Anti-vascular endothelial growth factor for proliferative diabetic retinopathy.

BACKGROUND: Proliferative diabetic retinopathy (PDR) is an advanced complication of diabetic retinopathy that can cause blindness. It consists of the presence of new vessels in the retina and vitreous haemorrhage. Although panretinal photocoagulation (PRP) is the treatment of choice for PDR, it has secondary effects that can affect vision. Anti-vascular endothelial growth factor (anti-VEGF), which produces an inhibition of vascular proliferation, could improve the vision of people with PDR. OBJECTIVES: To assess the effectiveness and safety of anti-VEGFs for PDR and summarise any relevant economic evaluations of their use. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 6); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov, and the WHO ICTRP. We did not use any date or language restrictions. We last searched the electronic databases on 1 June 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing anti-VEGFs to another active treatment, sham treatment, or no treatment for people with PDR. We also included studies that assessed the combination of anti-VEGFs with other treatments. We excluded studies that used anti-VEGFs in people undergoing vitrectomy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted data, and assessed the risk of bias (RoB) for all included trials. We calculated the risk ratio (RR) or the mean difference (MD), and 95% confidence intervals (CI). We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 15 new studies in this update, bringing the total to 23 RCTs with 1755 participants (2334 eyes). Forty-five per cent of participants were women and 55% were men, with a mean age of 56 years (range 48 to 77 years). The mean glycosylated haemoglobin (Hb1Ac) was 8.45% for the PRP group and 8.25% for people receiving anti-VEGFs alone or in combination. Twelve studies included people with PDR, and participants in 11 studies had high-risk PDR (HRPDR). Twelve studies were of bevacizumab, seven of ranibizumab, one of conbercept, two of pegaptanib, and one of aflibercept. The mean number of participants per RCT was 76 (ranging from 15 to 305). Most studies had an unclear or high RoB, mainly in the blinding of interventions and outcome assessors. A few studies had selective reporting and attrition bias. No study reported loss or gain of 3 or more lines of visual acuity (VA) at 12 months. Anti-VEGFs ± PRP probably increase VA compared with PRP alone (mean difference (MD) -0.08 logMAR, 95% CI -0.12 to -0.04; I2 = 28%; 10 RCTS, 1172 eyes; moderate-certainty evidence). Anti-VEGFs ± PRP may increase regression of new vessels (MD -4.14 mm2, 95% CI -6.84 to -1.43; I2 = 75%; 4 RCTS, 189 eyes; low-certainty evidence) and probably increase a complete regression of new vessels (RR 1.63, 95% CI 1.19 to 2.24; I2 = 46%; 5 RCTS, 405 eyes; moderate-certainty evidence). Anti-VEGFs ± PRP probably reduce vitreous haemorrhage (RR 0.72, 95% CI 0.57 to 0.90; I2 = 0%; 6 RCTS, 1008 eyes; moderate-certainty evidence). Anti-VEGFs ± PRP may reduce the need for vitrectomy compared with eyes that received PRP alone (RR 0.67, 95% CI 0.49 to 0.93; I2 = 43%; 8 RCTs, 1248 eyes; low-certainty evidence). Anti-VEGFs ± PRP may result in little to no difference in the quality of life compared with PRP alone (MD 0.62, 95% CI -3.99 to 5.23; I2 = 0%; 2 RCTs, 382 participants; low-certainty evidence). We do not know if anti-VEGFs ± PRP compared with PRP alone had an impact on adverse events (very low-certainty evidence). We did not find differences in visual acuity in subgroup analyses comparing the type of anti-VEGFs, the severity of the disease (PDR versus HRPDR), time to follow-up (< 12 months versus 12 or more months), and treatment with anti-VEGFs + PRP versus anti-VEGFs alone. The main reasons for downgrading the certainty of evidence included a high RoB, imprecision, and inconsistency of effect estimates. AUTHORS' CONCLUSIONS: Anti-VEGFs ± PRP compared with PRP alone probably increase visual acuity, but the degree of improvement is not clinically meaningful. Regarding secondary outcomes, anti-VEGFs ± PRP produce a regression of new vessels, reduce vitreous haemorrhage, and may reduce the need for vitrectomy compared with eyes that received PRP alone. We do not know if anti-VEGFs ± PRP have an impact on the incidence of adverse events and they may have little or no effect on patients' quality of life. Carefully designed and conducted clinical trials are required, assessing the optimal schedule of anti-VEGFs alone compared with PRP, and with a longer follow-up.

Lateral septum modulates cortical state to tune responsivity to threat stimuli.

Sudden unexpected environmental changes capture attention and, when perceived as potentially dangerous, evoke defensive behavioral states. Perturbations of the lateral septum (LS) can produce extreme hyperdefensiveness even to innocuous stimuli, but how this structure influences stimulus-evoked defensive responses and threat perception remains unclear. Here, we show that Crhr2-expressing neurons in mouse LS exhibit phasic activation upon detection of threatening but not rewarding stimuli. Threat-stimulus-driven activity predicts the probability but not vigor or type of defensive behavior evoked. Although necessary for and sufficient to potentiate stimulus-triggered defensive responses, LSCrhr2 neurons do not promote specific behaviors. Rather, their stimulation elicits negative valence and physiological arousal. Moreover, LSCrhr2 activity tracks brain state fluctuations and drives cortical activation and rapid awakening in the absence of threat. Together, our findings suggest that LS directs bottom-up modulation of cortical function to evoke preparatory defensive internal states and selectively enhance responsivity to threat-related stimuli.

Stimulus salience determines defensive behaviors elicited by aversively conditioned serial compound auditory stimuli.

Assessing the imminence of threatening events using environmental cues enables proactive engagement of appropriate avoidance responses. The neural processes employed to anticipate event occurrence depend upon which cue properties are used to formulate predictions. In serial compound stimulus (SCS) conditioning in mice, repeated presentations of sequential tone (CS1) and white noise (CS2) auditory stimuli immediately prior to an aversive event (US) produces freezing and flight responses to CS1 and CS2, respectively (Fadok et al., 2017). Recent work reported that these responses reflect learned temporal relationships of CS1 and CS2 to the US (Dong et al., 2019). However, we find that frequency and sound pressure levels, not temporal proximity to the US, are the key factors underlying SCS-driven conditioned responses. Moreover, white noise elicits greater physiological and behavioral responses than tones even prior to conditioning. Thus, stimulus salience is the primary determinant of behavior in the SCS paradigm, and represents a potential confound in experiments utilizing multiple sensory stimuli.

If you notice the skies above you becoming darker, your first thought might be to seek shelter. Experience will have taught you that darkening skies are often a sign of an approaching storm. Learning to recognise changes that occur prior to an unpleasant event can help us avoid danger. But this is not the only strategy people can use to predict when something bad is about to happen. Another option is to use the intensity, or salience, of sensory information. Soldiers fighting on the front line, for example, might rely on the loudness of enemy voices or vehicles to judge how close an advancing enemy is. This information will help them decide when to retreat. Different brain processes are active when individuals use each of these two strategies to predict when an upcoming event will occur. One approach to study these processes is to use a technique called "SCS conditioning". This involves exposing mice to two sounds, followed by a mild electric shock administered to the feet. The first sound is a pure tone; the second is a burst of white noise. After repeated trials, mice begin to show distinct responses to the two sounds. They freeze in response to the tone but run away upon hearing the white noise. These responses parallel behaviors seen in the wild. When mice detect a distant predator, they freeze to avoid detection. But if the predator comes too close for the mice to avoid being spotted, they instead try to flee. Some have argued that in the SCS task, mice learn that the white noise predicts an imminent shock. The mice therefore flee as soon as they hear it. By contrast, they learn that the tone predicts a delayed shock and therefore choose to freeze instead. However, by tweaking the SCS procedure, Hersman et al. now show that even if the white noise occurs before the tone, it is still more likely than the tone to trigger an escape response. In fact, mice are more reactive to white noise than tones even if the sounds are never paired with shocks. This suggests that mice find white noise naturally more noticeable than tones. Moreover, Hersman et al. show that tones can also trigger escape responses if they are sufficiently intense. Together these results suggest that mice use the intensity of the stimuli ­ rather than the length of time between each stimulus and the shock ­ to decide whether to freeze or flee. People with anxiety disorders often show exaggerated responses to things that do not pose a genuine threat. At present the pathways in the brain that are responsible for these excessive reactions are unclear. The results of Hersman et al. will aid research into the brain circuits that detect, assess and respond to threats. Understanding these circuits could in the future lead to better treatments for anxiety disorders.

Sedación paliativa en la agonía realizada por un servicio de urgencias de Atención Primaria a nivel domiciliario. Estudio observacional retrospectivo / Palliative sedation in agony performed at home by a primary care emergency service. A retrospective study

Objetivos: El objetivo de este estudio fue conocer las características de la sedación paliativa en la agonía a nivel domiciliario realizada por personal no especializado en cuidados paliativos y detectar áreas de mejora. Material y método: Estudio observacional retrospectivo. Se incluyeron todos los pacientes falle- cidos en domicilio entre septiembre de 2020 y febrero de 2021, que precisaron sedación indicada por el Servicio de Urgencias de Atención Primaria (SUAP) Málaga. Resultados: El porcentaje de sedación paliativa fue del 16,4 % [9,8-23,2 %]. Solo el 36 % [27- 45 %] de los pacientes se encontraba incluido en el proceso de cuidados paliativos. En el 67,2 % [59-76 %] de los casos, eran crónicos no oncológicos. La disnea fue el síntoma más prevalente (76,1 % [68-83 %]). El delirium estuvo presente en el 21,4 % [13-28 %] de los pacientes. El fár- maco más utilizado fue el midazolam (94,9 % [91-99 %]). La media de tiempo que pasa desde el inicio de la sedación hasta el fallecimiento es de 24,3 h [19,3-29,2h]. Las diferencias en las medias de supervivencia entre hombres (20,765 [13,7-27,7]) y mujeres (29,2 [22,1-33,3]) fueron estadísticamente significativas. El 72 % [64 %-80 %] de los pacientes no recibió ningún tipo de seguimiento desde el inicio de la sedación hasta el fallecimiento. Conclusiones: Existe concordancia entre los resultados obtenidos en este trabajo y los encontra- dos en la bibliografía consultada, en cuanto a la proporción de pacientes con sedación paliativa en la agonía, tiempo de duración de la misma y principales fármacos empleados. La edad media de los pacientes fue mayor en este estudio, así como la prevalencia de patología crónica no oncológica y de disnea como principal síntoma refractario. Llama la atención el desconocimien- to del nivel de sedación de nuestros pacientes, la falta de seguimiento y la infrautilización de levomepromazina en delirium. (AU)

Objectives: The objective of this study was to assess the characteristics of at-home palliative sedation in agony as carried out by care providers who are not specialists in palliative care, and to detect areas for improvement. Material and method: A retrospective, observational study. All patients who died at home be- tween September 2020 and February 2021, who required sedation as indicated by the Primary Care Emergency Service (SUAP) in Malaga, were included. Results: The percentage of palliative sedation was 16.4 % [9.8 %-23.2 %]. Only 36 % [27 %-45 %] of the patients were included in the palliative care process. In 67.2 % [59 %-76 %] of cases, they had non-cancer chronic conditions. Dyspnea was the most prevalent symptom (76.1 % [68 %-83 %]). Delirium was present in 21.4 % [13 %-28 %] of patients. The most widely used drug was midazolam (94.9 % [91 %-99 %]). Mean time from start of sedation to death is 24.3h [19.3h- 29.2h]. The differences in mean survival rate between men 20.765 [13.7-27.7] and women 29.2 [22.1-33.3] were statistically significant; 72 %[64 %-80 %] of the patients did not undergo any follow-up from start of sedation to death. Conclusions: There is agreement between the results obtained in this study and those found in the consulted bibliography regarding the proportion of patients with palliative sedation in agony, its duration, and the main drugs used. The mean age of the patients was higher in this study, as well as the prevalence of non-oncological chronic disease, with dyspnea as the main refractory symptom. The perceived lack of knowledge regarding sedation levels in our patients, as wellas lack of follow-up and underuse of levomepromazine in delirium, are striking. (AU)

Eugenesia y diagnóstico prenatal / Eugenics and prenatal diagnosis

El uso del diagnóstico prenatal en la práctica de la genética médica ha hecho que se recuerden teorías eugenésicas. Se realizó una revisión histórica de este término y se relacionó con el uso del diagnóstico prenatal (DPN) y el aborto selectivo a la luz de los conocimientos bioéticos actuales(AU)

Eugenesia y diagnóstico prenatal / Eugenics and prenatal diagnosis

El uso del diagnóstico prenatal en la práctica de la genética médica ha hecho que se recuerden teorías eugenésicas. Se realizó una revisión histórica de este término y se relacionó con el uso del diagnóstico prenatal (DPN) y el aborto selectivo a la luz de los conocimientos bioéticos actuales