System-level recommendations for improved wellness for gynecologic oncologists: A Society of Gynecologic Oncology Review.

Burnout and its negative sequelae are a persistent problem in gynecologic oncology, threatening the health of our physician workforce. Individual-level interventions such as stress management training, physical activity, and sleep hygiene only partially address this widespread, systemic crisis rooted in the extended work hours and stressful situations associated with gynecologic oncology practice. There is an urgent need for systematic, institution-level changes to allow gynecologic oncologists to continue the crucial work of caring for people with gynecologic cancer. We present recommendations for institution-level changes which are grounded in the framework presented by the National Plan for Health Workforce Well-Being by the National Academy of Medicine. These are aimed at facilitating gynecologic oncologists' well-being and reduction of burnout. Recommendations include efforts to create a more positive and inclusive work environment, decrease administrative barriers, promote mental health, optimize electronic medical record use, and support a diverse workforce. Implementation and regular evaluation of these interventions, with specific attention to at-risk groups, is an important next step.

Enhanced recovery after surgery (ERAS®) society guidelines for gynecologic oncology: Addressing implementation challenges - 2023 update.

BACKGROUND: Despite evidence supporting its use, many Enhanced Recovery After Surgery (ERAS) recommendations remain poorly adhered to and barriers to ERAS implementation persist. In this second updated ERAS® Society guideline, a consensus for optimal perioperative care in gynecologic oncology surgery is presented, with a specific emphasis on implementation challenges. METHODS: Based on the gaps identified by clinician stakeholder groups, nine implementation challenge topics were prioritized for review. A database search of publications using Embase and PubMed was performed (2018-2023). Studies on each topic were selected with emphasis on meta-analyses, randomized controlled trials, and large prospective cohort studies. These studies were then reviewed and graded by an international panel according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. RESULTS: All recommendations on ERAS implementation challenge topics are based on best available evidence. The level of evidence for each item is presented accordingly. CONCLUSIONS: The updated evidence base and recommendations for stakeholder derived ERAS implementation challenges in gynecologic oncology are presented by the ERAS® Society in this consensus review.

Prediction of short-term surgical complications in women undergoing pelvic exenteration for gynecological malignancies.

OBJECTIVE: Pelvic exenteration (PE) is an extensive surgery associated with high rates of postoperative morbidity and mortality. The absence of well-defined preoperative selection criteria to identify patients eligible for PE prompted the assessment of pre-operative predictors of 30-day major surgical complications. METHODS: Demographics and surgical characteristics of patients undergoing PE for gynecologic cancer in a single institution between 01/2004-12/2016 were reviewed. Postoperative complications within 30 days following surgery were graded using the Accordion grading system. Logistic regression was used to analyze potential risk factors for severe postoperative complications. RESULTS: A total of 138 patients were included in the cohort. Forty-five patients underwent total PE, 52 anterior PE, and 41 posterior PE. Among the 137 patients with follow-up, a severe postoperative complication was experienced by 37 patients (27.0%) and 3 patients (2.2%) experienced death within 90 days. The most frequent grade 3 complications were complications of urinary reconstruction (n = 15), wound dehiscence (n = 9), and abdominal abscess requiring intervention with drain or return to the operating room (n = 6). On multivariable analysis, independent predictors of severe postoperative complications were anterior or total PE (adjusted odds ratio (aOR): 11.66, 95% CI 2.56-53.18), pre-operative hemoglobin ≤10 mg/dl (aOR 2.70, 95% CI 1.02-7.14) and presence of 3+ comorbidities (aOR: 2.76, 95% CI 1.07-7.10). CONCLUSIONS: Major complications after exenteration are common. Surgical complexity and patient selection play a considerable role in predicting complications. These data can be used to better risk stratify patients undergoing PE.

Thyroid hormone influence on the susceptibility of mice to audiogenic seizures.

Serum thyroxine levels peak earlier and are significantly higher in audiogenic seizure-susceptible DBA/2J mice than in seizure-resistant C57BL/6J mice during early postnatal life. The seizure susceptibility of DBA/2J mice is suppressed by administration of an antithyroid drug or by radiothyroidectomy, while the seizure susceptibility of C57BL/6J mice is enhanced by treatment with excess thyroxine.

Isolated P2 rRNA promoters of Escherichia coli are strong promoters that are subject to stringent control.

Ribosomal RNA synthesis in Escherichia coli is under stringent control. The seven rRNA operons are highly conserved and are each transcribed from two tandem promoters, P1 and P2, which are located about 120 base-pairs apart. In exponentially growing cells the majority of the transcripts are initiated at the P1 promoters. The P1 promoters are highly regulated, and are under stringent as well as growth rate controls. Here we demonstrate that transcription from the rrnA P1 promoter diminishes P2 expression. In the absence of P1, the P2 promoter acts as a rather strong promoter. Insertion of a transcription terminator between P1 and P2 eliminates the inhibition of P2 by P1, suggesting that the physical movement of RNA polymerase originating at P1 and progressing along the P2 promoter is necessary for the interference process to take place. Similarly to P1, the solitary P2 promoter is subject to stringent control.

Genetic linkage between the AH locus and a major gene that inhibits susceptibility to audiogenic seizures in mice.

Mice of the DBA/2 (D2) strain are highly susceptible to sound-induced seizures at 21 days of age; whereas, mice of the C57BL/6 (B6) strain are resistant to these seizures. Although the difference in susceptibility to audiogenic seizures (ASs) between these two strains is inherited as a multiple-factor trait, an association was observed between susceptibility to ASs and the Ah locus. The Ah locus controls the inducibility of aryl hydrocarbon hydroxylase (AHH) activity by a number of aromatic hydrocarbons. B6 mice carry the Ahb allele and have inducible AHH activity; whereas, D2 mice carry the Ahd allele and have noninducible activity. Inducibility is inherited as a Mendelian dominant trait in crosses between these strains. Mice carrying the Ahb allele are generally less susceptible to ASs sat 21 days of age than are mice carrying the Ahd allele. The combined results from B6 X D2 recombinant inbred strains, congenic strains (where the Ahb allele was placed into the D2 genome and the Ahd allele placed into the B6 genome), the B6D2F1 X D2 backcross generation, and a random survey of various inbred strains, suggest that the association between these two traits is due to genetic linkage, rather than to pleiotrophy or to chance. A major gene that inhibits susceptibility to ASs appears to be closely linked to the Ah locus. This gene has been designated Ias, for inhibition of ASs. A large portion of the genetic variability of AS susceptibility may be due to the segregation of Ias.

Differential regulation of target genes by different alleles of the segmentation gene hunchback in Drosophila.

hunchback (hb) is a key regulatory gene in the early segmentation gene hierarchy of Drosophila. It codes for a transcription factor of the Cys2-His2 zinc finger type and shows two separate zinc finger domains in its coding region. hb forms a morphogenetic gradient in the middle of the embryo that is required for setting the spatial boundaries of several target genes. We have analyzed the molecular lesions found in the different hb alleles and have studied the differential effects of these alleles on a number of such target genes. We find that in mutants in which the HB protein lacks a functional second finger domain, the regulation of the target genes Krüppel (Kr) and knirps (kni) is differentially affected. While this domain is required for the correct regulation of Kr, it is not necessary for the repression of kni. Furthermore, mutations affecting this domain lead to a decreased protein stability. The integration of the expression pattern of target genes was found to be distorted in a second class of mutants between the two finger domains which lead to gain of function or neomorphic phenotypes. The effects of these mutations were studied in detail and it was found that they fall into two classes, the first one interfering with the function of the maternal hb product, the second leading to a delayed segmentation. The function of the latter class appears to be linked to the secondary expression of hb in the parasegment 4 (PS4) stripe at blastoderm stage.

Recombination and replication of plasmid-like derivatives of a short section of the mitochondrial chromosome of Neurospora crassa.

The 21-kbp mitochondrial chromosome of the stp-ruv strain of Neurospora crassa undergoes regional amplification yielding plasmid-like supercoiled circles varying in size from subunit length to very high multimers. A comparison of the base sequence of the five plasmids studied, with the region of the chromosome from which they were derived, indicated that the amplified chromosomal segments were determined by a recombination-excision process near or within two structurally distinctive regions. One of these, consisting of nearly uninterrupted strings of Cs and Gs straddling tandem PstI site direct repeats, could form an extended hairpin loop with only a few mismatches. It was found at or near the 5' exchange point of all of the plasmids. An extended 35-bp sequence containing 17-bp direct repeats was the primary 3' site of exchange. Base sequence changes were found in the vicinity of exchange points. Most notable of these was a G insertion and T to C transition within a section of the 5' region likely to form a hairpin loop, suggesting the involvement of a mismatch repair-like mechanism in the recombination process. The sequence, TATATAGACATATA, was identified as a likely candidate for the site of replication initiation. A nearly identical sequence was found common to all of the corresponding plasmids of Podospora anserina and was reported near the presumed replication origin of the Drosophila yakuba mitochondrial chromosome. A search of GenBank revealed a remarkable association of the consensus sequence, TATATAGAXATATA, with the plus strand of organelle DNA.

Genetic analysis of audiogenic seizure susceptibility in C57BL/6J X DBA/2J recombinant inbred strains of mice.

The inheritance of susceptibility to audiogenic seizures (ASs) was studied in the C57BL/6J (B6) and DBA/2J (D2) progenitor strains, their reciprocal F(1) hybrids, backcross generations and in 21 B6 x D2 recombinant inbred (RI) strains of mice at 21 days of age. All of the D2 mice tested experienced ASs, whereas none of the B6 mice responded to the sound. Although 23% of the F(1) mice experienced wild running, they were generally as resistant to ASs as their B6 parents. Mice of the F(1)x B6 backcross generation were also resistant to ASs. In the F(1)x D2 backcross generation, however, a significant preponderance (72%) of AS-susceptible mice was found. No significant association was observed between any of the four coat-color phenotypes that were segregating in this generation and susceptibility to ASs. A continuous distribution of mean seizure severity scores and several new audiogenic response phenotypes, distinctly different from the phenotypes of either progenitor strain, were found among the 21 RI strains. These and the results from the F(1)x D2 backcross generation suggest that the difference in AS susceptibility between 21-day-old B6 and D2 mice cannot be under the control of a single locus. In addition, no association was found between AS susceptibility and the chromosome 4 markers Lyb-2, Mup-1 and b among the 21 RI strains. An association was observed, however, between AS susceptibility and the Ah locus. Several of the RI strains that were AS resistant at 21 days of age became AS susceptible as adults. One RI strain was susceptible to ASs at both young and adult ages. The B6, D2 and F(1) mice were completely resistant to ASs at adult ages. Genetic differences were found among the RI strains for the incidence, onset, duration, and type of severity of ASs. A remarkable amount of phenotypic variability in the audiogenic response, which can be attributed only to the influence of environmental factors, occurred within several of the RI strains. A multiple-factor mode of inheritance involving a physiological threshold can account for our observations.

Regulatory and coding regions of the segmentation gene hunchback are functionally conserved between Drosophila virilis and Drosophila melanogaster.

The segmentation gene hunchback (hb) is involved in setting up the anterior-posterior axis of the Drosophila embryo. It is expressed maternally and zygotically and it plays a key role in integrating the effects of the anterior and posterior maternal systems. The hb gene from D. virilis has previously been cloned and was shown to be well conserved in its coding region, but less so in its upstream region which shows a more patchy pattern of conserved and diverged sequences. This work deals with the functional conservation of hb between the two species. We have mapped two additional regulatory elements for the expression of hb in the early embryo, namely the enhancer for the maternal expression and the enhancer region for the late blastoderm expression. Fragments containing these two elements, the previously identified bicoid dependent element for the early blastoderm expression of hb and the coding region were taken from D. virilis and tested in the D. melanogaster background. We find that all enhancer elements as well as the coding region are functionally conserved between the two species. Comparison of the upstream sequences that include the enhancer region for the late blastoderm expression reveal seven highly conserved blocks. Some of these contain consensus binding sites for transregulatory factors that are likely to control the respective expression domains.

ColE1 cloning of a ribosomal RNA promoter region from lambdarifd18 by selection for lambda integration and excision functions.

The expression of the ribosomal RNA gene carried by the lambda transducing phage lambdarifd18 is shown to be subject to stringent amino acid control. lambdarifd18 DNA was digested with endonuclease EcoRI and ligated to similarly restricted ColE1 plasmid DNA. Selection for expression of lambda integration and excision gene activity carried by the same DNA fragment results in cloning of the promoter proximal portion of the 16S ribosomal RNA gene. The resulting chemera expresses lambda integration and excision functions as well as encoding the promoter proximal half of a 16S ribosomal RNA gene.

A relA(S) suppressor mutant allele of Bacillus subtilis which maps to relA and responds only to carbon limitation.

The histidine analog 3-amino-1,2,4-triazole (AT) was used for the selection of spontaneous AT-resistant revertants of a relA mutant of Bacillus subtilis. One of these revertants, L3, showed a unique phenotype; it did not respond to amino acid starvation, like the relA mutant, but it did respond to glucose starvation by the accumulation of (p)ppGpp, unlike its parent. Genetic analysis revealed that this suppressor mutant (relA(S)) allele mapped to the relA locus at 239 degrees on the B. subtilis chromosome.

Psychomotor epilepsy and violence in a group of incarcerated adolescent boys.

The authors report the finding of psychomotor epilepsy in 18 of 97 incarcerated delinquent boys. Number of psychomotor symptoms was correlated with degree of violence in the members of this group. In addition, psychomotor symptoms were correlated more strongly with certain psychotic symptoms than with soft neurological signs or intellectual deficits. The relationship of violence to ictal and interictal states is explored.

Focal epilepsy with mesial temporal sclerosis after acute meningitis.

Following acute meningitis associated with severe convulsions in childhood, two patients had chronic, drug-resistant, temporal lobe epilepsy. This disorder was preceded by an entirely natural development, in one case extending for nine years and in the other case for eight years. Each patient was treated with right anterior temporal lobectomy. Classic mesial temporal sclerosis (Ammon's horn sclerosis) was found in both patients. Relief of the epilepsy was associated with remission of the concomitant social and psychiatric handicaps. At least ten years of follow-up are required in the evaluation of the treatment of early brain infections. Chronic focal epilepsy after childhood meningitis with febrile convulsions merits neurosurgical consideration.

Analysis of the shut-off of ribosomal RNA promoters in Escherichia coli upon entering the stationary phase of growth.

Most bacterial RNA consists of stable RNA which is composed of rRNA and tRNA. We have followed by primer extension analysis the level of ribosomal RNA synthesis along the growth phases of a cell culture. A sharp drop in rRNA synthesis was observed upon the transition from the exponential to the stationary phase of growth. Our results demonstrate that an effective shut-off of rRNA synthesis occurs also in the absence of ppGpp. Mutations in the host factors Fis and H-NS, which are known to regulate rrn P1 promoters, did not affect the shut-off process of ribosomal RNA promoters. We also tested the effect of RpoS, the sigma factor known to induce a number of genes in the stationary phase. It was shown that the host factors Fis, H-NS and RpoS do not play a major role in the regulation of the shut-off process of rRNA synthesis. The results presented demonstrate that the rate of rRNA synthesis provides a sensitive measure of the growth phase of the bacterial culture.

Kindling induces a long-lasting change in the activity of a hippocampal membrane calmodulin-dependent protein kinase system.

Septal kindling has been shown to produce a long-lasting decrease in endogenous calcium/calmodulin-dependent phosphorylation of hippocampal synaptic plasma membrane proteins, including two major bands of approximately 50,000 and 60,000 Daltons. These two proteins differ from the B-50 protein and tubulin, as evidenced by differences in migration in SDS-PAGE gels and by lack of cross-immunoreactivity with specific antibodies. Identity of these two proteins with the rho and sigma subunits of purified calmodulin-dependent kinase (CaM Kinase II) is suggested by similar migration in SDS-PAGE and two-dimensional gels, by similar calmodulin binding in two-dimensional gels, and similar 125I-peptide mapping of the 50,000 Dalton protein. These results demonstrate that septal kindling is associated with changes in the activity of a major Ca2+/calmodulin-dependent kinase system in hippocampal synaptic plasma membrane. This long-lasting modulation of kinase activity may provide a molecular insight into some aspects of neuronal plasticity.

Inherited convulsive disorders in mice.

In this chapter, we review the major inherited convulsive disorders found in mice and discuss their possible relationship to specific clinical seizure disorders in humans. These disorders in mice include audiogenic seizures, the epilepsy (El) mouse, various spontaneous seizures, the tottering/leaner syndrome, seizures associated with cerebellar abnormalities, seizures associated with myelin disorders, and alcohol withdrawal seizures. We find that for most major types of epilepsy in humans, there exists a similar counterpart in the mouse. Because human and rodent nervous systems respond similarly to seizure-provoking stimuli, it is possible that biochemical and physiological mechanisms of naturally occurring convulsive disorders are also similar in these species. The use of recombinant inbred (RI) and congenic mouse strains for genetic and biochemical studies of audiogenic seizures is presented. Using these strains, we have identified a major gene, Ias, that inhibits the spread of seizure activity. This gene was found through its close linkage with the Ah locus on chromosome 17. We also found that juvenile-onset and adult-onset audiogenic seizures are controlled by different genetic systems. The problem of juvenile-onset audiogenic seizure susceptibility is especially interesting because these seizures are genetically associated with an ecto-Ca2+-ATPase deficiency among the RI strains. This deficiency is the first neurochemical trait found to be inherited together with an idiopathic convulsive disorder, and may represent a potentially important basic mechanism of epilepsy. Because the brains of human epileptics are generally inaccessible for neurochemical research, the epileptic mouse mutants offer a convenient means of pursuing this type of research. The well-known genetic constitution of the mouse, together with the availability of numerous physiologically distinct convulsive disorders, makes the mouse ideally suited for molecular, genetic, and biochemical studies of convulsive behavior.