Mild hypophosphatasia may be twice as prevalent as previously estimated: an effective clinical algorithm to detect undiagnosed cases.

OBJECTIVES: Since the prevalence of hypophosphatasia (HPP), a rare genetic disease, seems to be underestimated in clinical practice, in this study, a new diagnostic algorithm to identify missed cases of HPP was developed and implemented. METHODS: Analytical determinations recorded in the Clinical Analysis Unit of the Hospital Universitario Clínico San Cecilio in the period June 2018 - December 2020 were reviewed. A new clinical algorithm to detect HPP-misdiagnosed cases was used including the following steps: confirmation of persistent hypophosphatasemia, exclusion of secondary causes of hypophosphatasemia, determination of serum pyridoxal-5'-phosphate (PLP) and genetic study of ALPL gene. RESULTS: Twenty-four subjects were selected to participate in the study and genetic testing was carried out in 20 of them following clinical algorithm criteria. Eighty percent of patients was misdiagnosed with HPP following the current standard clinical practice. Extrapolating these results to the current Spanish population means that there could be up to 27,177 cases of undiagnosed HPP in Spain. In addition, we found a substantial proportion of HPP patients affected by other comorbidities, such as autoimmune diseases (∼40 %). CONCLUSIONS: This new algorithm was effective in detecting previously undiagnosed cases of HPP, which appears to be twice as prevalent as previously estimated for the European population. In the near future, our algorithm could be globally applied routinely in clinical practice to minimize the underdiagnosis of HPP. Additionally, some relevant findings, such as the high prevalence of autoimmune diseases in HPP-affected patients, should be investigated to better characterize this disorder.

Six hundred years of South American tree rings reveal an increase in severe hydroclimatic events since mid-20th century.

South American (SA) societies are highly vulnerable to droughts and pluvials, but lack of long-term climate observations severely limits our understanding of the global processes driving climatic variability in the region. The number and quality of SA climate-sensitive tree ring chronologies have significantly increased in recent decades, now providing a robust network of 286 records for characterizing hydroclimate variability since 1400 CE. We combine this network with a self-calibrated Palmer Drought Severity Index (scPDSI) dataset to derive the South American Drought Atlas (SADA) over the continent south of 12°S. The gridded annual reconstruction of austral summer scPDSI is the most spatially complete estimate of SA hydroclimate to date, and well matches past historical dry/wet events. Relating the SADA to the Australia-New Zealand Drought Atlas, sea surface temperatures and atmospheric pressure fields, we determine that the El Niño-Southern Oscillation (ENSO) and the Southern Annular Mode (SAM) are strongly associated with spatially extended droughts and pluvials over the SADA domain during the past several centuries. SADA also exhibits more extended severe droughts and extreme pluvials since the mid-20th century. Extensive droughts are consistent with the observed 20th-century trend toward positive SAM anomalies concomitant with the weakening of midlatitude Westerlies, while low-level moisture transport intensified by global warming has favored extreme rainfall across the subtropics. The SADA thus provides a long-term context for observed hydroclimatic changes and for 21st-century Intergovernmental Panel on Climate Change (IPCC) projections that suggest SA will experience more frequent/severe droughts and rainfall events as a consequence of increasing greenhouse gas emissions.

Evaluating the Effect of a Telepsychiatry Educational Program on the Awareness, Knowledge, Attitude, and Skills of Telepsychiatry Among Spanish Psychiatrists during COVID-19 Pandemic.

Introduction: The COVID-19 pandemic has renewed the interest in telepsychiatry as a way to help psychiatrists care for their patients, but mental health providers' unfamiliarity and concerns may impede implementation of such services. This study aimed to determine the effect of an online educational intervention on awareness, knowledge, attitude, and skills (AKAS) of telepsychiatry among psychiatrists. Methods: The study used a pre-post-test design to compare AKAS of telepsychiatry among psychiatrists participating in an online course of practical telepsychiatry. The telemedicine AKAS questionnaire adapted to telepsychiatry was applied before and after the educational intervention, during the months of October to December 2020. Results: Responses from 213 participants were analyzed before the educational intervention and from 152 after it. The knowledge showed by Spanish psychiatrists before the educational intervention was good in 61% of participants, fair in 37%, and inadequate in 2%. With respect to attitudes toward telepsychiatry, 62% self-reported a high attitude, 33% moderate, and 5% low. With regard self-reported skills, 57% of the participating psychiatrists were highly skilled or experts, 22% moderately skilled, and 9% unskilled in handling telepsychiatry equipment. Despite the high baseline values, the educational intervention significantly improved psychiatrists' awareness, knowledge and attitudes toward telepsychiatry although not their skills. Conclusions: Online course of practical telepsychiatry was effective although future editions need to improve its focus on skills. This educational intervention represents an effort to promote the implementation of telepsychiatry as a health care alternative.

Identification of hereditary breast and ovarian cancer germline variants in Granada (Spain): NGS perspective.

The aim of this study was to assess the prevalence of germline variants in cancer-predisposing genes by either targeted (BRCA1/2) or multigene NGS panel in a high-risk Hereditary Breast and Ovarian Cancer (HBOC) cohort. Samples from 824 Caucasian probands were retrospectively collected and the impact of genetic diagnosis and genetic variants epidemiology in this cohort was evaluated. Performance of risk-reducing prophylactic measures, such as prophylactic mastectomy and/or prophylactic oophorectomy, was assessed through clinical follow-up of patients with a positive genetic result. Pathogenic variants predisposing to HBOC were identified in 11.9% (98/824) individuals at BRCA2 (47/98), BRCA1 (24/98), PALB2 (8/51), ATM (7/51), CHEK2 (6/51) MSH6, (2/51), RAD51C (2/51) and TP53 (2/386). Of them, 11 novel pathogenic variants and 12 VUS were identified, characterized, and submitted to ClinVar. Regarding clinical impact, the risk of developing basal or Her2 breast cancer was increased 15.7 times or 37.5 times for BRCA1 and MSH6 pathogenic variants respectively. On the contrary, the risk of developing basal or luminal A breast cancer was reduced to 81% or 77% for BRCA2 and BRCA1 pathogenic variants, respectively. Finally, 53.2% of individuals testing positive for class IV/V variants underwent prophylactic surgery (mastectomy, oophorectomy or both) being significantly younger at the cancer diagnosis than those undertaking prophylactic measures (p = 0.008). Of them, 8 carried a pathogenic/likely pathogenic variant in other genes different from BRCA1 and BRCA2, and the remaining (46.7%) decided to continue with clinical follow-up. No differences in pathogenicity or risk of developing cancer were found for BRCA1/2 between targeted and multigene sequencing strategies; however, NGS was able to resolve a greater proportion of high-risk patients.

Hypophosphatasia: A Unique Disorder of Bone Mineralization.

Hypophosphatasia (HPP) is a rare genetic disease characterized by a decrease in the activity of tissue non-specific alkaline phosphatase (TNSALP). TNSALP is encoded by the ALPL gene, which is abundantly expressed in the skeleton, liver, kidney, and developing teeth. HPP exhibits high clinical variability largely due to the high allelic heterogeneity of the ALPL gene. HPP is characterized by multisystemic complications, although the most common clinical manifestations are those that occur in the skeleton, muscles, and teeth. These complications are mainly due to the accumulation of inorganic pyrophosphate (PPi) and pyridoxal-5'-phosphate (PLP). It has been observed that the prevalence of mild forms of the disease is more than 40 times the prevalence of severe forms. Patients with HPP present at least one mutation in the ALPL gene. However, it is known that there are other causes that lead to decreased alkaline phosphatase (ALP) levels without mutations in the ALPL gene. Although the phenotype can be correlated with the genotype in HPP, the prediction of the phenotype from the genotype cannot be made with complete certainty. The availability of a specific enzyme replacement therapy for HPP undoubtedly represents an advance in therapeutic strategy, especially in severe forms of the disease in pediatric patients.

[Prolonged initial empirical antibiotic treatment and the risk of morbidity and mortality in very low birthweight infants]. / Tratamiento antibiótico empírico inicial prolongado y riesgo de morbimortalidad en recién nacidos de muy bajo peso al nacer.

INTRODUCTION: The objective of this study is to evaluate the association between the duration of ini tial empirical antibiotic treatment and the subsequent development of late-onset sepsis, necrotizing enterocolitis (NEC) and death in very low birth weight (VLBW) infants. PATIENTS AND METHODS: Quantitative, cross-sectional, analytical study of VLBW infants admitted to the neonatal ICU were included over a period of five years. Initial empirical antibiotic therapy was that which started immediately after birth, without knowing the results of blood cultures. It was considered prolonged antibiotic therapy when the treatment duration was > 5 days. Perinatal variables, as well as the inci dence of late-onset sepsis, confirmed NEC and mortality were analyzed. RESULTS: 266 VLBW infants were studied, with an average gestational age and birth weight of 28.8 ± 2.5 weeks and 1.127 ± 264 g respectively. 213 infants received initial empiric antibiotic therapy (80.0%), which was prolonged in 67.6% of cases. All infants received two different antibiotics. 136 episodes of late-onset sepsis were described. The most common pathogens were coagulase-negative Staphylococcus and Staphylococcus aureus. Among the newborns with prolonged antibiotic therapy, there were 20 cases of confirmed NEC and 15 of the studied infants died (10.4%). When comparing the use of antibiotic therapy during > 5 days versus treatment less than 5 days duration, a statistically significant association was observed between prolonged antibiotic therapy and late-onset sepsis (p = 0.03) and confirmed NEC (p = 0.03), but not of mortality (p = 0.12). CONCLUSION: The use of empirical antibiotic therapy for five days or more was associated with an increased risk of late-onset sepsis and NEC, but not of mortality in VLBW infants.

Urine Calcium and Bone Mineral Density in Calcium Stone-Forming Patients Treated with Alendronate and Hydrochlorothiazide.

INTRODUCTION: The objective was to evaluate the effect of hydrochlorothiazide and alendronate on urine calcium and bone mineral density in calcium stone-forming patients. MATERIAL AND METHODS: A prospective, non-randomized, non-observational comparative study was performed; this study included 111 patients with recurrent calcium stones, divided into 3 groups according to the treatment received. Group 1: 36 patients were treated with alendronate, 70 mg/week; Group 2: 34 patients were treated with alendronate, 70 mg/week + hydrochlorothiazide, 50 mg/day; Group 3: 41 patients were treated with hydrochlorothiazide, 50 mg/day. All patients received recommendations on diet and fluid intake. Other variables of bone mineral density were studied and analyzed, including bone remodeling markers and urinary calcium before and after 2 years of treatment. The statistical analysis was performed using the SPSS 17.0 program, with a statistical significance of p < 0.05. RESULTS: After 2 years of treatment, a significant difference was observed in the ß-crosslaps and a bone mineral density improvement in Group 1, along with a decrease in urinary calcium. In Group 3, a statistically significant difference was found in urinary calcium and fasting calcium/creatinine ratio, as well as an improvement in bone mineral density after 2 years of medical treatment. In Group 2 patients treated with the combination, there was an improvement in bone mineral density and a decrease in the ß-crosslaps marker similar to patients in Group 1, and a decrease in urinary calcium similar to those in Group 3. CONCLUSION: Combined alendronate + hydrochlorothiazide treatment offers the best results along with the improvement in bone mineral density and decrease in urine calcium in patients with recurrent calcium stones.

Oral propranolol in early stages of retinopathy of prematurity.

OBJECTIVE: To assess the effect of oral propranolol on the progression of early stages of retinopathy of prematurity (ROP) in very low birth weight (VLBW) infants. METHODS: We analyzed VLBW infants with ROP (stages 2-3, zones II-III). Newborns received oral propranolol (0.5 mg/kg/dose q8h), and were monitored throughout the treatment period for possible side effects. Propranolol was administered until regression of ROP. A historic control group of patients with equivalent ROP was used. We compared characteristics of both groups and the progression of retinopathy. RESULTS: Forty-seven newborns were included, 20 in the propranolol group and 27 in the control group. There were no significant differences in gestational age, birthweight or gender. The mean duration of treatment with propranolol was 58.2±17.6 days. Most patients started treatment with stage 2 disease (65.0%), and had zone III involvement (55.0%). In the treated group, 90.0% (18/20) of patients did not require intervention with laser or bevacizumab, compared to 51.8% in the control group (P<0.005). No cases of bradycardia, hypotension or hypoglycemia were observed. CONCLUSIONS: Oral propranolol in early stages of ROP could prevent disease progression and reduce the need for invasive rescue therapy with laser or bevacizumab. No significant side effects were reported.

Randomized Trial of Clarithromycin for Mediterranean Spotted Fever.

The classic antibiotic treatment for Mediterranean spotted fever (MSF) is based on tetracyclines or chloramphenicol, but chloramphenicol's bone marrow toxicity makes tetracyclines the treatment of choice. However, it is convenient to have alternatives available for patients who are allergic to tetracyclines, pregnant women, and children <8 years old. We conducted a randomized clinical trial to compare clarithromycin with doxycycline or josamycin in the treatment of MSF. Forty patients were evaluated (23 male; mean age, 39.87 years); 13 patients were aged <14 years. Seventeen patients received clarithromycin, and 23 received doxycycline or josamycin. The interval between the onset of symptoms and the start of treatment was 4.04 ± 1.70 days in the clarithromycin group versus 4.11 ± 1.60 days in the doxycycline/josamycin group (P = not significant [NS]). Time to the disappearance of fever after treatment was 2.67 ± 1.55 days in the clarithromycin group versus 2.22 ± 1.35 days in the doxycycline/josamycin (P = NS). The symptoms had disappeared at 4.70 ± 2.25 days in the clarithromycin group versus at 4.75 ± 3.08 days in the doxycycline/josamycin (P = NS). There were no adverse reactions to treatment or relapses in either group. In conclusion, clarithromycin is a good alternative to doxycycline or josamycin in the treatment of MSF.

Quantitative-fluorescent-PCR versus full karyotyping in prenatal diagnosis of common chromosome aneuploidies in southern Spain.

BACKGROUND: Quantitative-fluorescent polymerase chain reaction (QF-PCR) is a reliable, rapid, and economic technique for prenatal diagnosis of the most common abnormalities. However, conventional karyotyping is expensive and requires a much longer time to yield results. It is currently under debate whether the replacement or restriction of karyotyping reduces the quality of prenatal test results. This study was undertaken to determine the percentage of clinically significant chromosomal abnormalities that would not be detected if QF-PCR was the main analysis method and karyotyping reserved for cases with increased nuchal translucency (NT) and/or abnormal ultrasound findings and to estimate the difference in cost between QF-PCR and full karyotyping. METHODS: Nine hundred twenty-eight pregnant women underwent an invasive procedure at our center between May 2009 and December 2012, yielding 580 (62.5%) chorionic villous samples and 348 (37.5%) amniotic fluid samples. Samples were studied by both QF-PCR and full karyotyping. Karyotyping and detailed ultrasound findings were retrospectively analyzed. RESULTS: If QF-PCR was the main analytic method and full karyotyping reserved for cases with elevated NT (≥4.5) and/or abnormal ultrasound findings, 12.7% of the patients would have required full karyotyping, 99% of the clinically significant chromosomal abnormalities would have been detected, and the cost would have been 54% lower than a policy of full karyotyping for all. CONCLUSIONS: Detailed prenatal ultrasound scan can reduce the need for conventional karyotyping as a complement to QF-PCR in most prenatal samples, offering rapid results and reducing parental anxiety and healthcare costs.

Accidental implant screwdriver aspiration: A case series report with literature review and proposed action protocol.

This article presents the first reported case series of three cases of aspiration of a dental implant screwdriver, which was successfully removed by flexible bronchoscopy. The report highlights preventive measures that can be taken in the dental office and the clinical signs and symptoms of the presence of a dental implant screwdriver in the bronchial tree. The nine reports published to date on this phenomenon are reviewed and compared, and an action protocol for dental practitioners, anaesthetists and pulmonologists is proposed to address this emergency. Some early and late complications are also described.

Telerehabilitation as a Therapeutic Exercise Tool versus Face-to-Face Physiotherapy: A Systematic Review.

Digital physiotherapy, often referred to as "Telerehabilitation", consists of applying rehabilitation using telecommunication technologies. The objective is to evaluate the effectiveness of therapeutic exercise when it is telematically prescribed. METHODS: We searched PubMed, Embase, Scopus, SportDiscus and PEDro (30 December 2022). The results were obtained by entering a combination of MeSH or Emtree terms with keywords related to telerehabilitation and exercise therapy. RCTs on patients over 18 years and two groups were included, one working with therapeutic exercise through telerehabilitation and one working with conventional physiotherapy group. RESULTS: a total of 779 works were found. However, after applying the inclusion criteria, only 11 were selected. Telerehabilitation is most frequently used to treat musculoskeletal, cardiac and neurological pathologies. The preferred telerehabilitation tools are videoconferencing systems, telemonitoring and online platforms. Exercise programs ranged from 10 to 30 min and were similar in both intervention and control groups. In all the studies, results proved to be similar for telerehabilitation and face-to-face rehabilitation in both groups when measuring functionality, quality of life and satisfaction. CONCLUSION: this review generally concludes that intervention through telerehabilitation programs is as feasible and efficient as conventional physiotherapy in terms of functionality level and quality of life. In addition, telerehabilitation shows high levels of patients' satisfaction and adherence, being values equivalent to traditional rehabilitation.

Clinical relevance of timing of assessment of ICU mortality in patients with moderate-to-severe Acute Respiratory Distress Syndrome.

Mortality is a frequently reported outcome in clinical studies of acute respiratory distress syndrome (ARDS). However, timing of mortality assessment has not been well characterized. We aimed to identify a crossing-point between cumulative survival and death in the intensive care unit (ICU) of patients with moderate-to-severe ARDS, beyond which the number of survivors would exceed the number of deaths. We hypothesized that this intersection would occur earlier in a successful clinical trial vs. observational studies of moderate/severe ARDS and predict treatment response. We conducted an ancillary study of 1580 patients with moderate-to-severe ARDS managed with lung-protective ventilation to assess the relevance and timing of measuring ICU mortality rates at different time-points during ICU stay. First, we analyzed 1303 patients from four multicenter, observational cohorts enrolling consecutive patients with moderate/severe ARDS. We assessed cumulative ICU survival from the time of moderate/severe ARDS diagnosis to ventilatory support discontinuation within 7-days, 28-days, 60-days, and at ICU discharge. Then, we compared these findings to those of a successful randomized trial of 277 moderate/severe ARDS patients. In the observational cohorts, ICU mortality (487/1303, 37.4%) and 28-day mortality (425/1102, 38.6%) were similar (p = 0.549). Cumulative proportion of ICU survivors and non-survivors crossed at day-7; after day-7, the number of ICU survivors was progressively higher compared to non-survivors. Measures of oxygenation, lung mechanics, and severity scores were different between survivors and non-survivors at each point-in-time (p < 0.001). In the trial cohort, the cumulative proportion of survivors and non-survivors in the treatment group crossed before day-3 after diagnosis of moderate/severe ARDS. In clinical ARDS studies, 28-day mortality closely approximates and may be used as a surrogate for ICU mortality. For patients with moderate-to-severe ARDS, ICU mortality assessment within the first week of a trial might be an early predictor of treatment response.

Telepsychiatry: The future is already present.

This review paper analyzes the state of knowledge on Telepsychiatry (TP) after the crisis caused by COVID and the resulting need to use new modalities of care. Six essential aspects of TP are addressed: patient's and mental health staff satisfaction, diagnostic reliability, effectiveness of TP interventions, cost-effectiveness in terms of opportunity cost (or efficiency), legal aspects inherent to confidentiality and privacy in particular and the attitude of professionals toward TP. Satisfaction with TP is acceptable among both patients and professionals, the latter being the most reluctant. Diagnostic reliability has been demonstrated, but requires further studies to confirm this reliability in different diagnoses and healthcare settings. The efficacy of TP treatments is not inferior to face-to-face care, as has been proven in specific psychotherapies. Finally, it should be noted that the attitude of the psychiatrist is the most decisive element that limits or facilitates the implementation of TP.

References Values of Soluble α-Klotho Serum Levels Using an Enzyme-Linked Immunosorbent Assay in Healthy Adults Aged 18-85 Years.

α-Klotho protein is a powerful predictor of the aging process and lifespan. Although lowered circulating soluble α-Klotho levels have been observed in aged non-healthy individuals, no specific reference values across a wide range of ages and sex using an enzyme-linked immunosorbent assay (ELISA) are available for larger cohorts of healthy individuals. The present analytical cross-sectional study was aimed to establish the reference values of soluble α-Klotho serum levels in healthy adults by age and sex groups. A total of 346 (59% women) healthy individuals aged from 18 to 85 years were recruited. Subjects were divided by sex and age as: (i) young (18−34.9 years), (ii) middle-aged (35−54.9 years), and (iii) senior (55−85 years) individuals. The soluble α-Klotho levels were measured in serum using ELISA. Senior adults were the age-group that presented the lowest soluble α-Klotho serum levels (p < 0.01), with age showing a negative association with soluble α-Klotho serum levels (p < 0.001). No differences between sexes were observed. Therefore, soluble α-Klotho levels were especially decreased­regardless of sex­in our cohort of healthy individuals because of the physiological decline derived from the aging process. We recommend routine assessments of soluble α-Klotho levels using ELISA as a simple and cheap detectable marker of aging that improves quality of life in the elderly.

Mineral density and bone remodelling markers in patients with calcium lithiasis.

UNLABELLED: What's known on the subject? and What does the study add? Hypercalciuria is related with bone mineral density loss. This study demonstrates the relationship between recurrent calcium nephrolithiasis and bone mineral density loss and their correlation with bone markers. OBJECTIVES: • To show that a relationship exists between the loss of bone mineral density (BMD) and calcium renal lithiasis and that bone remodelling markers correlate with changes in BMD. • It is possible that many cases hypercalciuria are related to the increase of bone turnover and the predominance of bone resorption phenomena. PATIENTS AND METHODS: • The present study comprised a transversal investigation in three groups: group O, without lithiasis; group A, with a single episode of lithiasis; and group B, with relapsed calcium renal lithiasis. • An analysis was made of body mass index; abdominal X-ray and/or urography and renal ultrasonography; osteocalcin and ß-crosslaps bone markers; calcium and citrate concentrations in the urine; and femur and spinal column bone densitometry. • The results were analyzed by analysis of variance and Pearson's correlation coefficient. RESULTS: • Patients with relapsed calcium renal lithiasis present a greater BMD loss than those in the O or A groups. • Densitometry: T-score femur -0.2 group O, -0.5 group A, -1.2 group B (P= 0.001); T-score column -0.6 group O, -0.6 group A, -1.3 group B (P= 0.05). • A statistically significant negative correlation exists between values of ß-crosslaps and T-score femur (R=-0.251; P= 0.009) and T-score column (R=-0.324; P= 0.001); thus, a higher concentration of ß-crosslaps was accompanied by a lower value of the T-score and a greater loss of BMD. • A positive relationship is observed between ß-crosslaps and osteocalcin (R= 0.611; P < 0.001) and between calciuria and cocient ß-crosslaps/osteocalcin (R= 0.303; P= 0.001). CONCLUSIONS: • A statistically significant relationship is shown between the loss of BMD and relapsed calcium renal lithiasis. • Determination of bone remodelling markers (i.e. osteocalcin and ß-crosslaps) facilitates the diagnosis of osteopaenia/osteoporosis in these patients.

Racial Differences in Functional and Sleep Outcomes with Positive Airway Pressure Treatment.

It is unclear if the response to positive airway pressure (PAP) treatment is different between African American (AA) and European Americans (EA). We examined whether race modifies the effects of PAP on sleep and daytime function. We assessed Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire, Psychomotor Vigilance Task and actigraphy in 185 participants with moderate-to-severe obstructive sleep apnea before and 3-4 months after PAP treatment. The participants were middle-aged (mean, 55.1 years), 83.8% men and 60.5% AA. Linear regression models were used to examine the effect of race on outcomes. The AA had smaller reductions in ESS (mean change (95% confidence interval, CI) AA, -2.30 [-3.35, -1.25] vs. EA, -4.16 [-5.48, -2.84] and frequency of awakenings (AA, -0.73 [-4.92, 3.47] vs. EA, -9.35 [-15.20, -3.51]). A race × PAP usage interaction term was added to the model to examine if the change in outcomes per 1 h increase in PAP usage differed by race. AA exhibited greater improvement in wake after sleep onset (ß (95% CI) AA, -8.89 [-16.40, -1.37] vs. EA, 2.49 [-4.15, 9.12]) and frequency of awakening (ß (95% CI) AA, -2.59 [-4.44, -0.75] vs. EA, 1.71 [-1.08, 4.50]). The results indicate the importance of race in evaluating outcomes following PAP treatment.

HLC Pair Suppression as a Risk Factor for Bacterial Bloodstream Infections and Early Mortality in Newly Diagnosed Intact Immunoglobulin Multiple Myeloma Patients.

Despite the outstanding progresses in Multiple Myeloma treatment options in the last decades, it remains an incurable disease nowadays. Infectious events are a complication due to an impaired immune system associated with MM, sometimes a life-threatening one, particularly on the first months after the diagnosis. Both the underlying disease and treatment can contribute to the infection risk, so a biomarker that assess this risk could be highly relevant for a more tailored management of the patient. The measurement of the heavy+light chain (HLC) pairs of immunoglobulins in serum allows the quantification of both the monoclonal component and the non-monoclonal immunoglobulin of the same isotype. This approach has demonstrated high sensitivity for the detection of the clonality and prognostic value for MM. HLC pair suppression itself has prognostic power and it has been proposed to be a reflection of the immune system' attempt to control the tumor. In this study we evaluated the impact of the HLC pair suppression on the rate of bloodstream infections (BSI) and early death in 115 newly diagnosed MM patients. Twenty-one percent of the patients suffered a BSI in the first 6 months after diagnosis, of which 58% died within this period, accounting to 67% of the early deaths in global and highlighting the major impact of infections on MM patients in a "real world" setting. Severe HLC pair suppression identified patients with a higher risk of early BSI (HR: 6,97, p=0,009), and extreme HLC pair suppression together with BSI event and age >65 were independent risk factors for early death (p<0,001). Based on these factors, a stratification model was generated to allow identify patients at a higher risk of early death and poorer OS, with an apparently better performance than the ISS on the early death context. In conclusion, HLC pair suppression associates with both a higher risk of life-threatening early infection and early death in newly diagnosed MM patients. Patients older than 65 with extreme HLC pair suppression and BSI are at a high risk of early death, and thus patients presenting with these criteria have a very adverse prognosis.

Efficacy of dexamethasone treatment for patients with the acute respiratory distress syndrome caused by COVID-19: study protocol for a randomized controlled superiority trial.

BACKGROUND: There are no specific generally accepted therapies for the coronavirus disease 2019 (COVID-19). The full spectrum of COVID-19 ranges from asymptomatic disease to mild respiratory tract illness to severe pneumonia, acute respiratory distress syndrome (ARDS), multisystem organ failure, and death. The efficacy of corticosteroids in viral ARDS remains unknown. We postulated that adjunctive treatment of established ARDS caused by COVID-19 with intravenous dexamethasone might change the pulmonary and systemic inflammatory response and thereby reduce morbidity, leading to a decrease in duration of mechanical ventilation and in mortality. METHODS/DESIGN: This is a multicenter, randomized, controlled, parallel, open-label, superiority trial testing dexamethasone in 200 mechanically ventilated adult patients with established moderate-to-severe ARDS caused by confirmed SARS-CoV-2 infection. Established ARDS is defined as maintaining a PaO2/FiO2 ≤ 200 mmHg on PEEP ≥ 10 cmH2O and FiO2 ≥ 0.5 after 12 ± 3 h of routine intensive care. Eligible patients will be randomly assigned to receive either dexamethasone plus standard intensive care or standard intensive care alone. Patients in the dexamethasone group will receive an intravenous dose of 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10. The primary outcome is 60-day mortality. The secondary outcome is the number of ventilator-free days, defined as days alive and free from mechanical ventilation at day 28 after randomization. All analyses will be done according to the intention-to-treat principle. DISCUSSION: This study will assess the role of dexamethasone in patients with established moderate-to-severe ARDS caused by SARS-CoV-2. TRIAL REGISTRATION: ClinicalTrials.gov NCT04325061 . Registered on 25 March 2020 as DEXA-COVID19.