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BackgroundWhile a low CD4/CD8 ratio during HIV treatment correlates with immunosenescence, its value in identifying patients at an increased risk for clinical events remains unclear.MethodsWe analyzed data from the CoRIS cohort to determine whether CD4 count, CD8 count, and CD4/CD8 ratio at year two of antiretroviral therapy (ART) could predict the risk of serious non-AIDS events (SNAEs) during the next five years. These included major adverse cardiovascular events, non-AIDS-defining malignancies, and non-accidental deaths. We used pooled logistic regression with inverse probability weighting to estimate the survival curves and cumulative risk of clinical events.ResultsThe study included 4625 participants, of whom 4.3% experienced an SNAE during the follow-up period. A CD4/CD8 ratio ConclusionsOur results support the use of the CD4/CD8 ratio and CD8 count as predictors of clinical progression. Patients with CD4/CD8 ratio SummaryThis study found that a low CD4/CD8 ratio (

Background: The transmission of monkeypox virus occurs through direct contact, but transmission through saliva or exhaled droplets and aerosols has not yet been investigated. We aimed to assess the presence of monkeypox virus DNA and infectious virus in saliva samples and droplets and aerosols exhaled from patients infected with monkeypox virus. Methods: We did a cross-sectional study in patients with monkeypox confirmed by PCR who attended two health centres in Madrid, Spain. For each patient, we collected samples of saliva, exhaled droplets within a mask, and aerosols captured by air filtration through newly developed nanofiber filters. We evaluated the presence of monkeypox virus in the samples by viral DNA detection by quantitative PCR (qPCR) and isolation of infectious viruses in cell cultures. Findings: Between May 18 and July 15, 2022, 44 patients with symptomatic monkeypox attended two health centres in Madrid and were included in the study. All were cisgender men, with a median age of 35·0 years (IQR 11·3). We identified high loads of monkeypox virus DNA by qPCR in 35 (85%) of 41 saliva samples. Infectious monkeypox virus was recovered from 22 (67%) of 33 saliva samples positive for monkeypox virus DNA. We also found a significant association between the number of affected cutaneous areas or general symptoms and the viral load present in saliva samples. Droplets exhaled from patients with monkeypox, detected inside a mask, contained monkeypox virus DNA in 32 (71%) of 45 samples, with two of the 32 positive samples showing the presence of the infectious virus. Monkeypox virus DNA in aerosols, collected from the medical consultation room, were detected in 27 (64%) of 42 samples, despite patients wearing an FFP2 mask during the visit. Infectious virus was not recovered from aerosol samples. High levels of monkeypox virus DNA were identified in aerosols collected from a hospital isolation room housing a patient with monkeypox. Interpretation: The identification of high viable monkeypox virus loads in saliva in most patients with monkeypox and the finding of monkeypox virus DNA in droplets and aerosols warrants further epidemiological studies to evaluate the potential relevance of the respiratory route of infection in the 2022 monkeypox virus outbreak. This study was funded by the EU (Nextgeneration EU), Consejo Superior de Investigaciones Científicas (PTI Salud Global), and Ciberinfec (Acción estratégica MKPXV22). We thank Milagros Guerra and the Electron Microscopy Service at CBMSO for their support. We thank the contribution of Grupo Viruela Simio Madrid ISCIII/HCSC/Sandoval. Sí

Monkeypox is the most prevalent Orthopoxvirus zoonosis infection since the eradication of smallpox. The current multi-country outbreak involves five WHO regions affecting mainly Europe. Accurate clinical and virological aspects of the disease outside endemic areas are needed.We performed an observational study of cases diagnosed in Madrid (Spain) (May/June 2022). Confirmation from vesicular lesions swabs, Orthopoxvirus real-time PCR, sequencing, phylogenetic analysis, and direct detection by Electron microscopy was performed. In addition, a structured epidemiological questionnaire was completed systematically to gather sociodemographic, clinical, and behavioral data from all confirmed cases.We extracted data from 48 patients, all cisgender men. The median age was 35 years (IQR 29 - 44), and 87.5% were MSM. The most prevalent symptoms were the presence of vesicular-umbilicated and pseudo-pustular skin lesions (93.8%), asthenia (66.6%), and fever (52.1%). In addition, the location of the lesions in the genital or perianal area was related to the role in sexual intercourse (p0.001). Sequencing analysis indicated the virus circulating in Spain belongs to the western African clade. Like the other European cases in the outbreak, the Spanish isolates are a direct descendant of viruses previously detected in Nigeria, the UK, Singapore, and Israel in 2017-2018.Monkeypox is an emerging infectious disease in Europe where community transmission is reported, mainly in MSM. The first symptom was skin lesions instead of classical fever and rash. The disease follows a self-limited course, and there have been no cases with a serious presentation or severe complications.

Patients with antibody deficiency disorders, such as common variable immunodeficiency (CVID), or secondary immunodeficiency (SIDs) to B-cell lymphoproliferative disorder (B-CLPD), are two vulnerable groups of developing severe or chronic form of coronavirus disease caused by SARS-CoV-2 (COVID-19). Data on adaptive immune responses against SARS-CoV-2 is well described in healthy donors, but still limited in patients with antibody deficiency of different cause. Herein, we analyzed Spike-specific IFN-γ and anti-Spike IgG antibody responses at 3 and 6 months after exposure to SARS-CoV-2 derived from vaccination and infection in two cohorts of immunodeficient patients (CVID vs. SID) compared to healthy controls (HC). Baseline cellular responses before vaccine administration were measured in 10 CVID patients. Adequate specific cellular responses was observed in 18 out of 20 (90%) CVID patients, in 14 out of 20 (70%) out of 20 SID patients and in 74 out of 81 (96%) HC. Specific IFN-γ response was significantly higher in HC respect to CVID (1,908.5 mUI/ml versus 1,694.1 mUI/ml; p = 0.005). Pre-vaccine anti-SARS-CoV-2 cellular responses were detectable in 4 out of 10 CVID patients, who had COVID-19 prior to vaccination, noticing an increase in cellular responses after vaccination (p p = 0.040), without significant differences between CVID and HC (p = 0.123) and between CVID and SID (p = 0.683). High proportions of CVID and SID patients showed adequate specific cellular responses to S1 neoantigen, with divergence between cellular and humoral immune responses in CVID and SID patients. Our data might support the relevance of these immunological studies to determine the correlate of protection to severe disease and for deciding the need of additional boosters. Follow-up studies are required to evaluate the duration and variability of the immune response to COVID-19 vaccination or infection.

To evaluate the results of low-dose radiation therapy (LD-RT) to lungs in the management of patients with COVID-19 pneumonia.We conducted a prospective phase I-II trial enrolling COVID-19 patients ≥50 years-old, with bilateral lung involvement at imaging study and oxygen requirement (oxygen saturation ≤93% on room air). Patients received 1 Gy to whole lungs in a single fraction. Primary outcome was a radiological response assessed as severity and extension scores at days +3 and +7. Secondary outcomes were toxicity (CTCAE v5.0), days of hospitalization, changes in inflammatory blood parameters (ferritin, lymphocytes, C-reactive protein, d-dimer and LDH) and SatOForty-one patients were included. Median age was 71 (IQR 60-84). Eighteen patients (44%) previously received an anti-COVID treatment (tocilizumab, lopinavir/ritonavir, remdesivir) and thirty-two patients (84%) received steroids during LD-RT. The extension score improved significantly (p = 0.02) on day +7. Mean baseline extension score was 13.7 (SD ± 4.9) with a score of 12.2 (±5.2) at day 3, and 12.4 ± 4.7 at day 7. No differences were found in the severity score. SAFI improved significantly on day +3 and +7 (p 0.01). Median SAFI on day 0 was 147 (IQR 118-264), 230 (IQR 120-343) on day +3 and 293 (IQR 121-353) on day +7. Significant decrease was found in C-reactive protein on day +7 (p = 0.02) and in lymphocytes counts on day +3 and +7 (p = 0.02). The median number of days in hospital after RT was 11 (range 4-78). With a median follow-up of 60 days after LD-RT, 26 (63%) patients were discharged, 11 (27%) died because of COVID respiratory failure and 4 (10%) died of other causes.LD-RT is a feasible and well-tolerated treatment that could lead to rapid clinical improvement. Large randomized trials would be required to establish the efficacy of LD-RT to treat COVID-19 pneumonia.

The synthesis of a new C3v -symmetric crushed fullerene C60H24 (5) has been accomplished in three steps from truxene through sixfold palladium-catalyzed intramolecular arylation of a syn-trialkylated truxene precursor. Laser irradiation of 5 induces cyclodehydrogenation processes that result in the formation of C60, as detected by LDI-MS.

Skeletal rearrangements of simple 1,6-enynes have been studied in order to determine the factors that control the formation of five- or six-membered rings. Simple 1,6-enynes substituted only at C-4 preferentially give six-membered rings on skeletal rearrangement in the presence of gold(I) catalysts, whereas increasing electron-withdrawing character of substituents at C-4 leads to five-membered rings. Reactions of these simple enynes in the presence of PtCl4 as catalyst give exclusively exo-double skeletal rearrangements. Enynes substituted at the alkyne also react with AuI catalysts to give exclusively products of exo-double rearrangement. The different mechanisms have been analyzed by DFT calculations. Although a pathway for the formation of six-membered rings involving two steps in a ring-expansion/ring-contraction process was found, the activation energy of the first step is too high. Instead, this skeletal rearrangement appears to follow an exo-single skeletal rearrangement in which the initial cyclopropyl gold carbene opens to form a six-membered ring. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Enantioselective addition of methyllithium to aromatic imines catalyzed by C2 symmetric tertiary diamines is described. Eleven diamines have been tested, for which dramatic effect of the nitrogen substitution has been observed. Diamines bearing hindered group close to the nitrogen led to racemic product while homologous hindered diamines led to the best results. Enantiomeric excess up to 74% could be achieved. An explanation of the absolute configuration of the product obtained is given considering the mechanism of the reaction.

A variety of optically enriched amines have been obtained by addition of aryllithium reagents to aromatic imines using N,N'-tetramethylcyclohexane-1,2-diamine as chiral ligands. Enantiomeric excesses up to 90% could be obtained.

The reactions of masked ortho-benzoquinones with furan under sonochemical irradiation were studied. Variation of the acoustic energy, temperature, and solvent composition permitted to optimize the yields, and provided insights into the mechanism. While the radical pathway could not be established, a double Michael stepwise pathway seems more probable, as shown by the effect of solvent polarity and the regioselectivity. The sonochemical effect involves most likely a mechanical micromixing, giving evidence to its role even in homogeneous systems.

Diels-Alder cycloadditions of an o-quinone monoketal with different furans, under argon, are considerably accelerated by ultrasonic irradiation. Moreover, these sonochemical reactions are regiospecific and proceed with a high diastereoselectivity. The results can be ascribed to the chemical role of ultrasounds which may favor a single electron transfer mechanism with respect to ionic or nonpolar pathways.

Background Although much has been written about bacteremia, evidence of the clinical diagnostic accuracy of bacteremia sources in the absence of microbiological results and the impact of diagnostic accuracy on mortality is scarce. Methods This is a retrospective study of bacteremia episodes over a 2-year period at a general hospital in Madrid. Congruence analyses between clinically presumed and definite sources, acquisition, causative organism, empirical treatment and progression to death were performed. Results The study included 323 bacteremia episodes. Clinicians' diagnostic accuracy was higher for gastrointestinal (88.8%; 95% CI: 79%–84%), respiratory (93.9%; 95% CI: 79%–99%) and urinary tract sources (83.6%; 95% CI: 75%–89%) and lower for skin and soft tissues (77.2%; 95% CI: 54%–92%) and, notably, intravascular sources (56%; 95% CI: 39%–71%). Overall, a non-significant (3.45%; 95% CI: − 0.6%–13.5%, p = 0.47) increase in mortality was observed in the incorrectly suspected bacteremia source group. Mortality related to a definitive source was significantly higher when an intravascular origin was not suspected, resulting in a 26% increase in mortality (95% CI: 1%–52%, p = 0.03). Differences in mortality related to inaccurate source assumptions were non-significant when the definitive bacteremia sources were gastrointestinal, urinary, respiratory, skin and soft tissues or unknown. Mortality in the group receiving appropriate empirical antimicrobial treatment was 10.6% compared with 19.7% mortality in the group receiving inappropriate empirical antimicrobial treatment (OR 2; 95% CI: 1.01–4.25). Conclusions The diagnostic accuracy of bacteremia sources is high in all but intravascular sources. A non-suspected intravascular source and inappropriate empirical treatment are related to a higher mortality.

Background Malaria in pregnancy is associated with maternal and foetal morbidity and mortality in endemic areas, but information on imported cases to non-endemic areas is scarce. The aim of this study was to describe the clinical and epidemiological characteristics of malaria in pregnancy in two general hospitals in Madrid, Spain. Methods Retrospective descriptive study of laboratory-confirmed malaria in pregnant women at the Fuenlabrada University Hospital and the Príncipe de Asturias University Hospital, in Madrid, over a six- and 11-year period, respectively. Relevant epidemiological, clinical and laboratory data was obtained from medical records. Results There were 19 pregnant women among 346 malaria cases (5.4%). The average age was 27 years. The gestational age (trimester) was: 53% 3rd, 31% 1st, 16% 2nd. All but one were multigravidae. Three were HIV positive. All were sub-Saharan immigrants: two were recently arrived immigrants and seventeen (89%) had visited friends and relatives. None had taken prophylaxis nor seeked pre-travel advice. Presentation: 16 symptomatic patients (fever in fourteen, asthenia in two), three asymptomatic. Median delay in diagnosis: 7.5 days. Laboratory tests: anaemia (cut off Hb level 11 g/dl) 78.9% (mild 31.6%, moderate 31.6%, severe 15.8%) thrombocytopaenia 73.7%, hypoglycaemia 10.5%. All cases were due to Plasmodium falciparum, one case of hyperparasitaemia. Quinine + clindamycin prescribed in 84%. Outcomes: no severe maternal complications or deaths, two abortions, fifteen term pregnancies, no low-birth-weight newborns, two patients were lost to follow-up. Conclusions Though cases of malaria in pregnancy are uncommon, a most at risk group is clearly defined: young sub-Saharan mothers visiting friends and relatives without pre-travel counselling and recently-arrived immigrants. The most common adverse maternal and foetal effects were anaemia and stillbirth. Given that presentation can be asymptomatic, malaria should always be considered in patients with unexplained anaemia arriving from endemic areas. These findings could help Maternal Health programme planners and implementers to target preventive interventions in the immigrant population and should create awareness among clinicians.

Herpes esophagitis (HE) is common in immunosuppressed patients, but has rarely been reported in immunocompetent individuals, in whom it appears to be a self-limited illness. We describe 3 new cases of HE in otherwise healthy patients seen in our hospital within the last 5 years. We performed a comprehensive review of the previously reported cases of HE in immunocompetent adults and adolescents in the English and Spanish literature. We analyzed the clinical features, treatment, and outcome of this entity. A total of 56 patients were included (39 men and 17 women), with a mean age of 35 years. The most common clinical manifestations were odynophagia (60.7%), fever (51.8%), and retrosternal chest pain (46.4%). A prodrome of upper respiratory symptoms and concurrent orolabial herpetic lesions were present in 26.8% and 25% of cases, respectively. Gastrointestinal bleeding was a rare complication (5.3%). Endoscopy revealed multiple ulcers in most cases (58.9%), typically involving the distal or mid-esophagus (83%). The diagnosis was confirmed by histopathologic examination in 40 cases (71.4%), by tissue viral culture in 21 (37.5%), and by detection of viral genome in esophageal samples in 4 cases (7.1%). Herpes simplex virus type 1 (HSV-1) was identified in 27 cases and herpes simplex virus type 2 (HSV-2) only in 1 case. Serology was consistent with a primary infection in 11 of the 25 evaluable cases (44%). Acyclovir therapy was used in 45.4% of patients. The outcome was favorable in all cases, although an esophageal perforation occurred in 1 patient. HE is a rare but well-defined entity in healthy adults and adolescents, and is probably underdiagnosed. A high degree of suspicion and a prompt endoscopic examination are required for the diagnosis. It is usually a self-limited infection, but early treatment with acyclovir may hasten the resolution of symptoms. Nevertheless, the benefit of antiviral therapy remains unknown.

Diels-Alder cycloadditions of an o-quinone monoketal with different furans, under argon, are considerably accelerated by ultrasonic irradiation. Moreover, these sonochemical reactions are regiospecific and proceed with a high diastereoselectivity. The results can be ascribed to the chemical role of ultrasounds which may favor a single electron transfer mechanism with respect to ionic or nonpolar pathways.

The chemoselectivity of the palladium-mediated reaction of bromobenzene with various heterocyclic diamines was studied. Whatever the ligand used, 3-aminopyrrolidine underwent arylation of the secondary amine function (>82%), whereas the more flexible 3-aminoazepinine was arylated on its primary function (>70%). The ratio "arylation of primary amine versus arylation of secondary amine" of 3-aminopiperidine with bromobenzene varied from 90:10 (BINAP, electron-enriched and hindered biphenyls L2 or L3) to 32:68 with the Josiphos-type ligand L10. The same trend was observed when 4-aminopiperidine was used (82:18 with L2 and 17:83 with L10). This selectivity can be tuned by the choice of aryl halide partners having different steric and electronic properties. A cooperative effect of both nitrogens of diamines during the reaction was deduced from competitive experiments. Finally, 13C and 31P NMR experiments, carried out with 3-aminopyrrolidine at room temperature, support a fast coordination of the primary amine to the metal. Indeed, a palladium complex resulting from the unusual displacement of one phosphane group of the intermediate ArPdX(BINAP) by the primary amino group was characterized.

A new tertiary pseudo C2-symmetric 1,2-diamine derived from (1S,2S)-(+)-pseudoephedrine was synthesized and tested in the enantioselective addition of MeLi to aromatic imines. A comparative study with the analogous C2-symmetric ligand successfully used previously in the same reaction showed comparable selectivity and better reactivity for this novel diamine.

Enantioselective addition of various aryllithium reagents to aromatic imines was catalyzed (20 mol-%) by readily accessible 1,2-diamines to afford a wide range of protected diarylmethylamines in up to 94 % enantiomeric excess. Furthermore, the absolute configuration of these arylation products was determined by using X-ray crystallography.

The production of different extracellular ligninolytic enzymes was studied in autochthonous fungal strains from Argentina isolated from litter derived from hydrocarbon-polluted sites and from basidiocarps frowing on wood in forests. The strains tested were cultivated in a carbon-limited medium with shaking. Laccase activity reached higher levels than aryl-alcohol oxidase and manganese-dependent peroxidase activities in liquid cultures from different fungi. No lignin peroxidase activity was found in any strain assayed. Some species are reported for the first time as producers of different ligninolytic enzymes.

The skeletal rearrangement as well as the hydroxy- and methoxycyclization of 1,7-enynes proceeds at room temperature with cationic gold(I) catalysts.

Since 2009, the largest reported outbreak of leishmaniasis by Leishmania infantum in Europe was reported in Fuenlabrada, Spain. In our hospital, 90 adults with localized leishmanial lymphadenopathy (LLL) or visceral leishmaniasis (VL) were treated during this outbreak; 72% were men, and the mean age was 46.2 years (range 15–95 years). A total of 17 cases (19%) were LLL, an atypical form with isolated lymphadenopathies without other symptoms. All LLL cases occurred in immunocompetent subjects, and only one subject (6%) was a native of sub-Saharan Africa. Diagnosis was performed by fine needle aspiration cytology of the lymphadenopathy. Serology was negative in 38%. LLL outcomes at 6 months were benign, even with doses of liposomal amphotericin B that were often lower (10 mg/kg) than those recommended for VL in Mediterranean areas. A total of 73 subjects (81%) presented with typical VL; 66% of this group were immunocompetent, and 50% of those who were immunocompetent were descendants of natives of sub-Saharan Africa. The rK39 test and polymerase chain reaction were the most useful tests for confirmation of the diagnosis. An initial response to treatment was observed in 99% of cases, and relapses occurred in 14% of cases. Leishmaniasis should be included in the differential diagnosis of isolated lymphadenopathies in endemic areas. LLL could be considered a more benign entity, one different than VL, and less aggressive management should be studied in future investigations.

Arrival of inmigrants from malaria endemic areas has led to a emergence of cases of this parasitic disease in Spain. The objective of this study was to analyse the high incidence rate of imported malaria in Fuenlabrada, a city in the south of Madrid, together with the frequent the lack of chemoprophylaxis, for the period between 2004 and 2014. Both pregnant women and HIV risk groups have been considered.Retrospective descriptive study of laboratory-confirmed malaria at the Fuenlabrada University Hospital, in Madrid, during a 10-year period (2004-2014). These data were obtained reviewing medical histories of the cases. Relevant epidemiological, clinical and laboratory results were analysed, with focus on the following risk groups: pregnant women and individuals with HIV.A total of 185 cases were diagnosed (90.3 % Plasmodium falciparum). The annual incidence rate was 11.9/100,000 inhabitants/year. The average age was 30.8 years (SD: 14.3). Infections originating in sub-Saharan Africa comprised the 97.6 % of the cases. A total of 85.9 % were Visiting Friends and Relatives. Only a 4.3 % completed adequate prophylaxis. A total of 14.28 % of the fertile women were pregnant, and 8 cases (4.3 %) had HIV. None of them in these special groups completed prophylaxis.The incidence rate in Fuenlabrada is higher than in the rest of Spain, due to the large number of immigrants from endemic areas living in the municipality. However, the results are not representative of all the country. It seems to be reasonable to implement prevention and pre-travel assessment programs to increase chemoprophylaxis. Pregnancy tests and HIV serology should be completed for all patients to improve prophylactic methods.

Background Arrival of inmigrants from malaria endemic areas has led to a emergence of cases of this parasitic disease in Spain. The objective of this study was to analyse the high incidence rate of imported malaria in Fuenlabrada, a city in the south of Madrid, together with the frequent the lack of chemoprophylaxis, for the period between 2004 and 2014. Both pregnant women and HIV risk groups have been considered. Methods Retrospective descriptive study of laboratory-confirmed malaria at the Fuenlabrada University Hospital, in Madrid, during a 10-year period (2004–2014). These data were obtained reviewing medical histories of the cases. Relevant epidemiological, clinical and laboratory results were analysed, with focus on the following risk groups: pregnant women and individuals with HIV. Results A total of 185 cases were diagnosed (90.3 % Plasmodium falciparum). The annual incidence rate was 11.9/100,000 inhabitants/year. The average age was 30.8 years (SD: 14.3). Infections originating in sub-Saharan Africa comprised the 97.6 % of the cases. A total of 85.9 % were Visiting Friends and Relatives. Only a 4.3 % completed adequate prophylaxis. A total of 14.28 % of the fertile women were pregnant, and 8 cases (4.3 %) had HIV. None of them in these special groups completed prophylaxis. Conclusions The incidence rate in Fuenlabrada is higher than in the rest of Spain, due to the large number of immigrants from endemic areas living in the municipality. However, the results are not representative of all the country. It seems to be reasonable to implement prevention and pre-travel assessment programs to increase chemoprophylaxis. Pregnancy tests and HIV serology should be completed for all patients to improve prophylactic methods.

What does a Diels-Alder cycloaddition look like? This question is here addressed in the case of the increasingly significant cycloadditions of masked o-benzoquinones (MOBs), which serve as versatile dienes for the construction of complex and functionalized structures. So first, what the mechanism is not: It is not (by and large) a classical, concerted [4 + 2] cycloaddition. Experimental evidence is now supported by sonochemical studies, which were instrumental in elucidating the pathway. Reactions with furans are accelerated and improved under sonication, even when conducted at -10 degrees C. Variation of the acoustic energy, temperature, and solvent composition allows us to optimize the yields and provide insights into the mechanism. Ultrasound does not cause sonochemical switching, as an alternative radical pathway should be ruled out. Results are consistent with a polar mechanism as claimed recently in a theoretical study. Moreover, this also does justice to a series of seminal papers, largely ignored, that gave a clue to the crucial issue of furan regioselectivity based on a nucleophilic addition. Most effects caused by ultrasonic agitation are of mechanochemical nature and suggest the existence of a perfectly stirred reactor with enhanced mass transfer.