Neomycin Interferes with Phosphatidylinositol-4,5-Bisphosphate at the Yeast Plasma Membrane and Activates the Cell Wall Integrity Pathway.

The cell wall integrity pathway (CWI) is a MAPK-mediated signaling route essential for yeast cell response to cell wall damage, regulating distinct aspects of fungal physiology. We have recently proven that the incorporation of a genetic circuit that operates as a signal amplifier into this pathway allows for the identification of novel elements involved in CWI signaling. Here, we show that the strong growth inhibition triggered by pathway hyperactivation in cells carrying the "Integrity Pathway Activation Circuit" (IPAC) also allows the easy identification of new stimuli. By using the IPAC, we have found various chemical agents that activate the CWI pathway, including the aminoglycoside neomycin. Cells lacking key components of this pathway are sensitive to this antibiotic, due to the disruption of signaling upon neomycin stimulation. Neomycin reduces both phosphatidylinositol-4,5-bisphosphate (PIP2) availability at the plasma membrane and myriocin-induced TORC2-dependent Ypk1 phosphorylation, suggesting a strong interference with plasma membrane homeostasis, specifically with PIP2. The neomycin-induced transcriptional profile involves not only genes related to stress and cell wall biogenesis, but also to amino acid metabolism, reflecting the action of this antibiotic on the yeast ribosome.

Manganese Stress Tolerance Depends on Yap1 and Stress-Activated MAP Kinases.

Understanding which intracellular signaling pathways are activated by manganese stress is crucial to decipher how metal overload compromise cellular integrity. Here, we unveil a role for oxidative and cell wall stress signaling in the response to manganese stress in yeast. We find that the oxidative stress transcription factor Yap1 protects cells against manganese toxicity. Conversely, extracellular manganese addition causes a rapid decay in Yap1 protein levels. In addition, manganese stress activates the MAPKs Hog1 and Slt2 (Mpk1) and leads to an up-regulation of the Slt2 downstream transcription factor target Rlm1. Importantly, Yap1 and Slt2 are both required to protect cells from oxidative stress in mutants impaired in manganese detoxification. Under such circumstances, Slt2 activation is enhanced upon Yap1 depletion suggesting an interplay between different stress signaling nodes to optimize cellular stress responses and manganese tolerance.

What is the value of repeat kidney biopsies in patients with lupus nephritis?

INTRODUCTION: Recent studies with protocol biopsies have shown a mismatch between clinical and histological remission in lupus nephritis (LN). We aimed to evaluate histological changes in repeat kidney biopsies by clinical indication in patients with LN. METHODS: We analyzed 107 patients with LN in which a kidney biopsy was performed between 2008 and 2018. Of those, we included 26 (24.2%) who had ≥2 kidney biopsies. Classification was done according to the International Society of Nephrology/Renal Pathology Society. RESULTS: Mean time between biopsies was 71.5 ± 10.7 months. 73.1% of patients presented a change of class at repeat biopsy; 38.4% to a higher class and 34.6% to a lower class. A significant increase in glomerulosclerosis (% GS) (3.8% vs 18.7%, p = 0.006), interstitial fibrosis (3.8% vs 26.9%, p = 0.021), tubular atrophy (15.4% vs 57.7%, p = 0.001) and chronicity index (CI) (1 vs 3, p < 0.001) was observed at repeat biopsy. Subjects who developed chronic kidney disease progression had a lower rate of complete remission at 12 months (0% vs 37.5%, p = 0.02), higher % GS at first biopsy (7.9% vs 1.2%, p = 0.02) and higher CI (4 vs 2, p = 0.006), tubular atrophy (90% vs 37.6%, p = 0.008), interstitial fibrosis (50% vs 12.5%, p = 0.036) and vascular lesions (60% vs 18.8%, p = 0.031) at second biopsy. CONCLUSIONS: Our major finding was that patients with LN showed a significant increase in % GS, interstitial fibrosis, tubular atrophy and vascular lesions in repeat biopsies performed by clinical indication. This suggest that a second kidney biopsy may provide valuable and useful information regarding kidney disease progression.

Lack of changes in preterm delivery and stillbirths during COVID-19 lockdown in a European region.

Preliminary data in Europe have suggested a reduction in prematurity rates during the COVID-19 pandemic, implying that contingency measures could have an impact on prematurity rates. We designed a population-based prevalence proportion study to explore the potential link between national lockdown measures and a change in preterm births and stillbirths. Adjusted multivariate analyses did not show any decrease in preterm proportions during the lockdown period with respect to the whole prelockdown period or to the prelockdown comparison periods (2015-2019): 6.5% (95%CI 5.6-7.4), 6.6% (95%CI 6.5-6.8), and 6.2% (95%CI 5.7-6.7), respectively. Proportions of preterm live births did not change during lockdown when different gestational age categories were analyzed, nor when birthweight categories were considered. No differences in stillbirth rates among the different study periods were found: 0.33% (95%CI 0.04-0.61) during the lockdown period vs. 0.34% (95%CI 0.22-0.46) during the prelockdown comparison period (2015-2019).Conclusion: We did not find any link between prematurity and lockdown, nor between stillbirths and lockdown. Collaborative efforts are desirable to gather more data and additional evidence on this global health issue. What is Known: • Prematurity is associated with increased risk of morbidity and mortality. • Contingency measures during the COVID-19 pandemic may have an impact on reducing prematurity rates. What is New: • Prematurity and stillbirth rates remained stable in Castilla-y-León, a Spanish region, during COVID-19 lockdown. • The role of behavioral patterns and sociocultural factors in the prevention of preterm birth as a result of lockdown measures remains a subject for debate.

Not just the wall: the other ways to turn the yeast CWI pathway on.

The Saccharomyces cerevisiae cell wall integrity (CWI) pathway took this name when its role in the cell response to cell wall aggressions was clearly established. The receptors involved in sensing the damage, the relevant components operating in signaling to the MAPK Slt2, the transcription factors activated by this MAPK, as well as some key regulatory mechanisms have been identified and characterized along almost 30 years. However, other stimuli that do not alter specifically the yeast cell wall, including protein unfolding, low or high pH, or plasma membrane, oxidative and genotoxic stresses, have been also found to trigger the activation of this pathway. In this review, we compile almost forty non-cell wall-specific compounds or conditions, such as tunicamycin, hypo-osmotic shock, diamide, hydroxyurea, arsenate, and rapamycin, which induce these stresses. Relevant aspects of the CWI-mediated signaling in the response to these non-conventional pathway activators are discussed. The data presented here highlight the central and key position of the CWI pathway in the safeguard of yeast cells to a wide variety of external aggressions.

Waiting List and Kidney Transplant Vascular Risk: An Ongoing Unmet Concern.

BACKGROUND: Chronic kidney disease (CKD) is an important independent risk factor for adverse cardiovascular events in patients waitlisted for kidney transplantation (KT). Although KT reduces cardiovascular risk, these patients still have a higher all-cause and cardiovascular mortality than the general population. This concerning situation is due to a high burden of traditional and nontraditional risk factors as well as uremia-related factors and transplant-specific factors, leading to 2 differentiated processes under the framework of CKD, atherosclerosis and arteriosclerosis. These can be initiated by insults to the vascular endothelial endothelium, leading to vascular calcification (VC) of the tunica media or the tunica intima, which may coexist. Several pathogenic mechanisms such as inflammation-related endothelial dysfunction, mineral metabolism disorders, activation of the renin-angiotensin system, reduction of nitric oxide, lipid disorders, and the fibroblast growth factor 23-klotho axis are involved in the pathogenesis of atherosclerosis and arteriosclerosis, including VC. SUMMARY: This review focuses on the current understanding of atherosclerosis and arteriosclerosis, both in patients on the waiting list as well as in kidney transplant recipients, emphasizing the cardiovascular risk factors in both populations and the inflammation-related pathogenic mechanisms. Key Message: The importance of cardiovascular risk factors and the pathogenic mechanisms related to inflammation in patients waitlisted for KT and kidney transplant recipients.

A controlled study of the Collaborative Care Skills Workshops versus Psycho-educational Workshops among Spanish caregivers of relatives with an eating disorder.

The aim of this study was to test the hypothesis that a negative reaction to the illness would be reduced through the "Collaborative Care Skills Workshops" programme among Spanish caregivers of relatives with an eating disorder. Caregivers were randomly allocated to either the skill-based workshops (n = 32) or psycho-educational workshops (n = 31), and assessments were carried out over time (T0 vs. T1 vs. T2 ). There were no significant differences between interventions on primary or secondary caregiver outcomes or among the patients themselves. However, caregivers in both interventions showed greater improvement at T2 on accommodating and enabling behaviours and an improvement at T1 in terms of psychological distress and appraisals towards the caregiving experience. Eating pathology, psychological distress, and some indices of psychosocial adjustment were significantly lower among the patients following both interventions (T1 ). Overall, both interventions may be able to help caregivers and patients to decrease their psychological distress. HIGHLIGHTS: Involvement of family members in the treatment could be the best resource for aiding in their relative's recovery. This is the first controlled study to test the effectiveness of the Collaborative Care Skills Workshops in Spanish caregivers. Both interventions could be implemented as both help Spanish caregivers and patients.

Mortality in Elderly Waiting-List Patients Versus Age-Matched Kidney Transplant Recipients: Where is the Risk?

The number of elderly patients on the waiting list (WL) for kidney transplantation (KT) has risen significantly in recent years. Because KT offers a better survival than dialysis therapy, even in the elderly, candidates for KT should be selected carefully, particularly in older waitlisted patients. Identification of risk factors for death in WL patients and prediction of both perioperative risk and long-term post-transplant mortality are crucial for the proper allocation of organs and the clinical management of these patients in order to decrease mortality, both while on the WL and after KT. In this review, we examine the clinical results in studies concerning: a) risk factors for mortality in WL patients and KT recipients; 2) the benefits and risks of performing KT in the elderly, comparing survival between patients on the WL and KT recipients; and 3) clinical tools that should be used to assess the perioperative risk of mortality and predict long-term post-transplant survival. The acknowledgment of these concerns could contribute to better management of high-risk patients and prophylactic interventions to prolong survival in this particular population, provided a higher mortality is assumed.

Validity and Utility of the Patient Health Questionnaire (PHQ)-2 and PHQ-9 for Screening and Diagnosis of Depression in Rural Chiapas, Mexico: A Cross-Sectional Study.

BACKGROUND: Depressive disorders are frequently under diagnosed in resource-limited settings because of lack of access to mental health care or the inability of healthcare providers to recognize them. The Patient Health Questionnaire (PHQ)-2 and the PHQ-9 have been widely used for screening and diagnosis of depression in primary care settings; however, the validity of their use in rural, Spanish-speaking populations is unknown. METHOD: We used a cross-sectional design to assess the psychometric properties of the PHQ-9 for depression diagnosis and estimated the sensitivity and specificity of the PHQ-2 for depression screening. Data were collected from 223 adults in a rural community of Chiapas, Mexico, using the PHQ-2, the PHQ-9, and the World Health Organization Quality of Life BREF Scale (WHOQOL- BREF). RESULTS: Confirmatory factor analysis suggested that the 1-factor structure fit reasonably well. The internal consistency of the PHQ-9 was good (Cronbach's alpha > = 0.8) overall and for subgroups defined by gender, literacy, and age. The PHQ-9 demonstrated good predictive validity: Participants with a PHQ-9 diagnosis of depression had lower quality of life scores on the overall WHOQOL-BREF Scale and each of its domains. Using the PHQ-9 results as a gold standard, the optimal PHQ-2 cutoff score for screening of depression was 3 (sensitivity 80.00%, specificity 86.88%, area under receiver operating characteristic curve = 0.89; 95% confidence interval [0.84, 0.94]). CONCLUSION: The PHQ-2 and PHQ-9 demonstrated good psychometric properties, suggesting their potential benefit as tools for depression screening and diagnosis in rural, Spanish-speaking populations.

Isolated Fourth Nerve Palsy in Tuberculous Meningitis.

Tuberculous meningitis is a type of subacute meningitis and like other intracranial processes can compromise ocular motor nerves, causing palsies. Trochlear nerve is an unusual isolated manifestation in this type of pathology. The authors report a 5-year-old boy presented in their clinic with a trochlear nerve palsy as unique neurological manifestation of tuberculous meningitis. Treatment with complete anti-tuberculous therapy and botulinum A toxin was needed to get the complete resolution of the nerve palsy. In tuberculous meningitis, the presence of high protein levels and higher number of cells in cerebrospinal fluid is associated with cranial nerve involvement. Usually cranial nerve palsies occur in combination. VI cranial nerve alone or a combined disorder of VI and III cranial nerves are the palsies most frequently presented. Much less common is an isolated disorder of IV cranial nerve in the course of meningitis. The length of full treatment with anti-tuberculous therapy in this case was of 1 year. The persistence of palsy 1 month after the beginning of the symptoms indicated the possibility of a botulinum toxin injection with complete resolution of the process without disability, ocular motility has remained normal on follow-up.

A cognitive map for value-guided choice in ventromedial prefrontal cortex.

The prefrontal cortex is crucial for economic decision-making and representing the value of options. However, how such representations facilitate flexible decisions remains unknown. We reframe economic decision-making in prefrontal cortex in line with representations of structure within the medial temporal lobe because such cognitive map representations are known to facilitate flexible behaviour. Specifically, we framed choice between different options as a navigation process in value space. Here we show that choices in a 2D value space defined by reward magnitude and probability were represented with a grid-like code, analogous to that found in spatial navigation. The grid-like code was present in ventromedial prefrontal cortex (vmPFC) local field potential theta frequency and the result replicated in an independent dataset. Neurons in vmPFC similarly contained a grid-like code, in addition to encoding the linear value of the chosen option. Importantly, both signals were modulated by theta frequency - occurring at theta troughs but on separate theta cycles. Furthermore, we found sharp-wave ripples - a key neural signature of planning and flexible behaviour - in vmPFC, which were modulated by accuracy and reward. These results demonstrate that multiple cognitive map-like computations are deployed in vmPFC during economic decision-making, suggesting a new framework for the implementation of choice in prefrontal cortex.

Effects of cranioplasty in cerebral blood perfusion using quantification with 99m-Tc HMPAO SPECT-CT.

BACKGROUND AND PURPOSE: Syndrome of the trephined or sinking skin flap syndrome is an underdiagnosed condition of craniectomized patients that usually improves after cranioplasty. Among the pathophysiological theories proposed, the changes of cerebral blood perfusion (CBP) caused by cranial defects might have a role in the neurological deficiencies observed. We aim to assess the regional cortex changes in CBP after cranioplasty with Technetium 99m hexamethylpropylene-amine oxime (99mTc-HMPAO) SPECT-CT. METHODS: Twenty-eight craniectomized patients subject to cranioplasty were studied with 99mTc-HMPAO SPECT-CT in three different times, before cranioplasty, a week, and 3 months after. The images were processed with quantification software comparing CBP of 24 cortical areas with a reference area, and with a database of controls. A mixed effects model and T-Student were used. RESULTS: CBP increased significantly in both hemispheres after cranioplasty, either using ratio (ß = .019, p-value = .030 first postsurgical SPECT-CT and ß = .021, p-value = .015 in the second study, vs. presurgical) or Z-score (ß = .220, p-value = .026 and ß = .279, p-value = .005, respectively). Nine areas of the damaged side had a significant lower CBP ratio and Z-score than the undamaged. Posterior cingulate showed an increased CBP ratio (p-value = .034) and Z-score (p-value = .028) in the first postsurgical SPECT-CT. These posterior cingulate changes represent a 4.83% increase in ratio and 91.04% in Z-Score (p-value = .035 and .040, respectively). CONCLUSION: CBP changes significantly in specific cortical areas after cranioplasty. Posterior cingulate changes might explain some improvements in attention impairments. SPECT-CT could be a useful tool to assess CBP changes in these patients and might be helpful in their clinical management.

[Indicadores de salud perinatal en una región española entre los años 2015 y 2020.] / Perinatal health indicators in a region of Spain corresponding to the period 2015 to 2020.

OBJECTIVE: The availability in the literature of data related to perinatal variables in the Spanish population is very scarce. The aim of this study was to know the evolution of perinatal health indicators according to the risk groups of prematurity and birth weight, the proportion of multiple births, caesarean section and stillbirths. METHODS: We conducted a population-based cross-sectional study of births in eleven hospitals in Castilla y León (January 2015 to June 2020). There were 70,024 newborns from 68,769 deliveries. Jointpoint regression analysis was used to identify changes in trend over the years, and binomial logistic regression was used to adjust for the potential interaction of hospital type, sex, type of delivery and multiple births on the frequencies of prematurity and death. RESULTS: There was a 19.9% decrease in deliveries and a 42% decrease in multiple births, with no change in preterm (7.7%) and stillbirths (0.44%). The percentage of caesarean sections was 21.5% with a slight downward trend over time. Death (stillbirth) was associated with preterm multiple birth; especially with the male-male combination (p<0.05). Late preterm and early term newborns showed higher risk of death compared to term newborns: OR 7.7 (95%CI 5.6-10.7) and 2.4 (95%CI 1.6-3.6), respectively; as well as the low birth weight group (OR 17.6; 95%CI 13.9-22.2) and small for gestational age (OR 3.4; 95%CI 1.9-5.8), compared to those of adequate weight. CONCLUSIONS: Prior to the development of the COVID-19 pandemic there is a decline in births, including multiple births, with no change in stillbirths or prematurity. Late preterm and early term newborns are at increased risk of intrauterine death.

OBJETIVO: La disponibilidad en la literatura de datos relacionados con variables perinatales en la población española son muy escasos. El objetivo de este estudio fue conocer la evolución de los indicadores de salud perinatal atendiendo a los grupos de riesgo de prematuridad y de peso al nacimiento, la proporción de parto múltiple, de cesárea y de mortinatos. METODOS: Se realizó un estudio transversal poblacional de los partos en once hospitales de Castilla y León (enero de 2015 a junio de 2020). Hubo 70.024 recién nacidos (RN) procedentes de 68.769 partos. Se utilizó el análisis de regresión Jointpoint para identificar cambios en la tendencia a lo largo de los años, y la regresión logística binomial para ajustar la potencial interacción del tipo de hospital, el sexo, el tipo de parto y el parto múltiple en las frecuencias de prematuridad y de fallecimiento. RESULTADOS: Hubo un descenso de partos del 19,9% y de los múltiples del 42%, sin cambios en los RN prematuros (7,7%) ni en los mortinatos (0,44%). El porcentaje de cesáreas fue del 21,5% con una ligera tendencia temporal descendente. El fallecimiento (mortinato) se asoció al parto múltiple pretérmino; especialmente a la combinación varón-varón (p<0,05). Los RN pretérminos tardíos y términos precoces mostraron mayor riesgo de fallecer frente a los RN a término: OR 7,7 (IC95% 5,6-10,7) y 2,4 (IC95% 1,6-3,6), respectivamente; así como el grupo de bajo peso (OR 17,6; IC95% 13,9-22,2) y el pequeño para la edad gestacional (OR 3,4; IC95% 1,9-5,8), frente a los de peso adecuado. CONCLUSIONES: Previo al desarrollo de la pandemia por COVID-19 existe un descenso de la natalidad, incluidos los partos múltiples, sin cambios en los mortinatos ni en la prematuridad. Los RN pretérminos tardío y términos precoces tienen mayor riesgo de fallecer intraútero.

Spontaneous remission of nephrotic syndrome in membranous nephropathy with chronic renal impairment.

BACKGROUND: Spontaneous remission (SR) of nephrotic syndrome, in the absence of immunosuppressive treatment, is relatively common among patients with idiopathic membranous nephropathy (IMN) and normal renal function. However, it has not been reported in patients with chronic renal impairment. METHODS: All patients with IMN who had developed SR in the presence of chronic renal insufficiency were identified among the nephrology departments that belong to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Their characteristics and outcome after SR were studied. RESULTS: Eleven patients were identified. All of them showed renal insufficiency and nephrotic syndrome at the time of renal biopsy. Serum creatinine (Scr) continued to increase in the following months, reaching a peak value of 2.6 ± 1.5 mg/dL (range 1.7-6.5). Angiotensin converting enzyme inhibitors or spironolactone were prescribed in 10/11 patients at renal biopsy or shortly after it. Nephrotic proteinuria persisted during the first months of follow-up, but it started to spontaneously decrease 12 ± 7 months (2-30 months) after renal biopsy. Finally, complete (nine patients) or partial (two patients) remission of nephrotic syndrome was observed. Coinciding with proteinuria remission, renal function tended to improve. Nephrotic syndrome relapsed in two patients, accompanied by a rapid deterioration of renal function. In the remaining nine patients, remission persisted throughout a follow-up of 146 ± 64 months. Mean Scr at the last visit was 1.9 ± 0.9 mg/dL and proteinuria 0.2 g/24 h. CONCLUSION: SR of nephrotic syndrome can also be observed in membranous nephropathy patients exhibiting chronic renal impairment.

Adherence to hypothermia guidelines in newborns with hypoxic-ischemic encephalopathy.

INTRODUCTION: We do not have population data in Spain on the application of therapeutic hypothermia (TH). The objective was to examine adherence to management standards during TH of infants with hypoxic-ischemic encephalopathy (HIE). METHOD: Multicenter observational cohort study from the beginning of TH (year 2010) in 5 hospitals in a Spanish region, until year 2019. RESULTS: 133 patients were recruited, 72% diagnosed with moderate HIE and the rest of them with severe HIE. In 84% of infants, passive hypothermia was started at birth. Active TH was started at a median age of 5 h of life (IQR 3.3; 6.3), although the central targeted temperature (33-34 °C) was reached at a median age of 3.5 h (IQR 1; 6). Those born extramural, initiated active TH 3.3 h on average later than those born intramural, but without differences in the age at which the targeted temperature was reached. Sedoanalgesia was used in 97%. 100% were monitored with amplitude-integrated EEG and 59% with cerebral oxymetry. MRI was performed in 94% with moderate HIE vs. 65% with severe; P < .001. Neuron-specific enolase in cerebrospinal fluid was determined in 42%. The average duration of rewarming was median 10 h (IQR 8; 12), with no differences depending on the degree of HIE (P = .57). CONCLUSIONS: The implementation of TH successfully met the standards. However, aspects of care that could be improved were detected. Auditing newborn care with HIE is crucial to achieving programs with a high quality of care in each region.

Understanding no-show behaviour for cervical cancer screening appointments among hard-to-reach women in Bogotá, Colombia: A mixed-methods approach.

The global burden of cervical cancer remains a concern and higher early mortality rates are associated with poverty and limited health education. However, screening programs continue to face implementation challenges, especially in developing country contexts. In this study, we use a mixed-methods approach to understand the reasons for no-show behaviour for cervical cancer screening appointments among hard-to-reach low-income women in Bogotá, Colombia. In the quantitative phase, individual attendance probabilities are predicted using administrative records from an outreach program (N = 23384) using both LASSO regression and Random Forest methods. In the qualitative phase, semi-structured interviews are analysed to understand patient perspectives (N = 60). Both inductive and deductive coding are used to identify first-order categories and content analysis is facilitated using the Framework method. Quantitative analysis shows that younger patients and those living in zones of poverty are more likely to miss their appointments. Likewise, appointments scheduled on Saturdays, during the school vacation periods or with lead times longer than 10 days have higher no-show risk. Qualitative data shows that patients find it hard to navigate the service delivery process, face barriers accessing the health system and hold negative beliefs about cervical cytology.

Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy.

Spontaneous remission is a well known characteristic of idiopathic membranous nephropathy, but contemporary studies describing predictors of remission and long-term outcomes are lacking. We conducted a retrospective, multicenter cohort study of 328 patients with nephrotic syndrome resulting from idiopathic membranous nephropathy that initially received conservative therapy. Spontaneous remission occurred in 104 (32%) patients: proteinuria progressively declined after diagnosis until remission of disease at 14.7 +/- 11.4 months. Although spontaneous remission was more frequent with lower levels of baseline proteinuria, it also frequently occurred in patients with massive proteinuria: 26% among those with baseline proteinuria 8 to 12 g/24 h and 22% among those with proteinuria >12 g/24 h. Baseline serum creatinine and proteinuria, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, and a >50% decline of proteinuria from baseline during the first year of follow-up were significant independent predictors for spontaneous remission. Only six patients (5.7%) experienced a relapse of nephrotic syndrome. The incidence of death and ESRD were significantly lower among patients with spontaneous remission. In conclusion, spontaneous remission is common among patients with nephrotic syndrome resulting from membranous nephropathy and carries a favorable long-term outcome with a low incidence of relapse. A decrease in proteinuria >50% from baseline during the first year predicts spontaneous remission.

[Adherence to hypothermia guidelines in newborns with hypoxic-ischemic encephalopathy]. / Adherencia a los estándares en el tratamiento con hipotermia del recién nacido con encefalopatía hipóxico-isquémica.

INTRODUCTION: We do not have population data in Spain on the application of therapeutic hypothermia (TH). The objective was to examine adherence to management standards during TH of infants with hypoxic-ischemic encephalopathy (HIE). METHOD: Multicenter observational cohort study from the beginning of TH (year 2010) in 5 hospitals in a Spanish region, until year 2019. RESULTS: 133 patients were recruited, 72% diagnosed with moderate HIE and the rest of them with severe HIE. In 84% of infants, passive hypothermia was started at birth. Active TH was started at a median age of 5hours of life (IQR: 3.3-6.3), although the central targeted temperature (33-34°C) was reached at a median age of 3.5hours (IQR: 1-6). Those born extramural, initiated active TH 3.3hours on average later than those born intramural, but without differences in the age at which the targeted temperature was reached. Sedoanalgesia was used in 97%. The 100% were monitored with amplitude-integrated EEG and 59% with cerebral oxymetry. MRI was performed in 94% with moderate HIE vs. 65% with severe; P<.001. Neuron-specific enolase in cerebrospinal fluid was determined in 42%. The average duration of rewarming was median 10hours (IQR: 8-12), with no differences depending on the degree of HIE (P=.57). CONCLUSIONS: The implementation of TH successfully met the standards. However, aspects of care that could be improved were detected. Auditing newborn care with HIE is crucial to achieving programs with a high quality of care in each region.

Temporal Trends in the Severity and Mortality of Neonatal Hypoxic-Ischemic Encephalopathy in the Era of Hypothermia.

INTRODUCTION: There is a paucity of studies examining temporal trends in the incidence and mortality of moderate-to-severe hypoxic-ischemic encephalopathy (HIE) during the last decade of therapeutic hypothermia (TH). METHODS: Multicenter cross-sectional study of all infants ≥35 weeks gestational age diagnosed with moderate-to-severe HIE within 6 h of birth in an extensive region of Spain between 2011 and 2019, in order to detect trend changes over time in the (1) annual incidence, (2) severity of neurological and systemic organ involvement, and (3) neonatal death from HIE. RESULTS: Annual incidence rate of moderate-to-severe HIE was 0.84 (95% confidence interval [CI] 0.7-0.97) per 1,000 births, without trend changes over time (p = 0.8), although the proportion of severe HIE infants showed an average annual decline of 0.86 points (95% CI 0.75-0.98). There were 102 (70%) infants diagnosed with moderate HIE and 44 (30%) with severe HIE. TH was offered to 139/146 (95%) infants. Infants with clinical and/or electrical seizures showed a decreasing trend from 56 to 28% (p = 0.006). Mortality showed a nonstatistically significant decline (p = 0.4), and the severity of systemic damage showed no changes (p = 0.3). Obstetric characteristics remained unchanged, while higher perinatal pH values (p = 0.03) and Apgar scores (p = 0.05), and less need for resuscitation (p = 0.07), were found over time. CONCLUSION: The annual incidence of moderate-to-severe HIE has stabilized at around 1 per 1,000 births, with a temporal trend toward a decrease in severe HIE infants and a slight decline of mortality. No association was found between temporal trends and changes in perinatal/obstetric characteristics over time.

Peripheral Vascular Disease and Kidney Transplant Outcomes: Rethinking an Important Ongoing Complication.

Peripheral vascular disease (PVD) is highly prevalent in patients on the waiting list for kidney transplantation (KT) and after transplantation and is associated with impaired transplant outcomes. Multiple traditional and nontraditional risk factors, as well as uremia- and transplant-related factors, affect 2 processes that can coexist, atherosclerosis and arteriosclerosis, leading to PVD. Some pathogenic mechanisms, such as inflammation-related endothelial dysfunction, mineral metabolism disorders, lipid alterations, or diabetic status, may contribute to the development and progression of PVD. Early detection of PVD before and after KT, better understanding of the mechanisms of vascular damage, and application of suitable therapeutic approaches could all minimize the impact of PVD on transplant outcomes. This review focuses on the following issues: (1) definition, epidemiological data, diagnosis, risk factors, and pathogenic mechanisms in KT candidates and recipients; (2) adverse clinical consequences and outcomes; and (3) classical and new therapeutic approaches.