A Systematic Review of the Efficacy and Toxicity of Brachytherapy Boost Combined with External Beam Radiotherapy for Nonmetastatic Prostate Cancer.

CONTEXT: The optimum use of brachytherapy (BT) combined with external beam radiotherapy (EBRT) for localised/locally advanced prostate cancer (PCa) remains uncertain. OBJECTIVE: To perform a systematic review to determine the benefits and harms of EBRT-BT. EVIDENCE ACQUISITION: Ovid MEDLINE, Embase, and EBM Reviews-Cochrane Central Register of Controlled Trials databases were systematically searched for studies published between January 1, 2000 and June 7, 2022, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Eligible studies compared low- or high-dose-rate EBRT-BT against EBRT ± androgen deprivation therapy (ADT) and/or radical prostatectomy (RP) ± postoperative radiotherapy (RP ± EBRT). The main outcomes were biochemical progression-free survival (bPFS), severe late genitourinary (GU)/gastrointestinal toxicity, metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS), at/beyond 5 yr. Risk of bias was assessed and confounding assessment was performed. A meta-analysis was performed for randomised controlled trials (RCTs). EVIDENCE SYNTHESIS: Seventy-three studies were included (two RCTs, seven prospective studies, and 64 retrospective studies). Most studies included participants with intermediate-or high-risk PCa. Most studies, including both RCTs, used ADT with EBRT-BT. Generally, EBRT-BT was associated with improved bPFS compared with EBRT, but similar MFS, CSS, and OS. A meta-analysis of the two RCTs showed superior bPFS with EBRT-BT (estimated fixed-effect hazard ratio [HR] 0.54 [95% confidence interval {CI} 0.40-0.72], p < 0.001), with absolute improvements in bPFS at 5-6 yr of 4.9-16%. However, no difference was seen for MFS (HR 0.84 [95% CI 0.53-1.28], p = 0.4) or OS (HR 0.87 [95% CI 0.63-1.19], p = 0.4). Fewer studies examined RP ± EBRT. There is an increased risk of severe late GU toxicity, especially with low-dose-rate EBRT-BT, with some evidence of increased prevalence of severe GU toxicity at 5-6 yr of 6.4-7% across the two RCTs. CONCLUSIONS: EBRT-BT can be considered for unfavourable intermediate/high-risk localised/locally advanced PCa in patients with good urinary function, although the strength of this recommendation based on the European Association of Urology guideline methodology is weak given that it is based on improvements in biochemical control. PATIENT SUMMARY: We found good evidence that radiotherapy combined with brachytherapy keeps prostate cancer controlled for longer, but it could lead to worse urinary side effects than radiotherapy without brachytherapy, and its impact on cancer spread and patient survival is less clear.

Sweet light o' mine: Photothermal and photodynamic inactivation of tenacious pathogens using conjugated polymers.

Each year a rising number of infections can not be successfully treated owing to the increasing pandemic of antibiotic resistant pathogens. The global shortage of innovative antibiotics fuels the emergence and spread of drug resistant microbes. Basic research, development, and applications of alternative therapies are urgently needed. Since the 90´s, light-mediated therapies have promised to be the next frontier combating multidrug-resistance microbes. These platforms have demonstrated to be a reliable, rapid, and efficient alternative to eliminate tenacious pathogens while avoiding the emergence of resistance mechanisms. Among the materials showing antimicrobial activity triggered by light, conjugated polymers (CPs) have risen as the most promising option to tackle this complex situation. These materials present outstanding characteristics such as high absorption coefficients, great photostability, easy processability, low cytotoxicity, among others, turning them into a powerful class of photosensitizer (PS)/photothermal agent (PTA) materials. Herein, we summarize and discuss the advances in the field of CPs with applications in photodynamic inactivation and photothermal therapy towards bacteria elimination. Additionally, a section of current challenges and needs in terms of well-defined benchmark experiments and conditions to evaluate the efficiency of phototherapies is presented.

First quantitative assessment of the adsorption of a fluorocarbon gas on phospholipid monolayers at the air/water interface.

HYPOTHESIS: Fluorocarbon gases introduced above monolayers of phospholipids at the air/water interface were recently found to promote the adsorption of diverse molecular compounds, with potential application in drug-loaded microbubble design. Quantitative determination of the fluorocarbon present in the monolayers is strongly needed for the development of such applications. We hypothesized that neutron reflectometry (NR) and ellipsometry experiments would allow quantification of the fluorocarbon trapped in the monolayers. EXPERIMENTS: We report the first quantitative determination of the extents of adsorption of perfluorohexane (F-hexane) on different phospholipid monolayers with respect to both their phase and isotopic form. To this aim, we applied an approach based on co-modeling the data obtained from NR and ellipsometry. FINDINGS: We found that F-hexane adsorbs strongly in monolayers of dipalmitoylphosphatidylcholine (DPPC) when they are both in the liquid expanded (LE) and liquid condensed (LC) phases, but to different extents according to the isotopic form of the phospholipid. Kinetic resolution of the interfacial composition from data on both isotopic contrasts (assuming chemical identicality) was therefore not possible using NR alone, so an alternative NR/ellipsometry co-modeling treatment was applied to data from each isotopic contrast. F-hexane adsorbs more abundantly on monolayers of hydrogenous DPPC than chain-deuterated DPPC when they are in the LE phase, whilst the opposite was observed when they monolayers are in the LC phase. The extents of adsorption of F-hexane in monolayers of dimyristoylphosphatidylcholine (DMPC, LE phase) and distearoylphosphatidylcholine (DSPC, LC phase) concurs with the strong dependence of those with phospholipids of different isotopic contrasts according to the monolayer phase. This new methodology can lead to advances in the novel characterization of fluorocarbons interacting with phospholipid monolayers of relevance to applications such as in the shells of fluorocarbon-stabilized medically-oriented microbubbles.

Synthesis and physicochemical evaluation of fluorinated lipopeptide precursors of ligands for microbubble targeting.

Ligand-targeted microbubbles are focusing interest for molecular imaging and delivery of chemotherapeutics. Lipid-peptide conjugates (lipopeptides) that feature alternating serine-glycine (SG) n segments rather than classical poly(oxyethylene) linkers between the lipid polar head and a targeting ligand were proposed for the liposome-mediated, selective delivery of anticancer drugs. Here, we report the synthesis of perfluoroalkylated lipopeptides (F-lipopeptides) bearing two hydrophobic chains (C n F2 n +1, n = 6, 7, 8, 1-3) grafted through a lysine moiety on a hydrophilic chain composed of a lysine-serine-serine (KSS) sequence followed by 5 SG sequences. These F-lipopeptides are precursors of targeting lipopeptide conjugates. A hydrocarbon counterpart with a C10H21 chain (4) was synthesized for comparison. The capacity for the F-lipopeptides to spontaneously adsorb at the air/water interface and form monolayers when combined with dipalmitoylphosphatidylcholine (DPPC) was investigated. The F-lipopeptides 1-3 demonstrated a markedly enhanced tendency to form monolayers at the air/water interface, with equilibrium surface pressures reaching ≈7-10 mN m-1 versus less than 1 mN m-1 only for their hydrocarbon analog 4. The F-lipopeptides penetrate in the DPPC monolayers in both liquid expanded (LE) and liquid condensed (LC) phases without interfacial film destabilization. By contrast, 4 provokes delipidation of the interfacial film. The incorporation of the F-lipopeptides 1-3 in microbubbles with a shell of DPPC and dipalmitoylphosphatidylethanolamine-PEG2000 decreased their mean diameter and increased their stability, the best results being obtained for the C8F17-bearing lipopeptide 3. By contrast, the hydrocarbon lipopeptide led to microbubbles with a larger mean diameter and a significantly lower stability.

European Association of Urology Guidelines on Primary Urethral Carcinoma-2020 Update.

CONTEXT: Primary urethral carcinoma (PUC) is a rare cancer accounting for <1% of all genitourinary malignancies. OBJECTIVE: To provide updated practical recommendations for the diagnosis and management of PUC. EVIDENCE ACQUISITION: A systematic search interrogating Ovid (Medline), EMBASE, and the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews was performed. EVIDENCE SYNTHESIS: Urothelial carcinoma of the urethra is the predominant histological type of PUC (54-65%), followed by squamous cell carcinoma (16-22%) and adenocarcinoma (10-16%). Diagnosis of PUC depends on urethrocystoscopy with biopsy and urinary cytology. Pathological staging and grading are based on the tumour, node, metastasis (TNM) classification and the 2016 World Health Organization grading systems. Local tumour extent and regional lymph nodes are assessed by magnetic resonance imaging, and the presence of distant metastases is assessed by computed tomography of the thorax/abdomen and pelvis. For all patients with localised distal tumours (≤T2N0M0), partial urethrectomy or urethra-sparing surgery is a valid treatment option, provided that negative intraoperative surgical margins can be achieved. Prostatic Ta-Tis-T1 PUC can be treated with repeat transurethral resection of the prostate and bacillus Calmette-Guérin. In prostatic or proximal ≥ T2N0 disease, neoadjuvant cisplatin-based chemotherapy should be considered prior to radical surgery. All patients with locally advanced disease (≥T3N0-2M0) should be discussed within a multidisciplinary team. In men with locally advanced squamous cell carcinoma, curative radiotherapy combined with radiosensitising chemotherapy can be offered for definitive treatment and genital preservation. In patients with local urethral recurrence, salvage surgery or radiotherapy can be offered. For patients with distant metastatic disease, systemic therapy based on tumour characteristics can be evaluated. CONCLUSIONS: These updated European Association of Urology guidelines provide up-to-date guidance for the contemporary diagnosis and management of patients with suspected PUC. PATIENT SUMMARY: Primary urethral carcinoma (PUC) is a very rare, but aggressive disease. These updated European Association of Urology guidelines provide evidence-based guidance for clinicians treating patients with PUC.

Carotid ultrasound findings in rheumatoid arthritis and control subjects: A case-control study.

Rheumatoid arthritis (RA) is a chronic, inflammatory disease closely linked with atherosclerosis. Recommended cardiovascular disease (CVD) integral evaluation includes screening for asymptomatic atherosclerosis plaques with carotid ultrasound (US). The aim of this study is to evaluate the carotid US characteristics, including carotid intima media thickness (cIMT) and carotid plaque (CP), and compare RA-patients and controls in a Mexican-mestizo population. METHOD: Prospective cross-sectional, observational study comparing RA-patients and matched controls without RA. Medical history and physical exam was performed in all subjects by a rheumatologist and two clinical blinded radiologists did the carotid US. Increased cIMT was defined as ≥0.9 mm. CP was defined as a focal narrowing ≥0.5 mm of the surrounding lumen or a cIMT ≥1.2 mm. Multivariable analysis was done comparing RA-patients and control subjects characteristics with carotid US. RESULT: In the final analysis 209 patients were included, 103 patients with RA and 106 controls. Bilateral CP was found more than twice in RA than controls (15.5% vs 6.6%). Unilateral CP was more common in either side evaluated, being heterogeneous plaques the most common in RA-patients. The prevalence of increased cIMT was found higher in RA-patients either in both sides (right 37.9% vs 15.1%, P = 0.00; left 43.7% vs 19.8%, P = 0.00) were statistically significant. CONCLUSION: It was confirmed that RA-patients have greater subclinical atherosclerosis represented in the carotid US measuring cIMT and CP as surrogates. RA-patients with subclinical atherosclerotic disease have more heterogeneous plaques characteristics.

Adaptación del Inventario Revisado de Ansiedad Estado Competitiva - 2 a población deportiva argentina / Adaptation of the Revised Competitive State Anxiety Inventory - 2 to sport argentinian population

La ansiedad es un proceso afectivo que recibió mucha atención en Psicología del Deporte, ya que por sus características es un ámbito fructífero para estudiar este proceso. En Argentina no se hallaron instrumentos adaptados que evalúen este constructo en ámbitos deportivos. El objetivo del estudio realizado fue adaptar el Revised Competitive State Anxiety Inventory-2 (Cox, Martens & Russell, 2003) a una población de deportistas argentinos. Siguiendo la teoría multidimensional de la ansiedad de Martens (1974), este inventario posee 17 ítems distribuidos en tres factores: Ansiedad Somática (AS), Ansiedad Cognitiva (AC) y Autoconfianza (ACF). Se realizaron tres estudios instrumentales y uno de diferencias entre grupos para analizar si existen diferencias en los niveles de ansiedad en función del sexo, deporte y modalidad deportiva (individual - grupal). El estudio de entrevistas cognitivas posibilitó la ampliación del número de ítems por factor. Así, se analizó la estructura interna de 22 ítems mediante un análisis factorial confirmatorio. El inventario replicó la estructura factorial original con 8 ítems para ACF,7 para AS y 6 para AC. La confiabilidad presentó valores moderados a altos (de ρ = .84 a .96). Finalmente, se hallaron diferencias en función del sexo, deporte y modalidad deportiva en los niveles de AC y AS, mientras que las diferencias en ACF sólo se hallaron en función del sexo. El inventario posee adecuadas propiedades psicométricas y por lo tanto, es apropiado para la evaluación de la ansiedad estado competitiva en población deportiva argentina. Se espera que futuros estudios analicen las diferencias en los niveles de ansiedad considerando otros deportes, controlen el efecto de la edad y analicen la validez convergente del inventario.

Participating and/or competing in sports have certain characteristics that make the field of sports a productive one for the study of affective processes such as anxiety. It makes sense, then, that anxiety is a process that has received much attention in Sports Psychology since its beginnings as a discipline. Despite this, in Argentina there are currently no instruments to assess this construct in relation to sports. The aim of the present study was to adapt the Revised Competitive State Anxiety Inventory (CSAI-2R - Cox, Martens, & Russell, 2003) for use with Argentinean athletes. The CSAI-2R is composed of 17 items measuring three constructs, following Martens multidimensional anxiety theory (1974): Somatic Anxiety (SA), Cognitive Anxiety (CA), and Self-Confidence (SC). Three instrumental studies were carried out: cognitive interviews, a rating study and internal structure, and one of internal consistency. Finally, a group differences study was conducted. The cognitive interviews consisted in evaluating question comprehension by 10 athletes between the ages of 18 and 27 using a verbal probing technique. For the rating study, two experts in Sports Psychology and Psychometry judged the inventory's items in terms of their quality, as well as their congruence to the factors of interest. Lastly, for the studies of internal consistency and structure and of group differences study, the CSAI-2R was administered to 357 athletes 15 to 45 minutes prior to competing. The sample was made up of 162 females athletes and 195 males athletes between the ages of 11 and 47 (M = 21.83, SD = 5.90) overall averaging 9.18 years practicing their respective sports and all having competed at a regional to international level at least once a year (M = 2.94, SD = 2.38). The cognitive interviews helped clarify items, as well as add new ones (13 items) to be tested in subsequent studies. The rating study revealed complete agreement between the judges as regards congruence (k = 1.00; p < .05), although 8 items had to be eliminated due to poor quality (< 3). Thus, the final version the CSAI-2R replicated the original factorial structure with a total of 21 items. One item was eliminated and two had to be replaced because their factorial weight was below the established threshold of .40. Confirmatory Factor Analysis showed adequate indexes (CFI.954, TLI .948 RMSEA .062, 90% CI .055 .070, WRMR 1.199). Internal consistency of the inventory showed moderate to high composite reliability values, (from .84 to .90). Overall, the composite reliability for CSAI-2R was .96. Regarding sex differences, t tests yielded statistical differences in the levels of CA (Mmen = 11.32, Mwomen = 10.12, t(347) = 3.24, p < .05), SA (Mmen = 9.61, Mwomen = 10.81, t(347) = 3.81; p < .05), and SC (Mmen = 26.01, Mwomen = 24.55,t(347) = -2.87, p < .05). Also, sport modalities (group-individual) showed differences in SA (Mindividual = 10.89, Mgroup = 9.87, t (346) = 2.83, p < .05, d = .32) and AC (Mindividual = 9.94, Mgrupal = 10.94, t (347) = -2.47, p < .05, d = -.29). Finally, ANOVA showed differences in SA, F(3,345) = 4.39, p < .05 and CA, F(3, 345) = 3.31, p < .05 between sport type; Tukey post hoc tests showed that martial arts practitioners had higher levels of SA than soccer and hockey practitioners and lower levels of CA than field hockey practitioners. The CSAI-2R demonstrates good psychometric properties and, therefore, is an adequate instrument to assess competitive state-anxiety in Argentinian athletes. However, new instrumental studies are needed in order to check convergent validity and include new sports. Also, socio-demographic variables like age need to be taken into account in group differences studies.

Facilitation of KIR genotyping by a PCR-SSP method that amplifies short DNA fragments.

Detection of killer-cell immunoglobulin-like receptors (KIR) genes by polymerase chain reaction with sequence-specific primers (PCR-SSP) led in 1997 to the discovery that human genomes diverge largely in the KIR they encode. While only a few KIR genes are conserved in all humans, most individuals lack several those genes, which tend to associate in diverse haplotypic combinations. The PCR-SSP technique, updated to detect the more recently identified KIR genes and alleles, is still used widely to analyze the diversity of human populations, and to study the influence of KIR-gene variability on human health. Several published PCR-SSP methods for KIR genotyping, although simple and robust, have the drawback of relying on the amplification of DNA fragments spanning 0.5-2.0 kbp, which tends to fail in low-quality DNAs. Valuable collections of DNAs often include such poor quality samples, which lead to loss of data and resources. Even worse, undetected falsely negative or positive reactions may result in erroneous gene frequencies and in odd gene combinations. To address those problems, we have redesigned our previously published KIR genotyping method so that it produces short amplicons (less than 200 bp for most genes). This modification minimizes amplification failures, thus conferring greater consistency and reliability to KIR genotyping. In addition, the new PCR-SSP method detects recently described alleles of several KIR genes, and allows for discrimination between the major structural variants of KIR2DS4 and KIR3DP1 without increasing the number of reactions.

Influence of KIR gene diversity on the course of HSV-1 infection: resistance to the disease is associated with the absence of KIR2DL2 and KIR2DS2.

Herpes simplex virus type 1 (HSV-1) causes lifelong latent infections in most humans. Periodical virus reactivations from latency in the neurons of sensitive ganglia lead to transport to mucocutaneous regions and productive replication, which results in recurrent inflammatory herpetic lesions or in asymptomatic virus shedding. The medical consequences of such lesions and the frequency of recurrences vary greatly in different subjects. Furthermore, many infected individuals never suffer manifestations of the disease, even when exposed to stimuli that trigger clinical recurrences in other humans. The origin of the variability in the clinical course of HSV-1 infection remains unexplained. Herpesviruses and other pathogens sabotage the expression of major histocompatibility complex class I molecules by infected cells, thus subverting T-cell-mediated immunity. Subversion of antigen presentation is counteracted by natural killer cells, which survey the human leukocyte antigen (HLA) expression by specific receptors. These include the killer cell immunoglobulin-like receptors (KIRs), which are encoded by a complex of extremely diverse and rapidly evolving genes. Here, we analyze the contribution of KIR gene diversity to the variable clinical course of HSV-1 infection by comparing the distribution of these genes in humans with clinical manifestations of the disease with that in asymptomatically infected donors. This study provides preliminary evidence that the receptors KIR2DL2 and KIR2DS2 predispose to symptomatic HSV-1 infection and favor the frequently recurring forms of the disease. Possible contribution of the 'HLA-C1' ligand to HSV-1 disease was not statistically supported. Because of an absolute genetic linkage between KIR2DL2 and KIR2DS2, we could not determine which receptor was primarily responsible for the observed association, but our results suggest that presence in the genome of KIR2DL2 and KIR2DS2 hinders an effective cellular response to HSV-1.

Point mutation of an EYA1-gene splice site in a patient with oto-facio-cervical syndrome.

Mutations of the EYA1 gene (8q13.3) are the most common known cause of the branchio-oto-renal dysplasia (BOR), an autosomal dominant disease that includes developmental defects of branchial arch structures, middle and/or inner ear and kidney. The distinction between BOR and other dysplasias, such as oto-facio-cervical syndrome (OFC), is challenged by frequent association of the former to other diverse malformations, and by variable expressivity even within the same family. OFC is characterized by trophic alterations of the facies and shoulder girdle in addition to the malformations seen in BOR. Recent characterization of one OFC patient shed some light on the controversy over whether OFC and BOR are the same disease, and led to the hypothesis that OFC is caused by contiguous deletions of EYA1 and adjacent genes. By contrast, we show here that an OFC patient bears a single-nucleotide substitution in a splice site of EYA1. Our results indicate that not only major rearrangements, but also point mutations altering the EYA1 reading frame, can be found in patients with OFC syndrome.

Complete coding sequences and haplotypic associations of HLA-B*0707, -B*1524, -B*4405, -B*4802, -DRB1*0409, -DRB1*0411, -DRB1*1115, -DRB1*1305, and the novel allele -DRB1*0709. Group-specific amplification of cDNA from DRB1 alleles associated to DRB3 and DRB4.

We present here the characterization of the complete coding sequences, previously unavailable, of the human leukocyte antigen (HLA) alleles B*0707, B*1524, B*4405, B*4802, DRB1*0409, DRB1*0411, DRB1*1115, DRB1*1305, and that of a new allele, DRB1*0709. For the isolation of cDNA from the DRB1 gene, we designed a novel set of polymerase chain reaction (PCR) primers that makes it possible to amplify separately the groups of DRB1 alleles associated to each of the DRB3 and DRB4 loci. The primary structures, functional features, evolutionary relationships, haplotypic associations, and population distributions of each of the nine HLA-B and -DRB1 alleles reported here are reviewed.

Complementary DNA sequence of the HLA-B*3924 allele.

We have isolated the complete coding region of HLA-B*39 from a Spanish Caucasoid, using a new PCR primer for its 5' untranslated region. The cDNA matched partial genomic sequences of B*3924, an allele whose distribution appears to be restricted to Mediterranean and Arabian Caucasoids. A single amino acid change exclusive to B*3924 (threonine-98) distinguishes it from B*3903.

Complementary DNA sequence of the novel HLA-B*3704 allele.

The novel HLA-B*3704 allele was identified by polymerase chain reaction with sequence specific oligoneucletides (PCR-SSO) in a Spanish Caucasoid individual whose T-lymphocytes showed an ambiguous HLA-B phenotype. The nucleotide sequence of B*3704 was determined after reverse transcription-polymerase chain reaction (RT-PCR) amplification and molecular cloning of its complete coding region. B*3704 differs from B*3701 by a single nucleotide replacement that induces the substitution of histidine for tyrosine 171. Residue 171 is located in the alpha-helix of the alpha-2 domain, lining the A pocket of the peptide-binding site. Therefore, the His171 substitution seen in HLA-B*3704 is likely to affect its antigen-presenting properties and is probably responsible for the differentiated serological phenotype of this allele in comparison with B*3701.

Postorthodontic stability of the new attachment achieved by guided tissue regeneration following orthodontic movement: report of 2 cases.

Orthodontic treatment was provided after guided tissue regeneration of intrabony defects in 2 patients with periodontal disease. The new attachment obtained by guided tissue regeneration remained stable when subjected to orthodontic forces.