ALWAYS ICSI? A SWOT analysis.

PURPOSE: Intracytroplasmatic sperm injection (ICSI) is a common procedure used to improve reproductive results, even among couples without male factor infertility. However, the evidence available is still uncertain on the possible advantages and deficiencies that this procedure may have in patients with no formal indication for ICSI. METHODS: A SWOT (strengths, weaknesses, opportunities, threats) analysis examines the possible advantages and deficiencies of performing ICSI in these patients with no formal indication. RESULTS: The evidence suggests that ICSI is not justified for non-male factor infertile couples requiring in vitro conception. One of the major strengths associated to the procedure is the virtual elimination of cases further complicated by total fertilization failure and a combination between IVF and ICSI on sibling oocytes has been advised in the literature. Greater technical difficulties, higher costs and performing an unnecessary invasive technique in some cases represent some of the weaknesses of the procedure, and questions regarding safety issues should not be ruled out. CONCLUSION: Despite the widespread use of ICSI in patients without a formal diagnosis of male factor infertility, evidence demonstrating its effectiveness in this population is still lacking. Additional large and well-designed randomized controlled trials are needed to clarify definitive indications for ICSI in non-male factor infertility.

Referral Criteria for Asthma: Consensus Document.

Asthma is one of the most prevalent chronic diseases in Spain. Current treatments ensure that the disease is controlled in most cases. However, disease is often uncontrolled in daily clinical practice, mainly owing to underdiagnosis, loss to follow-up, and poor adherence to therapy. In order to improve this situation, we must coordinate all those health professionals who intervene in patient care. Therefore, the Spanish Society of Allergology and Clinical Immunology (SEAIC), the Spanish Society of Primary Care Physicians (SEMERGEN), the Spanish Society of Family and Community Medicine (semFYC), the Spanish Society of General and Family Physicians (SEMG), and the Spanish Society of Pneumology and Thoracic Surgery (SEPAR) have drawn up a consensus document in which they establish criteria for referral and guidelines for the diagnosis, control, and follow-up of patients with asthma. The document aims to facilitate continuing and improved care in this area.

Small-sized follicles could contribute to high-order multiple pregnancies: outcomes of 6552 intrauterine insemination cycles.

RESEARCH QUESTION: Can predictors of twin and high-order multiple pregnancy among women with multiple cycles of ovarian stimulation intrauterine insemination (IUI) be identified? DESIGN: Retrospective cohort study of IUI cycles carried out between January 2014 and December 2015 in a private clinic in Spain. The 4879 women and 6552 cycles analysed in this study include single IUI with ovarian stimulation using recombinant FSH. RESULTS: Number of follicles and follicle size were the only factors with a significant effect (P < 0.001) on the likelihood of achieving a twin or multifetal pregnancy. Follicles 12 mm or wider greatly increase the chances of achieving a twin or multifetal pregnancy. A total of 73 out of 127 (57.5%) twin pregnancies occurred in cycles with at least one additional follicle measuring 12 mm or wider, and 102 out of 127 twin pregnancies (80.3%) occurred in cycles with at least one additional follicle measuring 14 mm or wider. Cancellation criteria should consider the presence of follicles 12 mm or wider. CONCLUSION: Follicles measuring 12 mm or wider increase the risk of having a twin or a high-order multiple pregnancy rate. These data may help clinicians balance decision-making between cancelling and performing the cycle within an IUI procedure.

Hysteroscopic septum resection and reproductive medicine: A SWOT analysis.

Hysteroscopic septum resection in women with unfavourable reproductive and clinical outcomes has become common practice worldwide to improve reproductive results. No clear evidence on the possible advantages and drawbacks of this procedure has been published. In this opinion paper, based on a SWOT (strengths, weaknesses, opportunities, threats) analysis, the different aspects of this strategy are evaluated. Currently, no level 1 published evidence supports uterine resection in women with septate uterus. Clinical evidence from the studies analysed matches the more recent guidelines and suggests an improvement in reproductive outcomes after hysteroscopic resection of the septum, particularly in infertile women and women who have experienced recurrent miscarriages. In a patient with no history of infertility or prior pregnancy loss, it may be reasonable to consider septum incision after counselling about the potential risks and benefits of the procedure. Published clinical data in favour of the intervention, however, are based on studies with important methodological limitations. In this situation, the clinician and patient should reach an agreement together, based on the pros and cons of this intervention. Well-designed randomized controlled trials are required to confirm the clinical benefits and cost-effectiveness of this procedure.

Adenomyosis in infertile women: prevalence and the role of 3D ultrasound as a marker of severity of the disease.

BACKGROUND: Adenomyosis is linked to infertility, but the mechanisms behind this relationship are not clearly established. Similarly, the impact of adenomyosis on ART outcome is not fully understood. Our main objective was to use ultrasound imaging to investigate adenomyosis prevalence and severity in a population of infertile women, as well as specifically among women experiencing recurrent miscarriages (RM) or repeated implantation failure (RIF) in ART. METHODS: Cross-sectional study conducted in 1015 patients undergoing ART from January 2009 to December 2013 and referred for 3D ultrasound to complete study prior to initiating an ART cycle, or after ≥3 IVF failures or ≥2 miscarriages at diagnostic imaging unit at university-affiliated private IVF unit. Adenomyosis was diagnosed in presence of globular uterine configuration, myometrial anterior-posterior asymmetry, heterogeneous myometrial echotexture, poor definition of the endometrial-myometrial interface (junction zone) or subendometrial cysts. Shape of endometrial cavity was classified in three categories: 1.-normal (triangular morphology); 2.- moderate distortion of the triangular aspect and 3.- "pseudo T-shaped" morphology. RESULTS: The prevalence of adenomyosis was 24.4 % (n = 248) [29.7 % (94/316) in women aged ≥40 y.o and 22 % (154/699) in women aged <40 y.o., p = 0.003)]. Its prevalence was higher in those cases of recurrent pregnancy loss [38.2 % (26/68) vs 22.3 % (172/769), p < 0.005] and previous ART failure [34.7 % (107/308) vs 24.4 % (248/1015), p < 0.0001]. The presence of adenomyosis has been shown to be associated to endometriosis [35.1 % (34/97)]. Adenomyosis was diagnosed as a primary finding "de novo" in 80.6 % (n = 200) of the infertile patients. The impact on the uterine cavity was mild, moderate and severe in 63.7, 22.6 and 10.1 % of the cases, respectively. CONCLUSIONS: Our results indicate that adenomyosis is a clinical condition with a high prevalence that may affect the reproductive results. The described severity criteria may help future validating studies for better counseling of infertile couples.

Recombinant AAV-mediated in vivo long-term expression and antitumour activity of an anti-ganglioside GM3(Neu5Gc) antibody.

The ganglioside GM3(Neu5Gc) has gained increasing attention as therapeutic target because of its selective expression in various human tumours, such as melanoma, breast and lung cancer. 14F7 is a mouse IgG1 with specific reactivity to GM3(Neu5Gc)-positive tumours. The therapeutic activity of 14F7 has also been demonstrated in vivo, through its repetitive passive administration in tumour-bearing animals. In this work we used an alternative strategy to deliver recombinant 14F7 in vivo and analysed the therapeutic efficacy of this approach. We engineered a recombinant adeno-associated vector to direct the expression of secretable recombinant 14F7 in BALB/c animals. A single administration of the rAAV induced efficient production and secretion of the antibody in the bloodstream, with an expression level reaching plateau at ∼3 weeks after injection and persisting for almost a year. Strikingly, upon challenge with GM3(Neu5Gc)-positive X63-AG8.653 myeloma cells, tumour development was significantly delayed in animals treated with rAAV-14F7 with respect to animals treated with a control rAAV codifying for an irrelevant antibody. Finally, no significant differences in survival proportion were detected in animals injected with rAAV-14F7 or treated by standard administration of repetitive doses of purified monoclonal antibody 14F7.

Maternal KIR haplotype influences live birth rate after double embryo transfer in IVF cycles in patients with recurrent miscarriages and implantation failure.

STUDY QUESTION: In patients with recurrent miscarriages (RM) or recurrent implantation failure (RIF), does the maternal killer immunoglobulin-like receptor (KIR) haplotype have an impact on live birth rates per cycle after embryo transfer with the patient's own or donated oocytes? SUMMARY ANSWER: After double embryo transfer (DET) in patients with the maternal KIR AA haplotype, a significantly increased early miscarriage rate was observed when the patient's own oocytes were used, and a significantly decreased live birth rate per cycle after embryo transfer was observed when donated oocytes were used. WHAT IS ALREADY KNOWN: Interactions between fetal HLA-C and maternal KIR influence placentation during human pregnancy. There is an increased risk of RM, pre-eclampsia or fetal growth restriction in mothers with the KIR AA haplotype when the fetus has more HLA-C2 genes than the mother. STUDY DESIGN, SIZE AND DURATION: Between 2010 and 2014, we performed a retrospective study that included 291 women, with RM or RIF, who had a total of 1304 assisted reproductive cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnancy, miscarriage and live birth rates per cycle after single or DET, categorized by the origin of the oocytes and the presence of maternal KIR haplotypes, were studied. KIR haplotype regions were defined by the presence of the following KIR genes: Cen-A/2DL3; Tel-A/3DL1 and 2DS4; Cen-B/2DL2 and 2DS2; as well as Tel-B/2DS1 and 3DS1. MAIN RESULTS AND THE ROLE OF CHANCE: Higher rates of early miscarriage per cycle after DET with the patient's own oocytes in mothers with the KIR AA haplotype (22.8%) followed by those with the KIR AB haplotype (16.7%) compared with mothers with the KIR BB haplotype (11.1%) were observed (P = 0.03). Significantly decreased live birth rates per cycle were observed after DET of donated oocytes in mothers with the KIR AA haplotype (7.5%) compared with those with the KIR AB (26.4%) and KIR BB (21.5%) haplotypes (P = 0.006). No statistically significant differences were observed for pregnancy, miscarriage and live birth rates per cycle among those with maternal KIR AA, AB and BB haplotypes after single embryo transfer (SET) with the patient's own or donated oocytes. The large number of cases studied strengthens the results and provides sufficient power to the statistical analysis. LIMITATIONS, REASONS FOR CAUTION: During the IVF procedure, DET induces the expression of more than one paternal HLA-C and the oocyte-derived maternal HLA-C in the oocyte-donation cycles probably behaves like paternal HLA-C. Because this was a retrospective study, we did not have data about the HLA-C of the parent, donor, chorionic villi, or infant, which is a limitation because we cannot show differences according to paternal or oocyte donor HLA-C1 and HLA-C2. WIDER IMPLICATIONS OF THE FINDINGS: These new insights could have an impact on the selection of SET in patients with RM or RIF, and a KIR AA haplotype. Also, it may help in oocyte and/or sperm donor selection by HLA-C in patients with RM or RIF and a KIR AA haplotype. STUDY FUNDING/COMPETING INTERESTS: No funding was received for this study. The authors have no conflicts of interest to declare.

Long COVID: Factors influencing persistent symptoms and the impact of gender.

OBJECTIVE: This study aimed to characterize the prevalence as well as clinical and epidemiological features of persistent symptoms after acute COVID-19, focusing on gender-specific differences in a primary care setting. METHODS: A total of 1542 individuals with confirmed SARS-CoV-2 infection were enrolled. The study population comprised 55.77% females (mean age: 45.04 years). Risk factors for persistent COVID-19 were analyzed, revealing disparities between men and women. Symptom clusters and their prevalence were assessed over time, along with functional status using the post-COVID-19 functional status scale. RESULTS: The prevalence of persistent COVID-19 was 12.38%, with females exhibiting a 1.5 times higher risk. Females displayed a higher number of visits and persistent symptoms at 90 days, decreasing after one year. Symptom clusters varied between genders, with females experiencing more dermatological issues. Functional status analysis revealed that females had a better pre-infection status, similar status to males at 90 days, and improved status at 180-, 270-, and 365-days post-infection. Logistic regression analysis showed significant associations between persistence, gender, hospitalization, radiological abnormalities, age, and immunosuppression. CONCLUSION: This study provides insights into the prevalence and clinical characteristics of persistent COVID-19 in a primary care population. Females exhibited a higher risk of persistent symptoms and displayed distinct patterns in symptom clusters and functional status compared to males. These findings contribute to a better understanding of the long-term effects of COVID-19 and highlight the importance of gender-specific considerations in post-acute care.

A case of Japanese encephalitis in a 20 year-old Spanish sportsman, February 2013.

We report a severe case of imported Japanese encephalitis (JE) in a healthy young Spanish traveller who developed symptoms after spending three weeks in a touristic area of Thailand. The patient was diagnosed in Thailand and subsequently transferred to Barcelona, Spain, where the Thai laboratory results were confirmed based on IgM serology. Although JE is a rare disease in travellers, this case illustrates the need for seeking travel medical advice before visiting tropical countries.

Anaesthetic management of thyroid storm in a patient with Friederich's ataxia. A case report.

A 26-year-old patient with Friederich's ataxia with hypertrophic obstructive cardiomyopathy undergoing total thyroidectomy due to persistent amiodarone-induced thyrotoxicosis (despite high doses of antithyroid drugs and corticosteroids), presented an intraoperative episode suggestive of thyroid storm. Thyroid storm is an endocrine emergency that is associated with high morbidity and mortality. Early diagnosis and treatment, which is of vital importance to improve survival, includes symptomatic treatment, treatment of cardiovascular, neurological, and/or hepatic manifestations and thyrotoxicosis, measures to suppress or avoid triggering stimuli, and definitive treatment.

[Do patients deliver inhalers correctly? The AIRE project]. / ¿Desechan correctamente los pacientes sus dispositivos de inhalación? Proyecto AIRE.

OBJECTIVES: To assess users' attitudes and knowledge of users about how and where inhalers are removed after finalizing their use, and to describe their opinion about utilizing re-usable inhalers. METHODS: Cross-sectional, multi-center, and opinion survey, conducted to assess behavior and attitudes regarding the disposal of inhalers recycling and the use of re-usable inhalers, through the application of an ad hoc questionnaire about the knowledge and attitudes, with data about the use and recycling of inhalers. RESULTS: A total of 303 subjects (57.5±19.9 years; time of inhalers' use 9.6±9.8 years; asthma/COPD: 46.2%/25.7%) were included. Pressurized metered-dose inhalers were the most commonly used inhalers (30.5%). Most users considered the recycling of inhalers to be very important (7.75±2.76, out of 10), and rated highly the availability of having a monthly rechargeable inhaler every 6 months (7.77±2.79, out of 10). Only 33% of users had been informed by their healthcare professionals about the place of delivering the inhaler. With respect to recycling, 42.9% of all users recycled in the SIGRE point of the pharmacy. Regarding the final destination of inhalers, 43.6% thought that the removed inhalers were recycled or destroyed, but 35.3% did not know what would happen to the inhalers after placing in the SIGRE point. CONCLUSIONS: Despite users considered the importance of inhalers recycling and the availability of re-usable inhalers, a significant proportion does not recycle in the SIGRE point, has not been informed about the appropriate place of delivering the inhaler and ignores what happens to inhalers. Information campaigns are warranted.

[Comparing group educational intervention to individual and self-learning in COPD]. / Comparación de intervención educacional grupal frente a una individual y el autoaprendizaje en EPOC.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is considered a public health issue which affects 10.2% of Spanish population between 40 and 80 years of age. Many patients do not perform well the inhalation technique. Error rates vary between 50-80% depending on the device under study. These values haven been proven to decrease with educational interventions. OBJECTIVE: To ascertain whether a group educational intervention is superior to an individual intervention or to a conventional approach in these patients as regards quality of life measured by means of the total score of the COPD Assessment Test (CAT),of adherence to treatment, exacerbations and hospitalizations. MATERIAL AND METHODS: A multicenter, multidisciplinary cluster-randomized controlled clinical trial with three branches (conventional intervention, individual intervention and group intervention) in a cohort of COPD-patients. Sociodemographic data and risk factors were collected and several questionnaires were completed (CAT, BODEx, Barthel, Lawton y Brody). A descriptive analysis of qualitative and quantitative variables and a multiple linear regression were conducted. OUTCOMES: 149 patients of average age 69.08 (SD 1.26). Significant differences were observed in CAT in the different intervention groups according to the level of severity on BODEx. The rate of patients performing well the inhalation technique was significantly lower at the beginning of the study and the number of exacerbations was lower after the intervention. Last year's exacerbations were linearly related to post-intervention suffering. CONCLUSIONS: Better results are obtained using the traditional and individual interventions. There is a decrease in number of exacerbations, hospitalizations, CAT score and post-intervention inhalation technique.

Effects of hydration on the proton transfer mechanism in the adenine-thymine base pair.

We report the first density functional study of water catalytic effect in the double proton transfer (DPT) taking place in the adenine-thymine (AT) base pair. To gain more insight regarding the accuracy of several theoretical methods, the ability of various functionals and models for describing the geometry of this system has first been checked. According to our results, BP86/6-311++G(d,p) is the best option for describing the solvation effects in AT when applied to a two-water-molecule-featuring model. The two possible mechanisms for DPT in solution are explored: in the first one, water molecules only remain passive elements, whereas in the second one they are directly included in the reaction path. For the noncatalyzed mechanism, the stable structures constitute the canonical form of the base pair and the first proton transfer product. Nevertheless, by involving the two water molecules in the reaction, we found three stable species: canonical base pair, first proton transfer product, and double proton transfer product. Although the thermodynamic analysis confirms that AT does not contribute to spontaneous mutation through proton transfer catalyzed by surrounding water, our results suggest that microhydration may play a crucial role for DPT reaction in others DNA or RNA basis pair.

Density functional theory study of the stability and vibrational spectra of the beta-carotene isomers.

A density functional theory analysis of the stability and vibrational spectra of the beta-carotene isomers is carried out. The study includes the 7-, 9-, 11-, 13-, and 15-monocis isomers and the 7,13'-, 9,13-, 9,13'-, 9,15-, 11,11'-, and 13,15-dicis isomers. The optimized geometries needed to study the stability of the isomers are calculated at the B3LYP/6-31G(d) level of theory, and their energies are further recalculated at the higher B3LYP/6-311+G(2d,2p) level. In addition, the Wiberg bond orders and the natural bond orbital charges of the isomers are computed study the effect of the torsion of the beta-ionone rings on the conjugation degree of the polyene chain. The infrared and Raman spectra of the beta-carotene isomers are then calculated at the B3LYP/6-31G(d) level, scaling the calculated frequencies with an overall factor to account for the anharmonicity effects. The calculated frequencies are shown to compare quite well with the experiment, and the normal modes of the key bands are theoretically interpreted.

Intermolecular proton transfer in microhydrated guanine-cytosine base pairs: a new mechanism for spontaneous mutation in DNA.

Accurate calculations of the double proton transfer (DPT) in the adenine-thymine base pair (AT) were presented in a previous work [J. Phys. Chem. A 2009, 113, 7892.] where we demonstrated that the mechanism of the reaction in solution is strongly affected by surrounding water. Here we extend our methodology to the guanine-cytosine base pair (GC), for which it turns out that the proton transfer in the gas phase is a synchronous concerted mechanism. The O(G)-H-N(C) hydrogen bond strength emerges as the key parameter in this process, to the extent that complete transfer takes place by means of this hydrogen bond. Since the main effect of the molecular environment is precisely to weaken this bond, the direct proton transfer is not possible in solution, and thus the tautomeric equilibrium must be assisted by surrounding water molecules in an asynchronous concerted mechanism. This result demonstrates that water plays a crucial role in proton reactions. It does not act as a passive element but actually catalyzes the DPT.

[Mortality due to asthma in Spain, 1990-2015]. / Mortalidad por asma en España, 1990-2015.

INTRODUCTION: Asthma is a major public health problem affecting more than 300 million people worldwide. The importance of a disease can be measured by its prevalence, burden of care, and its morbidity and mortality. OBJECTIVE: To determine the mortality rates for asthma in Spain in the period 1990-2015. MATERIAL AND METHODS: The number of deaths attributed to asthma by gender and five-year age groups, together with the population as of July 1 between the years 1990-2015 were obtained from the National Institute of Statistics. Based on these data, the gross mortality rate per 100,000 global inhabitants was calculated, by gender and age groups. RESULTS: In 2015, 1,134 people (195 men and 939 women) died in Spain with a diagnosis of asthma as the main cause, with rates of 0.82 / 100,000 inhabitants compared to 2.58, respectively. The asthma mortality rates in Spain have remained stable for the last 25 years, and are slightly higher than those in the surrounding countries. While asthma mortality has declined by over 67% in males, it has increased by 32% in females. The deaths are concentrated in those over 65 years, and particularly over 80 years, where the value of death certificates is more limited. Mortality in the 5-35 years age groups is among the lowest in Europe.

A density functional theory study of the structure and vibrational spectra of beta-carotene, capsanthin, and capsorubin.

A theoretical study of the structure and the vibrational spectra of the beta-carotene molecule and its derivatives capsanthin and capsorubin is carried out. We first investigate systematically the theoretical method which provides the best results for beta-carotene by performing ab initio calculations at the HF/6-31G(d), SVWN/6-31G(d), PBE0/6-31G(d), BLYP/6-31G(d), B3LYP/6-31G(d), B3LYP/6-31G(d,p), B3LYP/6-311G(d), and B3LYP/6-311G(d,p) levels and by using previous theoretical results available in the literature obtained at the AM1 and BPW91/6-31G(d) levels. The influence of both the level of calculation and the size of the basis set used in the geometry optimization and in the determination of the IR and Raman spectra of this molecule is thus analyzed. It is confirmed that the hybrid functional B3LYP with the basis 6-31G(d) is the method that gives the best results as a whole. By use of this level of calculation, we next optimize the molecular geometries of related molecules of capsanthin and capsorubin, which to the best of our knowledge have only been studied at the semiempirical AM1 level. In addition we calculate the IR and Raman spectra of these molecules at the B3LYP/6-31G(d) level of theory. The results obtained for capsanthin show on the one hand that the double bond of the beta-ionone ring is outside the polyene chain plane, due to the repulsion between the hydrogen atoms of the ring methyl groups and the hydrogen atoms of the polyene chain, and on the other hand that the carbonyl double bond in the other headgroup is very close to planarity with the polyene chain, since in this case such a repulsion does not exist. For the molecule of capsorubin the two carbonyl groups also take the same coplanar orientation relative to the polyene chain. The IR and Raman spectra theoretically computed for these two molecules are finally compared with their experimental spectra and the vibrational normal modes of the main signals are interpreted.