The Effect of Adrenocorticotropin on the Nucleic Acids and Histochemistry of the Guinea-Pig Adrenal Cortex

The effect of adrenocorticotropin (Armour ACTHar gel) on the mean amount of deoxyribonucleic acid (DNA) per nucleus, and the scatter about this mean, in adrenal nuclei from mature guinea-pigs was studied, using cytophotometry of Feulgen stained nuclear smears. The results were compared with those from chemical analysis of the same material. The mean adrenal nuclear DM content was similar to that in a control specimen mounted on the same slide in each instance, except after administration of adrenocorticotropin for 5 and 7 days. Cytophotometric analyses showed a highly statistically significant increase (P<0.01) in mean adrenal nuclear DNA content after treatment of the animals with ACTH for 5 and 7 days, Chemical analyses gave values for adrenal nuclear DNA which were slightly higher than those for pooled kidney nuclei. The significance of these findings is discussed. Statistical analysis of the results indicates that only specimens on the same slide are to be compared when using cyto-photometry of the Feulgen reaction. If specimens on different slides are used for comparison a large error is introduced. The effect of ACTH was also studied on adrenocortical ribonucleic acid (RNA), plasmalogens, alkaline and acid phosphatase, ascorbic acid and glycogen in mature guinea-pigs after treatment with ACTH for similar periods of time (1, 3, 5, 7, 10, 14 and 21 days) and also for 3, 6, 12 and 18hr and for 28 days. A gradual increase in adrenocortical ribonucleic acid occurred with ACTH treatment. This increase was found in all zones of the adrenal cortex. Depletion of lipid and of plasmalogens was evident in the zona fasciculata and zona reticularis after ACTH administration for 3, 6, 12 and 18 hr. In the other experimental groups of animals an increase in lipid and plasmalogens occurred with continued ACTH administration. At 28 days, however, some depletion of these substances was found in the zona reticularis. ACTH administration caused an increased concentration of alkaline and acid phosphatase in all adrenocortical zones. The increase was most evident after treatment with ACTH for 5 and 7 days, when hyperplasia was maximal. Ascorbic acid depletion was observed after ACTH treatment for 3, 6, 12 and 18 hr and for 1 day. The adrenocortical content and distribution of ascorbic acid was normal in adrenals of guinea-pigs receiving ACTH for longer periods. Glycogen depletion occurred at 12 and 18 hr only. The findings are discussed and compared with results of other authors who studied the pituitary-adrenal relationship. It is evident that ribonucleic acid, alkaline and acid phosphatase and ascorbic acid have important roles in adrenocortical Physiology. The results suggest that ribonucleic acid and phosphatases are probably concerned with adrenocortical hyperplasia. It seems more likely, however, that ascorbic acid and glycogen are concerned with secretion of adrenocortical hormones, as depletion of these substances occurred when secretion of ketosteroids was probably at a maximum

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially