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Clostridioides difficile, the major cause of antibiotic-associated diarrhea, is a strict anaerobic, sporulating Firmicutes. However, during its infectious cycle, this anaerobe is exposed to low oxygen (O2) tensions, with a longitudinal decreasing gradient along the gastrointestinal tract and a second lateral gradient with higher O2 tensions in the vicinity of the cells. A plethora of enzymes involved in oxidative stress detoxication has been identified in C. difficile, including four O2-reducing enzymes: two flavodiiron proteins (FdpA and FdpF) and two reverse rubrerythrins (revRbr1 and revRbr2). Here, we investigated the role of the four O2-reducing enzymes in the tolerance to increasing physiological O2 tensions and air. The four enzymes have different, yet overlapping, spectra of activity. revRbr2 is specific to low O2 tensions (<0.4%), FdpA to low and intermediate O2 tensions (0.4%-1%), revRbr1 has a wider spectrum of activity (0.1%-4%), and finally FdpF is more specific to tensions > 4% and air. These different O2 ranges of action partly arise from differences in regulation of expression of the genes encoding those enzymes. Indeed, we showed that revrbr2 is under the dual control of σA and σB. We also identified a regulator of the Spx family that plays a role in the induction of fdp and revrbr genes upon O2 exposure. Finally, fdpF is regulated by Rex, a regulator sensing the NADH/NAD+ ratio. Our results demonstrate that the multiplicity of O2-reducing enzymes of C. difficile is associated with different roles depending on the environmental conditions, stemming from a complex multi-leveled network of regulation. IMPORTANCE: The gastrointestinal tract is a hypoxic environment, with the existence of two gradients of O2 along the gut, one longitudinal anteroposterior decreasing gradient and one proximodistal increasing from the lumen to the epithelial cells. O2 is a major source of stress for an obligate anaerobe such as the enteropathogen C. difficile. This bacterium possesses a plethora of enzymes capable of scavenging O2 and reducing it to H2O. In this work, we identified the role of the four O2-reducing enzymes in the tolerance to the physiological O2 tensions faced by C. difficile during its infectious cycle. These four enzymes have different spectra of action and protect the vegetative cells over a large range of O2 tensions. These differences are associated with a distinct regulation of each gene encoding those enzymes. The complex network of regulation is crucial for C. difficile to adapt to the various O2 tensions encountered during infection.
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PURPOSE: To describe phenotypic, genotypic, and histopathological features of inherited retinal dystrophies associated with the CRX gene (CRX-RDs). DESIGN: Retrospective multicenter cohort study including histopathology. SUBJECTS: Thirty-nine patients from 31 families with pathogenic variants in the CRX gene. METHODS: Clinical data of 152 visits were collected from medical records with a median follow-up time of 9.1 years (IQR, 3.3-15.3 years; range, 0.0-48.8 years). Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset CRX-RD was performed. MAIN OUTCOME MEASURES: Visual acuity, retinal imaging, electroretinography (ERG), genotype-phenotype correlation, and histopathological examination were evaluated. RESULTS: The age at onset ranged from birth to the 8th decade of life. Median visual acuity was 1.00 logMAR (IQR, 0.69-1.48 logMAR; range, 0.06-3.00 logMAR) at a mean age of 52.0 ± 19.9 years (range, 4.6-81.9 years). Sufficient imaging was available for 36 out of 39 patients (92.3%), and all showed degeneration of at least the macula. Out of these 36 patients, 22 (61.1%) had only macular dystrophy. Another 10 patients (27.8%) had additional degeneration beyond the vascular arcades, and 4 patients (11.1%) panretinal degeneration. Two patients (5.1%) had Leber congenital amaurosis (LCA). In total, 21 different disease-associated heterozygous CRX variants were identified (10 missense, 8 frameshift, 2 deletion, 1 deletion-insertion variants). Missense variants in the CRX homeodomain and two variants deleting all functional domains, thus causing haploinsufficiency, generally tended to cause milder late-onset phenotypes. Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset retinal dystrophy due to a heterozygous deletion of exons 3 and 4 of the CRX gene revealed loss of laminar integrity and widespread photoreceptor degeneration especially in the central retina, with extensive loss of photoreceptor nuclei and outer segments. CONCLUSION: This study illustrates the large clinical and genetic heterogenic spectrum of CRX-RDs, ranging from LCA to mild late-onset maculopathy resembling occult macular dystrophy. Haploinsufficiency and missense variants tended to be associated with milder phenotypes. Patients showed degeneration predominantly affecting the central retina on imaging. The histopathological findings also mirror these clinical findings and features similar to previously reported animal models of CRX-RDs.
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Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.
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PURPOSE: The purpose of this study was to evaluate the accuracy of peripheral oxygen saturation (SpO 2 ) measurements from Polar Elixir™ pulse oximetry technology compared with arterial oxygen saturation (SaO 2 ) measurements during acute stepwise steady-state inspired hypoxia at rest. A post hoc objective was to determine if SpO 2 measurements could be improved by recalibrating the Polar Elixir™ algorithm with SaO 2 values from a random subset of participants. METHODS: The International Organization for Standardization (ISO) protocol (ISO 80601-2-61:2017) for evaluating the SpO 2 accuracy of pulse oximeter equipment was followed whereby five plateaus of SaO 2 between 70% and 100% were achieved using stepwise reductions in inspired O 2 during supine rest. Blood samples drawn through a radial arterial catheter from 25 participants were first used to compare SaO 2 with SpO 2 measurements from Polar Elixir™. Then the Polar Elixir™ algorithm was recalibrated using SaO 2 data from 13 random participants, and SpO 2 estimates were recalculated for the other 12 participants. For SaO 2 values between 70% and 100%, root mean square error, intraclass correlation coefficients (ICC), Pearson correlations, and Bland-Altman plots were used to assess the accuracy, agreement, and strength of relationship between SaO 2 values and SpO 2 values from Polar Elixir™. RESULTS: The initial root mean square error for Polar Elixir™ was 4.13%. After recalibrating the algorithm, the RMSE was improved to 2.67%. The ICC revealed excellent levels of agreement between SaO 2 and Polar Elixir™ SpO 2 values both before (ICC(1,3) = 0.837, df = 574, P < 0.001) and after (ICC(1,3) = 0.942, df = 287, P < 0.001) recalibration. CONCLUSIONS: Relative to ISO standards, Polar Elixir™ yielded accurate SpO 2 measurements during stepwise inspired hypoxia at rest when compared with SaO 2 values, which were improved by recalibrating the algorithm using a subset of the SaO 2 data.
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Algoritmos , Hipoxia , Oximetría , Saturación de Oxígeno , Humanos , Oximetría/instrumentación , Oximetría/métodos , Masculino , Hipoxia/sangre , Femenino , Saturación de Oxígeno/fisiología , Adulto , Análisis de los Gases de la Sangre/instrumentación , Análisis de los Gases de la Sangre/métodos , Adulto Joven , Oxígeno/sangre , CalibraciónRESUMEN
BACKGROUND: Cardiovascular patients experience high rates of adverse outcomes following discharge from hospital, which may be preventable through early identification and targeted action. This study aimed to investigate the effectiveness and explainability of machine learning algorithms in predicting unplanned readmission and death in cardiovascular patients at 30 days and 180 days from discharge. METHODS: Gradient boosting machines were trained and evaluated using data from hospital electronic medical records linked to hospital administrative and mortality data for 39,255 patients admitted to four hospitals in New South Wales, Australia between 2017 and 2021. Sociodemographic variables, admission history, and clinical information were used as potential predictors. The performance was compared to LASSO regression, as well as the HOSPITAL and LACE risk score indices. Important risk factors identified by the gradient-boosting machine model were explored using Shapley values. RESULTS: The models performed well, especially for the mortality outcomes. Area under the receiver operating characteristic curve values were 0.70 for readmission and 0.87-0.90 for mortality using the full gradient boosting machine algorithms. Among the top predictors for 30-day and 180-day readmission were increased red cell distribution width, old age (especially above 80 years), high measured troponin and urea levels, not being married or in a relationship, and low albumin levels. For mortality, these included increased red cell distribution width, old age (especially older than 70 years), high measured troponin and urea levels, high neutrophil and monocyte counts, and low eosinophil and lymphocyte counts. The Shapley values gave clear insight into the dynamics of decision-tree-based models. CONCLUSIONS: We demonstrated an explainable predictive algorithm to identify cardiovascular patients who are at high risk of readmission or death at discharge from the hospital and identified key risk factors.
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Enfermedades Cardiovasculares , Aprendizaje Automático , Readmisión del Paciente , Humanos , Readmisión del Paciente/estadística & datos numéricos , Masculino , Femenino , Anciano , Enfermedades Cardiovasculares/mortalidad , Persona de Mediana Edad , Anciano de 80 o más Años , Factores de Riesgo , Nueva Gales del Sur/epidemiología , Algoritmos , AdultoRESUMEN
Since the emergence of SARS-CoV-2, different variants and subvariants successively emerged to dominate global virus circulation as a result of immune evasion, replication fitness or both. COVID-19 vaccines continue to be updated in response to the emergence of antigenically divergent viruses, the first being the bivalent RNA vaccines that encodes for both the Wuhan-like and Omicron BA.5 subvariant spike proteins. Repeated infections and vaccine breakthrough infections have led to complex immune landscapes in populations making it increasingly difficult to assess the intrinsic neutralizing antibody responses elicited by the vaccines. Hong Kong's intensive COVID-19 containment policy through 2020-2021 permitted us to identify sera from a small number of infection-naïve individuals who received 3 doses of the RNA BNT162b2 vaccine encoding the Wuhan-like spike (WT) and were boosted with a fourth dose of the WT vaccine or the bivalent WT and BA.4/5 spike (WT + BA.4/5). While neutralizing antibody to wild-type virus was comparable in both vaccine groups, BNT162b2 (WT + BA.4/BA.5) bivalent vaccine elicited significantly higher plaque neutralizing antibodies to Omicron subvariants BA.5, XBB.1.5, XBB.1.16, XBB.1.9.1, XBB.2.3.2, EG.5.1, HK.3, BA.2.86 and JN.1, compared to BNT162b2 monovalent vaccine. The single amino acid substitution that differentiates the spike of JN.1 from BA.2.86 resulted in a profound antigenic change.
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Vacuna BNT162 , COVID-19 , Humanos , Anticuerpos ampliamente neutralizantes , SARS-CoV-2/genética , Vacunas contra la COVID-19 , COVID-19/prevención & control , Anticuerpos Neutralizantes , Vacunación , Anticuerpos AntiviralesRESUMEN
Compared to healthy volunteers, participants with post-acute sequelae of SARS-CoV-2 infection (PASC) demonstrated increased plasma levels of the prothrombotic protein NEDD9, which associated inversely with indices of pulmonary vascular function. This suggests persistent pulmonary vascular dysfunction may play a role in the pathobiology of PASC.
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The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Cápside , Proteínas de la Cápside , Fármacos Anti-VIH/farmacologíaRESUMEN
Cells are unceasingly confronted by oxidative stresses that oxidize proteins on their cysteines. The thioredoxin (Trx) system, which is a ubiquitous system for thiol and protein repair, is composed of a thioredoxin (TrxA) and a thioredoxin reductase (TrxB). TrxAs reduce disulfide bonds of oxidized proteins and are then usually recycled by a single pleiotropic NAD(P)H-dependent TrxB (NTR). In this work, we first analyzed the composition of Trx systems across Bacteria. Most bacteria have only one NTR, but organisms in some Phyla have several TrxBs. In Firmicutes, multiple TrxBs are observed only in Clostridia, with another peculiarity being the existence of ferredoxin-dependent TrxBs. We used Clostridioides difficile, a pathogenic sporulating anaerobic Firmicutes, as a model to investigate the biological relevance of TrxB multiplicity. Three TrxAs and three TrxBs are present in the 630Δerm strain. We showed that two systems are involved in the response to infection-related stresses, allowing the survival of vegetative cells exposed to oxygen, inflammation-related molecules and bile salts. A fourth TrxB copy present in some strains also contributes to the stress-response arsenal. One of the conserved stress-response Trx system was found to be present both in vegetative cells and in the spores and is under a dual transcriptional control by vegetative cell and sporulation sigma factors. This Trx system contributes to spore survival to hypochlorite and ensure proper germination in the presence of oxygen. Finally, we found that the third Trx system contributes to sporulation through the recycling of the glycine-reductase, a Stickland pathway enzyme that allows the consumption of glycine and contributes to sporulation. Altogether, we showed that Trx systems are produced under the control of various regulatory signals and respond to different regulatory networks. The multiplicity of Trx systems and the diversity of TrxBs most likely meet specific needs of Clostridia in adaptation to strong stress exposure, sporulation and Stickland pathways.
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Bacterias , Reductasa de Tiorredoxina-Disulfuro , Bacterias/metabolismo , Reductasa de Tiorredoxina-Disulfuro/genética , Reductasa de Tiorredoxina-Disulfuro/química , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Tiorredoxinas/metabolismo , Firmicutes/metabolismo , Oxígeno , GlicinaRESUMEN
INTRODUCTION: Signatures of a type-I interferon (IFN-I) response are observed in the post mortem brain in Alzheimer's disease (AD) and other tauopathies. However, the effect of the IFN-I response on pathological tau accumulation remains unclear. METHODS: We examined the effects of IFN-I signaling in primary neural culture models of seeded tau aggregation and P301S-tau transgenic mouse models in the context of genetic deletion of the IFN-I receptor (IFNAR). RESULTS: Polyinosinic:polycytidylic acid (PolyI:C), a synthetic analog of viral nucleic acids, evoked a potent cytokine response that enhanced seeded aggregation of tau in an IFN-I-dependent manner. IFN-I-induced vulnerability could be pharmacologically prevented and was intrinsic to neurons. Aged P301S-tau mice lacking Ifnar1 had significantly reduced tau pathology compared to mice with intact IFN signaling. DISCUSSION: We identify a critical role for IFN-I in potentiating tau aggregation. IFN-I is therefore identified as a potential therapeutic target in AD and other tauopathies. HIGHLIGHTS: Type-I IFN (IFN-I) promotes seeded tau aggregation in neural cultures. IFNAR inhibition prevents IFN-I driven sensitivity to tau aggregation. IFN-I driven vulnerability is intrinsic to neurons. Tau pathology is significantly reduced in aged P301S-tau mice lacking IFNAR.
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Enfermedad de Alzheimer , Interferón Tipo I , Tauopatías , Ratones , Animales , Proteínas tau/genética , Interferón Tipo I/uso terapéutico , Tauopatías/patología , Ratones Transgénicos , Enfermedad de Alzheimer/patología , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Natural SARS-CoV-2 infection may elicit antibodies to a range of viral proteins including non-structural protein ORF8. RNA, adenovirus vectored and sub-unit vaccines expressing SARS-CoV-2 spike would be only expected to elicit S-antibodies and antibodies to distinct domains of nucleocapsid (N) protein may reliably differentiate infection from vaccine-elicited antibody. However, inactivated whole virus vaccines may potentially elicit antibody to wider range of viral proteins, including N protein. We hypothesized that antibody to ORF8 protein will discriminate natural infection from vaccination irrespective of vaccine type. METHODS: We optimized and validated the anti-ORF8 and anti-N C-terminal domain (NCTD) ELISA assays using sera from pre-pandemic, RT-PCR confirmed natural infection sera and BNT162b2 (BNT) or CoronaVac vaccinees. We then applied these optimized assays to a cohort of blood donor sera collected in April-July 2022 with known vaccination and self-reported infection status. RESULTS: We optimized cut-off values for the anti-ORF8 and anti-N-CTD IgG ELISA assays using receiver-operating-characteristic (ROC) curves. The sensitivity of the anti-ORF8 and anti-N-CTD ELISA for detecting past infection was 83.2% and 99.3%, respectively. Specificity of anti-ORF8 ELISA was 96.8 % vs. the pre-pandemic cohort or 93% considering the pre-pandemic and vaccine cohorts together. The anti-N-CTD ELISA specificity of 98.9% in the pre-pandemic cohort, 93% in BNT vaccinated and only 4 % in CoronaVac vaccinated cohorts. Anti-N-CTD antibody was longer-lived than anti-ORF8 antibody after natural infection. CONCLUSIONS: Anti-N-CTD antibody assays provide good discrimination between natural infection and vaccination in BNT162b2 vaccinated individuals. Anti-ORF8 antibody can help discriminate infection from vaccination in either type of vaccine and help estimate infection attack rates (IAR) in communities.
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COVID-19 , Vacunas Virales , Humanos , COVID-19/diagnóstico , COVID-19/prevención & control , Vacuna BNT162 , SARS-CoV-2 , Vacunación , Anticuerpos AntiviralesRESUMEN
PURPOSE: To date, there is no standard treatment regimen for carbonic anhydrase inhibitors (CAIs) in X-linked retinoschisis (XLRS) patients. This retrospective study aims to evaluate the efficacy of CAIs on visual acuity and cystoid fluid collections (CFC) in XRLS patients in Dutch and Belgian tertiary referral centers. DESIGN: Retrospective cohort study. PARTICIPANTS: Forty-two patients with XLRS. METHODS: In total, 42 patients were enrolled. To be included, patients had to have previous treatment with an oral CAI (acetazolamide), a topical CAI (brinzolamide/dorzolamide), or a combination of an oral and a topical CAI for at least 4 consecutive weeks. We evaluated the effect of the CAI on best-corrected visual acuity (BCVA) and central foveal thickness (CFT) on OCT. MAIN OUTCOME MEASURES: Central foveal thickness and BCVA. RESULTS: The median age at the baseline visit of the patients in this cohort study was 14.7 (range, 43.6) years, with a median (interquartile range [IQR]) follow-up period of 4.0 (2.2-5.2) years. During the follow-up period, 25 patients were treated once with an oral CAI (60%), 24 patients were treated once with a topical CAI (57%), and 11 patients were treated once with a combination of both topical and oral CAI (26%). We observed a significant reduction of CFT for oral CAI by 14.37 µm per 100 mg per day (P < 0.001; 95% confidence interval [CI], -19.62 to -9.10 µm) and for topical CAI by 7.52 µm per drop per day (P = 0.017; 95% CI, -13.67 to -1.32 µm). The visual acuity changed significantly while on treatment with oral CAI by -0.0059 logMAR per 100 mg (P = 0.008; 95% CI, -0.010 to -0.0013 logMAR). Seven patients (17%) had side effects leading to treatment discontinuation. CONCLUSIONS: Our data indicate that treatment with (oral) CAI may be beneficial for short-term management of CFC in patients with XLRS. Despite a significant reduction in CFT, the change in visual acuity was modest and not of clinical significance. Nonetheless, the anatomic improvement of the central retina in these patients may be of value to create an optimal retinal condition for future potential treatment options such as gene therapy. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.
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Inhibidores de Anhidrasa Carbónica , Retinosquisis , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Inhibidores de Anhidrasa Carbónica/administración & dosificación , Retinosquisis/tratamiento farmacológico , Retinosquisis/diagnóstico , Retinosquisis/fisiopatología , Estudios Retrospectivos , Masculino , Tomografía de Coherencia Óptica/métodos , Adulto , Adolescente , Femenino , Estudios de Seguimiento , Adulto Joven , Resultado del Tratamiento , Niño , Líquido Subretiniano , Persona de Mediana Edad , Sulfonamidas/administración & dosificación , Administración OralRESUMEN
BACKGROUND: Optimising the immunogenicity of COVID-19 vaccines to improve their protection against disease is necessary. Fractional dosing by intradermal (ID) administration has been shown to be equally immunogenic as intramuscular (IM) administration for several vaccines, but the immunogenicity of ID inactivated whole severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the full dose is unknown. This study (NCT04800133) investigated the superiority of antibody and T-cell responses of full-dose CoronaVac by ID over IM administration in adolescents. METHODS: Participants aged 11-17 years received two doses of IM or ID vaccine, followed by the 3rd dose 13-42 days later. Humoral and cellular immunogenicity outcomes were measured post-dose 2 (IM-CC versus ID-CC) and post-dose 3 (IM-CCC versus ID-CCC). Doses 2 and 3 were administered to 173 and 104 adolescents, respectively. RESULTS: Spike protein (S) immunoglobulin G (IgG), S-receptor-binding domain (RBD) IgG, S IgG Fcγ receptor IIIa (FcγRIIIa)-binding, SNM [sum of individual (S), nucleocapsid protein (N), and membrane protein (M) peptide pool]-specific interleukin-2 (IL-2)+CD4+, SNM-specific IL-2+CD8+, S-specific IL-2+CD8+, N-specific IL-2+CD4+, N-specific IL-2+CD8+ and M-specific IL-2+CD4+ responses fulfilled the superior and non-inferior criteria for ID-CC compared to IM-CC, whereas IgG avidity was inferior. For ID-CCC, S-RBD IgG, surrogate virus neutralisation test, 90% plaque reduction neutralisation titre (PRNT90), PRNT50, S IgG avidity, S IgG FcγRIIIa-binding, M-specific IL-2+CD4+, interferon-γ+CD8+ and IL-2+CD8+ responses were superior and non-inferior to IM-CCC. The estimated vaccine efficacies were 49%, 52%, 66% and 79% for IM-CC, ID-CC, IM-CCC and ID-CCC, respectively. The ID groups reported more local, mild adverse reactions. CONCLUSION: This is the first study to demonstrate superior antibody and M-specific T-cell responses by ID inactivated SARS-CoV-2 vaccination and serves as the basis for future research to improve the immunogenicity of inactivated vaccines.
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Immunocompromised patients often fail to raise protective vaccine-induced immunity against the global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Although monoclonal antibodies have been authorized for clinical use, most have lost their ability to potently neutralize the evolving Omicron subvariants. Thus, there is an urgent need for treatment strategies that can provide protection against these and emerging SARS-CoV-2 variants to prevent the development of severe coronavirus disease 2019. Here, we report on the design and characterization of a long-acting viral entry-blocking angiotensin-converting enzyme 2 (ACE2) dimeric fusion molecule. Specifically, a soluble truncated human dimeric ACE2 variant, engineered for improved binding to the receptor-binding domain of SARS-CoV-2, was fused with human albumin tailored for favorable engagement of the neonatal fragment crystallizable receptor (FcRn), which resulted in enhanced plasma half-life and allowed for needle-free transmucosal delivery upon nasal administration in human FcRn-expressing transgenic mice. Importantly, the dimeric ACE2-fused albumin demonstrated potent neutralization of SARS-CoV-2 immune escape variants.
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Implanted deep brain stimulation (DBS) devices are crucial in the treatment of movement disorders. Hardware extrusion is among the most frequent complications of the implantation process and requires reconstruction with well-vascularized tissues. The authors present a case of periosteal turnover flap for coverage of an exposed DBS device. An 11-year-old female patient with spastic cerebral palsy presented with an exposed DBS device located in the right parietal area. The exposed device was covered by a proximally based periosteal flap. Postoperative evaluations at months 1, 2, 3, and 8 revealed no signs of infection or dehiscence. This brief clinical study shows that reconstruction with periosteal turnover flaps is both an easy and excellent choice for secondary closure of exposed DBS devices.
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Estimulación Encefálica Profunda , Trastornos del Movimiento , Femenino , Humanos , Niño , Colgajos QuirúrgicosRESUMEN
Introduction: Patients with severe kidney diseases are at risk of complications from COVID-19; however, little is known about the effectiveness of COVID-19 vaccines in children and adolescents with kidney diseases. Methods: We investigated the immunogenicity and safety of an accelerated 3-dose primary series of COVID-19 vaccination among 59 pediatric patients with chronic kidney disease (CKD) (mean age 12.9 years; 30 male) with or without immunosuppression, dialysis, or kidney transplant. Dosage was 0.1 ml BNT162b2 to those aged 5 to 11 years, and 0.3 ml BNT162b2 to those aged 11 to 18 years. Results: Three doses of either vaccine type elicited significant antibody responses that included spike receptor-binding domain (S-RBD) IgG (90.5%-93.8% seropositive) and surrogate virus neutralization (geometric mean sVNT% level, 78.6%-79.3%). There were notable T cell responses. Weaker neutralization responses were observed among those on immunosuppression, especially those receiving higher number of immunosuppressants or on mycophenolate mofetil. Neutralization was reduced against Omicron BA.1 compared to wild type (WT, i.e., ancestral) (post-dose 3 sVNT% level; 82.7% vs. 27.4%; P < 0.0001). However, the T cell response against Omicron BA.1 was preserved, which likely confers protection against severe COVID-19. Infected patients exhibited hybrid immunity after vaccination, as evidenced by the higher Omicron BA.1 neutralization response among these infected patients who received 2 doses compared with those who were uninfected. Generally mild or moderate adverse reactions following vaccines were reported. Conclusion: An accelerated 3-dose primary series with BNT162b2 is immunogenic and safe in young children and adolescents with kidney diseases.
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Newborns can acquire immunological protection to SARS-CoV-2 through vaccine-conferred antibodies in human breast milk. However, there are some concerns around lactating mothers with regards to potential short- and long-term adverse events and vaccine-induced changes to their breast milk microbiome composition, which helps shape the early-life microbiome. Thus, we sought to explore if SARS-CoV-2 mRNA vaccine could change breast milk microbiota and how the changes impact the levels of antibodies in breast milk. We recruited 49 lactating mothers from Hong Kong who received two doses of BNT162b2 vaccine between June 2021 and August 2021. Breast milk samples were self-collected by participants pre-vaccination, one week post-first dose, one week post-second dose, and one month post-second dose. The levels of SARS-CoV-2 spike-specific IgA and IgG in breast milk peaked at one week post-second dose. Subsequently, the levels of both antibodies rapidly waned in breast milk, with IgA levels returning to baseline levels one month post-second dose. The richness and composition of human breast milk microbiota changed dynamically throughout the vaccination regimen, but the abundances of beneficial microbes such as Bifidobacterium species did not significantly change after vaccination. Additionally, we found that baseline breast milk bacterial composition can predict spike-specific IgA levels at one week post-second dose (Area Under Curve: 0.72, 95% confidence interval: 0.58-0.85). Taken together, our results identified specific breast milk microbiota markers associated with high levels of IgA in the breast milk following BNT162b2 vaccine. Furthermore, in lactating mothers, BNT162b2 vaccines did not significantly reduce probiotic species in breast milk.
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Chronic pain after spine surgery (CPSS) is often characterized by intractable low back pain and/or radiating leg pain, and has been reported in 8-40% of patients that received lumbar spine surgery. We conducted a literature search of PubMed, MEDLINE/OVID with a focus on studies about the etiology and treatments of CPSS and low back pain. Our aim was to provide a narrative review that would help us better understand the pathogenesis and current treatment options for CPSS. This knowledge will aid in the development of optimal strategies for managing postoperative pain symptoms and potentially curing the underlying etiologies. Firstly, we reviewed recent advances in the mechanistic study of CPSS, illustrated both structural (e.g., fibrosis and scaring) and non-structural factors (e.g., inflammation, neuronal sensitization, glial activation, psychological factor) causing CPSS, and highlighted those having not been given sufficient attention as the etiology of CPSS. Secondly, we summarized clinical evidence and therapeutic perspectives of CPSS. We also presented new insights about the treatments and etiology of CPSS, in order to raise awareness of medical staff in the identification and management of this complex painful disease. Finally, we discussed potential new targets for clinical interventions of CPSS and future perspectives of mechanistic and translational research. CPSS patients often have a mixed etiology. By reviewing recent findings, the authors advocate that clinicians shall comprehensively evaluate each case to formulate a patient-specific and multi-modal pain treatment, and importantly, consider an early intraoperative intervention that may decrease the risk or even prevent the onset of CPSS. Translational potential statement: CPSS remains difficult to treat. This review broadens our understanding of clinical therapies and underlying mechanisms of CPSS, and provides new insights which will aid in the development of novel mechanism-based therapies for not only managing the established pain symptoms but also preventing the development of CPSS.