines, treatment remains suboptimal as it often does not result in significant symptom relief. Capsaicin 8% patch has been used for the treatment of several peripheral neuropathic pain etiologies with encouraging results. OBJECTIVES: To assess the results of capsaicin 8% patch on neuropathic pain by evaluating pain intensity and the painful treatment area. STUDY DESIGN: Observational retrospective cohort study. SETTING: All patients submitted to capsaicin treatment at the Chronic Pain Unit of the Hospital Centre of Tondela Viseu, from 2011 through 2019. METHODS: Records of capsaicin treatments were reviewed, and the data collected. The primary outcome was pain intensity and painful treatment area reduction between the first and last treatment. Also, the number of treatments performed, neuropathic pain duration, anatomic location, pain etiology, and concomitant oral pain medication at baseline and upon treatment conclusion was also listed. RESULTS: Postsurgical neuropathic pain was the most common etiology (49%), followed by postherpetic (28%). The median (interquartile range [IQR]) baseline pain intensity assessed by the Numeric Rating Scale (NRS-11) was 6 (5-8) and the median (IQR) final NRS-11 was 3 (1-5), with a median (IQR) relative difference of -0.5 (-0.85-0.17) with statistically significant differences (P < 0.001) between baseline and last pain intensity, regarding all groups. Also, there was a reduction in the painful treatment area between baseline and the last evaluation, with a median (IQR) relative difference of -0.4 (-0.625-0.167). LIMITATIONS: A relatively small sample and occasional different timing for pain intensity and pain treatment area assessment due to logistical difficulties. CONCLUSIONS: Capsaicin 8% patch is a valuable option for the treatment of peripheral neuropathic pain, providing a significant reduction in pain intensity and painful area. It is well tolerated and has a high treatment compliance.Ethics Committee Reference Number: 16/16//04/2021.


Asunto(s)
Capsaicina , Neuralgia , Capsaicina/uso terapéutico , Humanos , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Calidad de Vida , Estudios Retrospectivos , Parche Transdérmico
11.
Infect Immun ; 90(7): e0017522, 2022 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-35674445

RESUMEN

The advent of pneumococcal conjugate vaccines led to the near disappearance of most of the included serotypes in high-income settings but also the rise of nonvaccine-type colonization and disease. Alternative strategies, using genetically conserved proteins as antigens, have been evaluated preclinically and clinically for years, so far unsuccessfully. One possible explanation for the failure of these efforts is that the choice of antigens may not have been sufficiently guided by an understanding of the gene expression pattern in the context of infection. Here, we present a targeted transcriptomic analysis of 160 pneumococcal genes encoding bacterial surface-exposed proteins in mouse models, human colonization, and human meningitis. We present the overlap of these different transcriptomic profiles. We identify two bacterial genes that are highly expressed in the context of mouse and human infection: SP_0282, an IID component of a mannose phosphotransferase system (PTS), and SP_1739, encoding RNase Y. We show that these two proteins can confer protection against pneumococcal nasopharyngeal colonization and intraperitoneal challenge in a murine model and generate opsonophagocytic antibodies. This study emphasizes and confirms the importance of studies of pneumococcal gene expression of bacterial surface proteins during human infection and colonization and may pave the way for the selection of a protein-based vaccine candidate.


Asunto(s)
Infecciones Neumocócicas , Animales , Proteínas Bacterianas/genética , Humanos , Ratones , Nasofaringe/microbiología , Infecciones Neumocócicas/microbiología , Vacunas Neumococicas/genética , Serogrupo , Streptococcus pneumoniae/genética , Transcriptoma , Vacunas Conjugadas
12.
Anaesthesiol Intensive Ther ; 54(2): 103-107, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35579280

RESUMEN

BACKGROUND: Hip fractures are extremely common and are considered a public health problem. The best anaesthetic technique for this surgery remains controversial. The aim of this study is to determine the impact of anaesthesia on perioperative and 30-day mortality and length of stay, in patients undergoing hip fracture surgery. MATERIAL: Adults undergoing hip fracture surgery, between January 1st, 2017 and December 31st, 2018, were retrospectively identified and categorized according to the anaesthetic technique. Perioperative and 30-day mortality rates and the length of stay were analysed. RESULTS: We identified 562 patients who underwent hip fracture surgery, 361 of whom were submitted to general anaesthesia and 201 to regional anaesthesia. The adjusted analysis showed no statistically significant difference in the risk of perioperative and 30-day mortality (odds ratio 1.12, 95% CI: 0.62-2.03; odds ratio 1.17, 95% CI: 0.72-1.92) or length of stay (0, 9 days [-1.6 to 3.4], P = 0.301). CONCLUSIONS: Our results were similar to those of studies already published in other countries. Within the limitations of our study, we concluded that there is no impact of the anaesthetic technique on perioperative and 30-day mortality rates and on the length of stay, for hip fracture surgery. In future studies, it will be opportune to investigate factors that influence the safety of anaesthetic techniques and that are subject to intervention by the anaesthesiologist.


Asunto(s)
Anestesia de Conducción , Anestésicos , Fracturas de Cadera , Anestesia General , Fracturas de Cadera/cirugía , Humanos , Tiempo de Internación , Complicaciones Posoperatorias , Estudios Retrospectivos
13.
BMC Vet Res ; 18(1): 153, 2022 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-35477456

RESUMEN

BACKGROUND: The Laminaria digitata is an abundant macroalga and a sustainable feedstock for poultry nutrition. L. digitata is a good source of essential amino acids, carbohydrates and vitamins, including A, D, E, and K, as well as triacylglycerols and minerals, in particular iron and calcium. However, the few studies available in the literature with broilers document the application of this macroalga as a dietary supplement rather than a feed ingredient. No study has addressed up until now the effects of a high-level incorporation (> 2% in the diet) of L. digitata on plasma biochemical markers and hepatic lipid composition, as well as minerals and pigments profile in the liver of broilers. Our experimental design included one hundred and twenty Ross 308 male birds contained in 40 wired-floor cages and distributed to the following diets at 22 days of age (n = 10) for 15 days: 1) a corn-soybean basal diet (Control); 2) the basal diet plus 15% of L. digitata (LA); 3) the basal diet plus 15% of L. digitata with 0.005% of Rovabio® Excel AP (LAR); and 4) the basal diet plus 15% of L. digitata with 0.01% of the recombinant CAZyme, alginate lyase (LAE). RESULTS: L. digitata compromised birds' growth performance by causing a reduction in final body weight. It was found an increase in hepatic n-3 and n-6 fatty acids, in particular C18:2n-6, C18:3n-6, C20:4n-6, C20:5n-3, C22:5n-3 and C22:6n-3 with the addition of the macroalga, with or without feed enzymes, to the broiler diets. Also, the beneficial C18:3n-3 fatty acid was increased by combining L. digitata and commercial Rovabio® Excel AP compared to the control diet. The sum of SFA, MUFA and the n-6/n-3 PUFA ratio were decreased by L. digitata, regardless the addition of exogenous enzymes. ß-carotene was enhanced by L. digitata, individually or combined with CAZymes, being also responsible for a positive increase in total pigments. Macrominerals, in particular phosphorous and sulphur, were increased in the liver of broilers fed L. digitata individually relative to the control. For microminerals, copper, iron and the correspondent sum were consistently elevated in the liver of broilers fed L. digitata, individually or combined with exogenous CAZymes. The powerful discriminant analysis tool based on the hepatic characterization revealed a good separation between the control group and L. digitata diets but failed to discriminate the addition of feed enzymes. CONCLUSIONS: Overall, this study highlights the value of L. digitata as a feed ingredient for the poultry industry. Moreover, we can conclude that the effect of L. digitata overpowers the effect of feed enzymes, both the Rovabio® Excel AP and the alginate lyase. Having in mind the negative effects observed on birds' performance, our main recommendation at this stage is to restraint L. digitata incorporation level in forthcoming nutritional studies.


Asunto(s)
Laminaria , Animales , Pollos , Dieta/veterinaria , Ácidos Grasos/metabolismo , Femenino , Hierro , Laminaria/metabolismo , Hígado/metabolismo , Masculino , Minerales , Polisacárido Liasas
14.
Cell Rep Med ; 3(3): 100557, 2022 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-35474751

RESUMEN

Effective control of SARS-CoV-2 infection on primary exposure may reveal correlates of protective immunity to future variants, but we lack insights into immune responses before or at the time virus is first detected. We use blood transcriptomics, multiparameter flow cytometry, and T cell receptor (TCR) sequencing spanning the time of incident non-severe infection in unvaccinated virus-naive individuals to identify rapid type 1 interferon (IFN) responses common to other acute respiratory viruses and cell proliferation responses that discriminate SARS-CoV-2 from other viruses. These peak by the time the virus is first detected and sometimes precede virus detection. Cell proliferation is most evident in CD8 T cells and associated with specific expansion of SARS-CoV-2-reactive TCRs, in contrast to virus-specific antibodies, which lag by 1-2 weeks. Our data support a protective role for early type 1 IFN and CD8 T cell responses, with implications for development of universal T cell vaccines.


Asunto(s)
COVID-19 , Interferón Tipo I , Linfocitos T CD8-positivos , Citometría de Flujo , Humanos , SARS-CoV-2/genética
15.
Cell Rep ; 39(2): 110650, 2022 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-35417711

RESUMEN

HIV-1 replicates in CD4+ T cells, leading to AIDS. Determining how HIV-1 shapes its niche to create a permissive environment is central to informing efforts to limit pathogenesis, disturb reservoirs, and achieve a cure. A key roadblock in understanding HIV-T cell interactions is the requirement to activate T cells in vitro to make them permissive to infection. This dramatically alters T cell biology and virus-host interactions. Here we show that HIV-1 cell-to-cell spread permits efficient, productive infection of resting memory T cells without prior activation. Strikingly, we find that HIV-1 infection primes resting T cells to gain characteristics of tissue-resident memory T cells (TRM), including upregulating key surface markers and the transcription factor Blimp-1 and inducing a transcriptional program overlapping the core TRM transcriptional signature. This reprogramming is driven by Vpr and requires Vpr packaging into virions and manipulation of STAT5. Thus, HIV-1 reprograms resting T cells, with implications for viral replication and persistence.


Asunto(s)
Infecciones por VIH , VIH-1 , Humanos , Linfocitos T CD4-Positivos/metabolismo , VIH-1/genética , Células T de Memoria , Fenotipo , Replicación Viral , Productos del Gen vpr del Virus de la Inmunodeficiencia Humana/genética
16.
Clin Infect Dis ; 75(2): 305-313, 2022 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-34410361

RESUMEN

BACKGROUND: Post-vaccination infections challenge the control of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: We matched 119 cases of post-vaccination severe acute respiratory syndrome coronavirus 2 infection with BNT162b2 mRNA or ChAdOx1 nCOV-19 to 476 unvaccinated patients with COVID-19 (September 2020-March 2021) according to age and sex. Differences in 60-day all-cause mortality, hospital admission, and hospital length of stay were evaluated. Phylogenetic, single-nucleotide polymorphism (SNP), and minority variant allele (MVA) full-genome sequencing analysis was performed. RESULTS: Overall, 116 of 119 cases developed COVID-19 post-first vaccination dose (median, 14 days). Thirteen of 119 (10.9%) cases and 158 of 476 (33.2%) controls died (P < .001), corresponding to the 4.5 number needed to treat (NNT). Multivariably, vaccination was associated with a 69.3% (95% confidence interval [CI]: 45.8 to 82.6) relative risk (RR) reduction in mortality. Similar results were seen in subgroup analysis for patients with infection onset ≥14 days after first vaccination and across vaccine subgroups. Hospital admissions (odds ratio, 0.80; 95% CI: .51 to 1.28) and length of stay (-1.89 days; 95% CI: -4.57 to 0.78) were lower for cases, while cycle threshold values were higher (30.8 vs 28.8, P = .053). B.1.1.7 was the predominant lineage in cases (100 of 108, 92.6%) and controls (341 of 446, 76.5%). Genomic analysis identified 1 post-vaccination case that harbored the E484K vaccine-escape mutation (B.1.525 lineage). CONCLUSIONS: Previous vaccination reduces mortality when B.1.1.7 is the predominant lineage. No significant lineage-specific genomic changes during phylogenetic, SNP, and MVA analysis were detected.


Asunto(s)
COVID-19 , SARS-CoV-2 , Vacuna BNT162 , Estudios de Casos y Controles , ChAdOx1 nCoV-19 , Genómica , Humanos , Filogenia , SARS-CoV-2/genética , Vacunación
17.
Nat Cancer ; 2(8): 835-852, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34734190

RESUMEN

Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We, therefore, investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of cell state accounts for a significant component of bottleneck selection during induction chemotherapy.


Asunto(s)
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras , Linfoma de Burkitt/tratamiento farmacológico , Ciclo Celular , Humanos , Quimioterapia de Inducción , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Recurrencia
18.
SAGE Open Med Case Rep ; 9: 2050313X211049908, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34659770

RESUMEN

Scarlet fever is essentially a childhood disease, although it may occur in all ages. Early diagnosis and treatment are essential in preventing the spread of infection and progression to life-threatening complications. The case presented describes the clinical difficulty in the diagnosis of scarlet fever in an adult patient with acute involvement of the airway (oedematous laryngitis) and the need for emergent orotracheal intubation and eventually tracheotomy. A high degree of suspicion related to the airway involvement is of utmost importance in an emergency room setting.

19.
J Infect ; 83(6): 693-700, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34610391

RESUMEN

OBJECTIVES: Recently emerging SARS-CoV-2 variants have been associated with an increased rate of transmission within the community. We sought to determine whether this also resulted in increased transmission within hospitals. METHODS: We collected viral sequences and epidemiological data of patients with community and healthcare associated SARS-CoV-2 infections, sampled from 16th November 2020 to 10th January 2021, from nine hospitals participating in the COG-UK HOCI study. Outbreaks were identified using ward information, lineage and pairwise genetic differences between viral sequences. RESULTS: Mixed effects logistic regression analysis of 4184 sequences showed healthcare-acquired infections were no more likely to be identified as the Alpha variant than community acquired infections. Nosocomial outbreaks were investigated based on overlapping ward stay and SARS-CoV-2 genome sequence similarity. There was no significant difference in the number of patients involved in outbreaks caused by the Alpha variant compared to outbreaks caused by other lineages. CONCLUSIONS: We find no evidence to support it causing more nosocomial transmission than previous lineages. This suggests that the stringent infection prevention measures already in place in UK hospitals contained the spread of the Alpha variant as effectively as other less transmissible lineages, providing reassurance of their efficacy against emerging variants of concern.


Asunto(s)
COVID-19 , Infección Hospitalaria , Infección Hospitalaria/epidemiología , Hospitales , Humanos , SARS-CoV-2 , Reino Unido/epidemiología
20.
Braz J Anesthesiol ; 2021 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-34571080

RESUMEN

BACKGROUND AND OBJECTIVES: Chronic shoulder pain is a frequent cause of suffering and impaired quality of life. Treatment includes non-pharmacological and pharmacological therapies, and interventional procedures such as suprascapular nerve blocks and radiofrequency. This prospective study aims to evaluate the efficacy of ultrasound-guided pulsed radiofrequency of suprascapular nerve for chronic shoulder pain in a clinical setting. METHODS: Therapeutic efficacy was evaluated through pain intensity using numeric pain rating scale at baseline, immediately, 3, and 6 months after, and patient's motor function improvement. The secondary outcome was patient satisfaction. RESULTS: A total of 34 patients were enrolled and all patients presented a reduction in the numeric pain rating scale immediately after treatment. Pain reduction from baseline to 6 months after the procedure was 34.4% and 36.9% static and dynamic, respectively. The median percentage reduction was statistically significant immediately, 3 and 6 months after. There was also an improvement in range of motion, 39.6% in abduction, 24.1% in flexion, and 29.5% in extension. Ninety percent of patients reported patient's global impression of change superior to six. CONCLUSION: This study concludes that ultrasound-guided pulsed radiofrequency of suprascapular nerve reduces pain intensity for at least 6 months, accompanied by improvement of motor function and higher levels of patients' satisfaction. Therefore, this technique represents a valid analgesic approach to chronic shoulder pain.

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