Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Drosophila Myt1 Is the Major Cdk1 Inhibitory Kinase for Wing Imaginal Disc Development

Mitosis is triggered by activation of Cdk1, a cyclin-dependent kinase. Conserved checkpoint mechanisms normally inhibit Cdk1 by inhibitory phosphorylation during interphase, ensuring that DNA replication and repair is completed before cells begin mitosis. In metazoans, this regulatory mechanism is also used to coordinate cell division with critical developmental processes, such as cell invagination. Two types of Cdk1 inhibitory kinases have been found in metazoans. They differ in subcellular localization and Cdk1 target-site specificity: one (Wee1) being nuclear and the other (Myt1), membrane-associated and cytoplasmic. Drosophila has one representative of each: dMyt1 and dWee1. Although dWee1 and dMyt1 are not essential for zygotic viability, loss of both resulted in synthetic lethality, indicating that they are partially functionally redundant. Bristle defects in myt1 mutant adult flies prompted a phenotypic analysis that revealed cell-cycle defects, ectopic apoptosis, and abnormal responses to ionizing radiation in the myt1 mutant imaginal wing discs that give rise to these mechanosensory organs. Cdk1 inhibitory phosphorylation was also aberrant in these myt1 mutant imaginal wing discs, indicating that dMyt1 serves Cdk1 regulatory functions that are important both for normal cell-cycle progression and for coordinating mitosis with critical developmental processes

The bric à brac locus consists of two paralogous genes encoding BTB/POZ domain proteins and acts as a homeotic and morphogenetic regulator of imaginal development in Drosophila.

The bric a brac (bab) locus acts as a homeotic and morphogenetic regulator in the development of ovaries, appendages and the abdomen. It consists of two structurally and functionally related genes, bab1 and bab2, each of which encodes a single nuclear protein. Bab1 and Bab2 have two conserved domains in common, a BTB/POZ domain and a Psq domain, a motif that characterizes a subfamily of BTB/POZ domain proteins in DROSOPHILA: The tissue distribution of Bab1 and Bab2 overlaps, with Bab1 being expressed in a subpattern of Bab2. Analysis of a series of mutations indicates that the two bab genes have synergistic, distinct and redundant functions during imaginal development. Interestingly, several reproduction-related traits that are sexually dimorphic or show diversity among Drosophila species are highly sensitive to changes in the bab gene dose, suggesting that alterations in bab activity may contribute to evolutionary modification of sex-related morphology

Lower-bound theorems for pseudomanifolds

10.1007/BF02574038Discrete & Computational Geometry131203-21

<i>Smc5/6</i> mutants are hypersensitive to ionizing radiation.

<p>(A–C) <i>Smc6, MAGE</i> or <i>Smc5</i> homozygous, trans-heterozygous or hemizygous mutants have reduced survival when exposed to 40 Gy of IR. Bars represent the survival index (<i>p</i>) ± SEM. “□” indicates flies eclosed from the same cross. Absence of a bar indicates that no flies survived at that IR dose. (A) <i>Smc6</i> mutants are hypersensitive to IR. <i>R1</i> (<i>jnj^R1</i>) and <i>X1</i> (<i>jnj^X1</i>) are <i>Smc6</i> alleles. <i>Df</i> (<i>Df(3R)Exel6198</i>) is a deficiency chromosome uncovering the <i>Smc6</i> locus. (B) <i>MAGE</i> mutants are hypersensitive to IR. <i>RZ</i> (<i>sst^RZ</i>) and <i>XL</i> (<i>sst^XL</i>) are <i>MAGE</i> alleles. <i>Df</i> (<i>Df(3R)Antp¹</i>) is a deficiency chromosome uncovering the <i>MAGE</i> locus. (C) <i>Smc5</i> mutants are hypersensitive to IR. <i>P5</i> (<i>Smc5^{P{GSV1}GS3245}</i>) and <i>P7</i> (<i>Smc5^{P{GSV6}GS14577}</i>) are <i>Smc5</i> alleles. <i>Df</i> (<i>Df(3L)BSC418</i>) is a deficiency chromosome uncovering the <i>Smc5</i> locus.</p

Overview of <i>Smc6, MAGE</i>, and <i>Smc5</i> gene location, structural organization and mutant alleles.

<p>(A) <i>Smc6</i> is a 14 exon gene located on 3R:95E8–95F1. <i>jnj^R1</i> contains a 4 bp deletion in the 2nd coding exon. <i>jnj^X1</i> contains a 473 bp deletion of sequences upstream of exon 1 (196 bp), the entire exon 1 (252 bp), and a portion of intron 1 (25 bp), with a 12 bp vestige of the original P element remaining. <i>Smc6</i> genomic locus (3R:20,014,770.20,019,145 [−]) is shown. (B) <i>MAGE</i> is a single exon gene located on the right arm of the 3rd chromosome at position 84C7–84C7. <i>sst^RZ</i> has a point mutation that converts a glutamine at position 109 to a stop codon. <i>sst^XL</i> carries a targeted deletion of the entire coding sequence of <i>MAGE</i>. <i>MAGE</i> genomic locus (3R:2,979,960.2,980,898 [−]) is shown. (C) <i>Smc5</i> is a 16 exon gene located in 78D6–78D7 of the left arm of the 3rd chromosome. Exons encoding the longest transcripts are shown. Both <i>P{GSV1}GS3245</i> and <i>P{GSV6}GS14577</i> are inserted in the second coding exon. The <i>Smc5</i> genomic locus (3L:21,562,309.21,566,623 [+]) is shown. CDS, coding sequence.</p

Eye phenotypes in caffeine-sensitive mutant flies.

<p>(A) Caffeine-dependent eye phenotype of <i>Smc6 (jnj)</i> and <i>MAGE (sst)</i> mutants. Fly genotypes are as follows. Control: <i>EGUF/+; FRT82B +/FRT82B GMR-hid</i>. <i>Smc6</i> (loss of <i>Smc6</i> in eye cells): <i>EGUF/+; FRT82B jnj^R1/FRT82B GMR-hid. MAGE</i> (loss of <i>MAGE</i> in eye cells): <i>EGUF/+; FRT82B sst^RZ/FRT82B GMR-hid</i>. (B-D) <i>Smc6, MAGE</i> or <i>Smc5</i> homozygous, trans-heterozygous or hemizygous mutants have reduced survival when raised in media with caffeine. Bars represent the survival index (<i>p</i>) and error bars represent SEM. “□” indicates flies eclosed from the same cross. Absence of a bar indicates no surviving flies. Wildtype control flies are <i>w¹¹¹⁸</i>. (B) <i>Smc6</i> mutants are sensitive to caffeine. <i>R1</i> (<i>jnj^R1</i>) is an allele from the caffeine screen, <i>X1</i> (<i>jnj^X1</i>) was generated by an imprecise excision of a P-element adjacent to the 5′UTR of <i>Smc6</i>, and <i>Df</i> (<i>Df(3R)Exel6198</i>) is a deficiency chromosome uncovering the <i>Smc6</i> locus. (C) <i>MAGE</i> mutants are sensitive to caffeine. <i>RZ</i> (<i>sst^RZ</i>) is an allele from the caffeine screen, <i>XL</i> (<i>sst^XL</i>) is a targeted knockout, and <i>Df</i> (<i>Df(3R)Antp¹</i>) is a deficiency chromosome uncovering the <i>MAGE</i> locus. (D) <i>Smc5</i> mutants are sensitive to caffeine. Both <i>P5</i> (<i>Smc5^{P{GSV1}GS3245}</i>) and <i>P7</i> (<i>Smc5^{P{GSV6}GS14577}</i>) contain P-element insertions in a coding exon of <i>Smc5</i>, and <i>Df</i> (<i>Df(3L)BSC418</i>) is a deficiency chromosome uncovering the <i>Smc5</i> locus.</p

Caffeine-dependent genetic interaction of <i>MAGE</i> with <i>ATM</i>, <i>ATR</i> and <i>Rad51</i>(<i>SpnA</i>).

<p>(A) Representative eye phenotypes of <i>MAGE</i> (<i>EGUF/+; FRT82B sst^RZ/FRT82B GMR-hid</i>, loss of <i>MAGE</i> in eye cells), <i>ey>ATMi</i> (knockdown of <i>ATM</i> in eye cells), <i>ey>ATMi;MAGE</i> (<i>EGUF/UAS-ATM-RNAi;FRT82B sst^RZ/FRT82B GMR-hid,</i> loss of <i>MAGE</i> and knockdown of ATM in eye cells) and <i>ey>ATRi;MAGE</i> (<i>EGUF/UAS-ATR-RNAi;FRT82B sst^RZ/FRT82B GMR-hid,</i> loss of <i>MAGE</i> and knockdown of ATR in eye cells) flies that were reared on either standard media or media containing 2 mM caffeine. The EGUF system carrying the <i>eyeless-Gal4</i> driver was used to drive the UAS-RNAi transgenes in the eye and also makes the eye homozygous for <i>MAGE</i> (<i>sst^RZ)</i>. Controls for the effects of each eyeless-driven RNAi alone were carried out for <i>ATM</i> and <i>ATR</i> resulting in wild type appearing eyes, but only the results of <i>ATM</i> RNAi are shown here as an example. (B) Representative eye phenotypes of <i>MAGE</i> knockdown (<i>eyeless-Gal4/+;UAS-MAGE-RNAi/UAS-Dicer2,</i> knockdown of <i>MAGE</i> in eye cells) and <i>MAGE Rad51</i> double knockdown (<i>eyeless-Gal4/UAS-SpnA-RNAi;UAS-MAGE-RNAi/UAS-Dicer2</i>, knockdown of <i>MAGE</i> and <i>Rad51</i> in eye cells) flies that were reared on either standard media or media containing 2 mM caffeine.</p