The Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Outcomes of Patients Treated with Immune Checkpoint Inhibitors: a Retrospective Cohort Study.

AIMS: Renin-angiotensin-aldosterone system inhibitors (RAASi) are associated with improved survival outcomes in patients receiving immune checkpoint inhibitors (ICIs), but the data on the response to treatment and tumour-based endpoints across different tumour types are unknown. MATERIALS AND METHODS: We carried out a retrospective study at two tertiary referral centres in Taiwan. All adult patients treated with ICIs between January 2015 and December 2021 were included. The primary outcome was overall survival and the secondary outcomes were progression-free survival (PFS) and clinical benefit rates. RESULTS: In total, 734 patients were enrolled in our study, of which 171 were RAASi users and 563 were non-users. Compared with non-users, RAASi users had a longer median overall survival [26.8 (interquartile range 11.3-not reached) versus 15.2 (interquartile range 5.1-58.4) months, P < 0.001] and PFS [12.2 (interquartile range 3.9-34.5) versus 5.0 (interquartile range 2.2-15.2) months, P < 0.001]. In univariate Cox proportional hazard analyses, the use of RAASi was associated with a 40% reduction in the risk of mortality [hazard ratio 0.58 (95% confidence interval 0.44-0.76), P < 0.001] and disease progression [hazard ratio 0.62 (95% confidence interval 0.50-0.77), P < 0.001]. The association remained significant after adjusting for underlying comorbidities and cancer therapy in multivariate Cox analyses. A similar trend was observed for PFS. Furthermore, RAASi users experienced a greater clinical benefit rate than non-users (69% versus 57%, P = 0.006). Importantly, the use of RAASi before ICI initiation was not associated with improved overall survival and PFS. RAASi were not associated with an increased risk of adverse events. CONCLUSION: The use of RAASi is associated with improved survival outcomes, treatment response and tumour-based endpoints in patients undergoing immunotherapy.

The effect of dexmedetomidine on myocardial ischemia/reperfusion injury in patients undergoing cardiac surgery with cardiopulmonary bypass: a meta-analysis.

OBJECTIVE: The purpose of this study was to evaluate the effect of dexmedetomidine administration on myocardial ischemia/reperfusion (I/R) injury in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). MATERIALS AND METHODS: Online databases including PubMed, the Cochrane Library, Web of Science, Medline, and EMBASE were searched for clinical trials that investigated the application of dexmedetomidine in CPB patients prior to May 2021. A total of 17 studies involving 866 patients were included in this study. RESULTS: The result of the meta-analysis showed that there was a significant difference in serum creatinine-kinase-MB (CK-MB) between the dexmedetomidine group and the control group at the end of the operation and 24 h after the operation. Compared to the control group, cardiac troponin I (cTn-I) concentration in the dexmedetomidine group was significantly decreased at the end of the operation, 24 h after the operation, and 48 h after the operation. There was also a significant difference between the dexmedetomidine group and the control group in the length of a patient's ICU stay. CONCLUSIONS: Dexmedetomidine can reduce CK-MB and cTn-I concentrations and shorten the length of ICU stays for patients undergoing cardiac surgery with CPB. It can also provide myocardial protection from I/R injury.

Complete mitochondrial genomes of the Bright Sunbeam Curetis bulis and the Small Copper Lycaena phlaeas (Lepidoptera: Lycaenidae) and their phylogenetic implications.

In this study, the complete mitochondrial genomes of Curetis bulis and Lycaena phlaeas were determined and analyzed. The circular genomes are 15,162 bp long for C. bulis and 15,280 bp long for L. phlaeas, with a total A+T content of 82.6 and 83.1%, respectively. Both mitogenomes contain 37 genes, and their gene orders are similar to those of other lepidopterans. All protein-coding genes (PCGs) are initiated by ATN codons, except for cox1, which is started with the CGA codon; all PCGs terminate in the typical stop codon TAA, except for cox1, cox2, and nad4, which end with a single T. The codons TTA (Leu), ATT (Ile), TTT (Phe), ATA (Met), and AAT (Asn) appear the most frequently. Both of the mitogenome A+T-rich regions harbor the motif ATAGA, followed by a 19-bp poly(T) stretch, with C. bulis containing a microsatellite-like (AT)5 element next to the ATTTA motif, and L. phlaeas containing a microsatellite-like (TA)6 (AT) element next to the ATTTA motif. The phylogenetic trees of the 17 representative butterfly species, including the two species of this study, were reconstructed with the maximum likelihood and Bayesian inference methods, based on the 13 PCG nucleotide sequence data. The results of the phylogenetic analyses strongly supported the relationships of ((((Lycaenidae + Pieridae) + Nymphalidae) + Hesperiidae) + Papilionidae), which was markedly different from the traditional morphological view of the Lycaenidae and Nymphalidae considered to be sisters of each other.

Plasma melatonin, pinealocyte morphology, and surface receptors/antigen expression on macrophages/microglia in the pineal gland following a high-altitude exposure.

The present study examined the effects of high-altitude exposure on the pineal gland, the main source of production of melatonin. It was surmised that hypoxia experienced at high altitude, caused by decreased oxygen tension in the ambient air, might lead to some structural alterations in the pineal gland and, hence, affect its melatonin production. Adult Wistar rats were exposed to an altitude of 8,000 m for 2 hr in an altitude chamber and then sacrificed at various time intervals after the exposure. Normal rats kept at ground level were used as controls. Blood samples were collected at various time intervals for measurement of plasma melatonin level, and the pineal glands from both groups were processed for electron microscopy and immunohistochemistry. The plasma melatonin level showed a steady increase following altitude exposure peaking at 7 days and returned to control levels thereafter. Between 1 and 4 days after altitude exposure, the mitochondrial number and lipid droplets in the pinealocytes appeared to be reduced compared with those in control rats. At 7 days, however, the mitochondrial numbers and lipid droplets were noticeably increased. At the same time interval, the expression of complement type 3 receptors and major histocompatibility class II antigens as detected with the antibodies OX-42 and OX-6, respectively, in macrophages/microglia was up-regulated compared with that in the control rats and those killed at earlier times. This was attributed to the increased serum melatonin after the altitude exposure. By 14 and 21 days, the ultrastructure of pinealocytes and immunoreactivity of macrophages/microglia were comparable with those in the control rats. We conclude from this study that an altitude exposure in rats leads to an increase in melatonin production, which returned to control levels with passage of time.

Upregulation of adrenocorticotrophic hormone in the corticotrophs and downregulation of surface receptors and antigens on the macrophages in the adenohypophysis following an exposure to high altitude.

Altitude exposures lead to the development of hypobaric hypoxia because of low oxygen tension in the ambient air. This study has shown the vigorous upregulation of adrenocorticotrophic hormone (ACTH) expression in corticotrophs of the pars distalis (adenohypophysis) of rats 1-7 days after an altitude exposure. Concomitant to this was the increase in number and hypertrophy of the immunoreactive corticotrophs. It was suggested that this had resulted in an upsurge of ACTH production which may have suppressed the immuno-expression of complement type 3 receptors and major histocompatibility complex class II antigens constitutively expressed by the parenchymal macrophages through paracrine action. Along with ACTH, altered levels of other hormones following such exposures may also contribute to suppression of antigen presenting function and phagocytic activity of macrophages. The effects of altitude (hypobaric hypoxia) exposure, however, were reversible as the above immunohistochemical changes returned to normal 21-28 days after the hypobaric hypoxic insult.

Expression of Fos immunoreactivity in some catecholaminergic brainstem neurons in rats following high-altitude exposure.

This study examined the response of neurons of the cardiorespiratory centers, i.e., the nucleus tractus solitarius and the ventrolateral medulla as well as the area postrema in adult and postnatal rats subjected to high-altitude exposure at 4,000 m and 8,000 m. In adult control rats, sporadic Fos-positive neurons were detected in the above-mentioned areas. On exposure to 4,000 m altitude, the number of Fos-positive neurons was noticeably increased. At 8,000 m, the incidence of labeled cells was markedly increased, with many of them doubly labeled for tyrosine hydroxylase. In postnatal rats, Fos expression was not detected in these areas in either control rats or rats exposed to 4,000 m altitude. Fos-positive cells, however, were observed in the these areas in postnatal rats exposed to 8,000 m. In the latter, tyrosine hydroxylase labeling was observed in some Fos-positive cells in the nucleus tractus solitarius and ventrolateral medulla. In rats killed at 24 hr after exposure to high altitude, Fos expression in both the adult and the postnatal rats was comparable to that in their corresponding control rats. Present results suggest that Fos expression in various brainstem areas was induced by reduced oxygen tension in the ambient air at high altitude. Double labeling of some Fos-positive neurons with tyrosine hydroxylase indicates an increased sympathetic activation, which may be involved in the mediation of cardiorespiratory responses to hypoxia. This, however, was less evident in the postnatal animals. It is possible that the peripheral chemoreceptors or the regulation of autonomic functions is not fully developed in this age group.

Effects of optical correction media on contrast sensitivity.

Contrast sensitivity functions (CSFs) were obtained for 257 emmetropic subjects (514 eyes) and 35 contact lens users (64 eyes) in the Republic of Singapore Air Force using the Vistech Contrast Test System. For the emmetropes, contrast sensitivity tests were carried out with and without plano spectacles (PS). For the myopes, we compared their performances with spectacles, daily-wear soft contact lenses (CLs), and CL plus PS at Snellen visual acuities of 6/6 or better. Paired t-tests showed that there were no significant differences (P > 0.05) when CSFs of the emmetropes were measured with and without PS and when that of the CL users were measured with spectacles, CL and CL plus PS. We therefore conclude that myopic optical correction media do not retard CSF significantly based on the Vistech charts, although they may reduce image size and modify light transmission by being imperfect transparencies. The observed decrease in CSF for myopes even after myopic correction might therefore be related to other factors associated with myopia, such as retinal changes or possibly mild amblyopia.