Absence of metabolic effects of the topical carbonic anhydrase inhibitors MK-927 and sezolamide during two-week ocular administration to normal subjects.

Potential systemic effects of the racemic carbonic anhydrase inhibitor MK-927 and its S-enantiomer, sezolamide hydrochloride, after topical ocular administration were investigated in a double-masked, randomized, placebo-controlled study in 16 healthy volunteers. A controlled diet was started 4 days before initiation of treatment and continued throughout the study. For 14 days six volunteers received bilaterally one drop of 2% MK-927 (1.2 mg) q.i.d., six received one drop of 1.8% sezolamide (1.1 mg) q.i.d., and four received the common vehicle q.i.d. Blood and urine electrolytes and acid-base profiles were measured before and on days 1, 7, and 14 of treatment, and 24-hour urine samples were collected daily. All values were compared with those on the pretreatment day. Taking the circadian variations of the parameters into account, no significant treatment effect was observed in either the daily profiles or the 14-day cumulative sodium, potassium, and citrate excretions. Because the usual variability of the measured biologic parameters has been reduced markedly by the stringent requirements of this study, it can be concluded that the induction of clinically significant metabolic changes by topically administered MK-927 or sezolamide is unlikely

JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Item does not contain fulltextPURPOSE: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. METHODS: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. RESULTS: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. CONCLUSION: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting

Sex, gender, and decisions at the family -> work interface

What is the linkage between individuals’ sex and the interface between their work and family roles? The answer to this question is by no means straightforward as gender roles, work roles, and family roles evolve. To address the question, the authors examine the influence of family-domain factors on work-domain decisions and their linkages to sex and gender. According to the logic of appropriateness, a theory of decision making, people develop and apply rules in decision-making situations that are consistent with their personal identities. The authors identify three broad types of decisions in the work domain—role entry, participation, and exit decisions—that may be influenced by factors in the family domain according to such rules. Next, they review the literature on the linkage between individuals’ sex and an example of each of these types of decisions: the role entry decision about whether to start a business, the role participation decision about the number of hours to devote to one’s job or business, and the role exit decision about whether to quit a job. The review suggests that (a) family-domain factors mediate effects of sex on work-domain decisions and (b) sex moderates relationships between family-domain factors and work-domain decisions. Based on the review, the authors offer a model of the linkages among sex, family-domain factors, and work-domain decisions that incorporates constructs from theories of the psychology of gender (femininity) and identity theories (family role salience). Finally, the authors offer guidelines for future theory and research to test and extend the model

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

Aim The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. Methods This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. Results Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. Conclusion One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

Aim The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. Methods This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. Results Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. Conclusion One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease.Scientific Assessment and Innovation in Neurosurgical Treatment Strategie