Leaning in and moving forward: a call to action and review of diversity initiatives in SAGES.

BACKGROUND: Diversity, equity, and inclusion have been an intentional focus for SAGES well before the COVID-19 pandemic and the coincident societal recognition of social injustices and racism. Longstanding inequities within our society, healthcare, and the surgery profession have come to light in the aftermath of events that rose to attention around the time of Covid. In so doing, they have brought into focus disparities, injustices, and inequalities that have long been present in the field of surgery, selectively affecting the most vulnerable. METHODS: This White paper examines the current state of diversity within the field of surgery and SAGES (Society of American Gastrointestinal and Endoscopic Surgeons) approach and effort to pave the way forward to meaningful change. We delineate the imperative for diversity, equity, and inclusion for all. By all, we mean to be inclusive of the diversity of gender and sexual orientation, race, ethnicity, geography, sex, and disability in the field of surgery. RESULTS: SAGES is an organization that lives at the intersection of education and innovation. It has a vital role in assisting the surgical profession in addressing these issues and needs and being a force alongside others for sustained and necessary change. SAGES can only realize these goals through a commitment across all aspects of the organization to embed diversity, equity, and inclusion into our very fabric. CONCLUSION: True diversity, equity, and inclusion within a surgical organization is vital for its longevity, growth, relevance, and impact. Unfortunately, the absence of DEI limits opportunity, robs the organization of collective intelligence in an environment in which its presence is critical, contributes to health inequities, and impoverishes all within the society and its value to all with whom it interfaces. SAGES is an organization that lives at the intersection of education and innovation. It has a vital role in assisting the surgical profession in addressing these issues and needs and being a force alongside others for sustained and necessary change. SAGES can only realize these goals through a commitment across all aspects of the organization to embed diversity, equity, and inclusion into our very fabric. Strategies like those highlighted in this White Paper, may be within our grasp and we can learn yet more if we remain in a place of humility and teachability in the future.

Guideline-discordant care among females undergoing groin hernia repair: the importance of sex as a biologic variable.

PURPOSE: Females suffer higher rates of operative recurrence and chronic pain following groin hernia repair. Guidelines recommend minimally invasive (MIS) groin hernia repair as the preferred approach to reduce these adverse outcomes. It is unknown what proportion of females receive MIS hernia repair. Therefore, our goal was to investigate adoption of evidence-based practices in groin hernia repair using sex as a biological variable. METHODS: Retrospective cohort study of adults undergoing elective groin hernia repair (2014-2019) within a statewide quality improvement collaborative. Primary outcome was surgical approach. Multivariable logistic regression was performed to analyze the likelihood of undergoing MIS hernia repair. Secondary outcomes were 30-day adjusted rates of clinical and patient-reported outcomes (PROs). PROs included regret to undergo surgery among patients who completed post-operative surveys. RESULTS: Among 23,723 patients, the majority (90.7%) were males. Compared to males, females less often underwent an MIS surgical approach (37.4% vs 45.1%, p < 0.0001). After adjustment for patient and clinical variables, females remained significantly less likely to undergo MIS groin hernia repair (aOR 0.88, 95% CI 0.80-0.97). Adjusted clinical outcomes were not different between males and females. Among 4325 patients who completed post-operative surveys, adjusted rates of regret to undergo surgery were higher among females (12.9% vs 8.5%, p = 0.003). CONCLUSIONS: Even after adjusting for differences, females were less likely to receive guideline-concordant groin hernia repair and were more likely to regret surgery. Understanding the behaviors of surgeons who treat females with groin hernia may inform quality metrics to promote best practices in this population.

New intragenic and promoter region deletion mutations in FERMT1 underscore genetic homogeneity in Kindler syndrome.

BACKGROUND: Kindler syndrome (KS) is a rare autosomal recessive skin disorder, which was recently reclassified as a subtype of epidermolysis bullosa. Despite the fact that loss-of-function mutations in the FERMT1 gene, encoding kindlin-1, have been shown to cause the syndrome in numerous patients, a small number of typical cases of KS in which FERMT1 mutations could not be identified has raised the possibility that the disorder may be genetically heterogeneous. AIM: To assess two highly consanguineous families with clinical characteristics of KS. RESULTS: In the first family, a hitherto unreported deletion (c.137-140delTAGT) in FERMT1 was detected, which is predicted to lead to premature termination of translation. However, direct sequencing of the coding region of FERMT1 failed to disclose any pathogenic change in the second family. To confirm the possibility that the disease in this family may be due to a mutation in another gene, we used homozygosity mapping, and found that all affected family members share a segment of homozygosity on 20p12.3, spanning the FERMT1 gene. Accordingly, a large and highly unusual deletion (g.-711-1241del) spanning the putative FERMT1 promoter sequence and the first noncoding exon of the gene was found to cosegregate with the disease phenotype in this family, and to prevent transcription of the gene, as attested by the lack of FERMT1 message in the skin of a patient. CONCLUSION: The present data provide evidence in support of genetic homogeneity in KS.

Non-syndromic autosomal recessive congenital ichthyosis in the Israeli population.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is the term given to a complex and heterogeneous group of cornification disorders associated with mutations in at least eight distinct genes. Mutation distribution and prevalence rates are instrumental for the design of diagnostic strategies in ARCI but have not yet been systematically explored in the Israeli population. Previous data suggest that the demographic features specific to Middle Eastern populations, such as a high frequency of consanguineous marriages, may have an effect on the molecular epidemiology of genodermatoses. METHODS: We systematically assessed all families with ARCI presenting at our clinics over a period of 9 years, using a combination of homozygosity mapping, direct sequencing and PCR-restriction fragment length polymorphism assays. RESULTS: In total, 20 families with ARCI were assessed, and causative mutations were identified in 7 genes: TGM1 (30% of patients), ALOX12B (20%), ABCA12 (5%), CYP4F22 (10%), ALOXE3 (10%), LIPN (5%) and NIPAL4 (5%) Two families (10%) had mutations mapped to an ARCI-associated locus on 12p11.2-q13, while no mutation was found for one additional kindred. In the subgroup of families of Arab Muslim origin, mutations were identified most frequently in ALOX12B and TGM1 (31%), whereas the other subgroups displayed a subtype distribution very similar to that previously reported in western populations. CONCLUSIONS: The present data point to the need for population-tailored mutation screening strategies in genetically heterogeneous genodermatoses, based on the relative prevalence of the disease subsets.

Epidermolytic palmoplantar keratoderma caused by activation of a cryptic splice site in KRT9.

Epidermolytic palmoplantar keratoderma (EPPK) is caused by mutations in KRT9 and less often, KRT1. All known mutations in KRT9 have been found in regions of the gene encoding the conserved central α-helix rod domain. In the present study, we investigated the molecular basis of EPPK in a patient of Ashkenazi Jewish origin. The patient was found to carry a novel missense mutation in KRT9, resulting in the substitution of a poorly conserved leucine for valine at position 11 of the amino acid sequence. Despite its unusual location, the mutation was shown to be pathogenic through activation of a cryptic donor splice site, resulting in the deletion of 162 amino acids. The present data indicate the need to screen keratin genes in their entirety, as mutations altering domains of lesser functional importance may exert their deleterious effect at the transcriptional level.

Laparoscopic versus open inguinal hernia repair in octogenarians.

PURPOSE: This retrospective chart review was designed to compare outcomes for open and laparoscopic repair of inguinal hernias in the population over the age of 80. METHODS: A retrospective chart review was conducted for 104 patients over 80 years old who underwent inguinal hernia repair (2005-2008) at The Mount Sinai Medical Center. Patients were grouped into laparoscopic or open repair cohorts and compared accordingly. RESULTS: The open group (n = 73) and the laparoscopic group (n = 31) had mean ages of 84 and 83 years, respectively. The mean American Society of Anesthesiologists score was 2.6 for the open cohort and 2.3 for the laparoscopic group (P < 0.05). Peri-operative complications in the open and laparoscopic groups were not found to be statistically significant. There was no mortality in either group. CONCLUSIONS: With octogenarians, laparoscopic inguinal hernia repair can be performed as a safe alternative to open repair with comparable rates of morbidity and mortality.

Erythrokeratoderma variabilis caused by a recessive mutation in GJB3.

BACKGROUND: Erythrokeratoderma variabilis (EKV) is a rare disorder of cornification usually associated with dominant mutations in the genes GJB3 and GJB4, which code for connexin (Cx)31 and Cx30.3, respectively, and contribute to the formation of functional gap junctions in the epidermis. AIM: To identify the molecular basis of recessive EKV in a consanguineous family of Middle Eastern origin. METHODS: Direct sequencing and site-directed mutagenesis was used to search for the disease-causing mutation and identify its molecular consequences. RESULTS: A novel missense mutation (c.G88A) was found in the human GJB3 gene, resulting in substitution of the amino acid isoleucine for valine at position 30 (p.V30I). Under in vitro conditions, p.V30I prevents Cx31 reaching the cell membrane and taking part in gap-junction formation. CONCLUSIONS: Autosomal recessive inheritance should be considered when providing genetic counselling to consanguineous families at risk for EKV.

An exceptional mutational event leading to Chanarin-Dorfman syndrome in a large consanguineous family.

Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive metabolic disorder featuring congenital ichthyosis combined with pleiomorphic visceral manifestations associated with tissue accumulation of cytoplasmic lipid droplets. Mutations in the ABHD5 gene, encoding a crucial cofactor for adipose triglyceride lipase, have been found to underlie all CDS cases reported to date. The purposed of this study was to ascertain the genetic defect underlying CDS in a large multigenerational family. We used a combination of direct sequencing, reverse transcriptase-polymerase chain reaction (RT-PCR) and microsatellite marker genotyping to identify a novel CDS-causing mutation in ABHD5. Although no pathogenic mutation could be identified in the coding sequence of the ABHD5 gene, polymorphic marker genotyping analysis supported linkage to this gene locus. Accordingly, direct sequencing of RT-PCR amplification products generated from patient skin-derived total RNA, revealed in all four patients the presence of a 101 bp insertion between exon 3 and exon 4. Bioinformatic analysis and direct sequencing indicated that this insertion resulted from an exceptional mutational event, namely, the insertion of a LINE element into intron 3 of the ABHD5 gene, leading to aberrant splicing out of the mutant intron 3. Our results confirm genetic homogeneity in CDS and underscore the importance of RNA studies in the molecular diagnosis of genodermatoses.

Assessing the risk of clopidogrel-related bleeding complications in patients undergoing inguinal herniorrhaphy.

BACKGROUND: To date, no studies have investigated how the preoperative management of clopidogrel, an irreversible antiplatelet agent, influences the outcome following minor operative procedures. The purpose of this study is to determine if clopidogrel use within 7 days of inguinal herniorrhaphy increases the postoperative risk for bleeding-related morbidity or mortality. METHODS: A retrospective chart review was performed of 46 patients on clopidogrel who underwent inguinal herniorrhaphy from 2004 to 2008. Patients were grouped based on the last administered dose of clopidogrel; <7 days (A) and ≥ 7 days (B). RESULTS: Of the 46 patients, 20 were in group A and 26 were in group B. No significant differences in operative blood loss, perioperative transfusion requirement, postoperative bleeding complications, intensive care unit (ICU) requirements, mortality, or 30-day readmission/reoperation rates were demonstrated between patients in groups A and B. Patients in group A had a significantly increased postoperative admission rate (65% vs. 15%, P = 0.0002) and increased mean hospital stay (1.0 vs. 0.15 days, P = 0.003). However, urinary retention, pain management, and the monitoring of other conditions accounted for over 80% of these admissions. One patient in group A (5%) developed a postoperative hematoma, which is consistent with the complication rate seen in the general population after inguinal herniorrhaphy. Overall, no difference in admission secondary to hematoma or postoperative bleeding was demonstrated. CONCLUSION: Clopidogrel use within 7 days of inguinal herniorrhaphy did not increase the risk for perioperative bleeding complications. No mortalities, readmissions, or ICU requirements occurred, regardless of the timing of clopidogrel cessation. The increased risk for hospital admission and length of stay seen in group A is likely to be attributable to nonbleeding-related patient factors rather than clopidogrel use. Thus, it may not be necessary to interrupt clopidogrel therapy prior to inguinal herniorrhaphy in high-risk patients.

CEDNIK syndrome results from loss-of-function mutations in SNAP29.

BACKGROUND: CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5 years ago in one family to be associated with a loss-of-function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis. OBJECTIVES: To delineate the molecular consequences of disease-causing mutations in SNAP29. METHODS: We used direct sequencing, in vitro mutagenesis and three-dimensional organotypic cell cultures. RESULTS: We identified a novel homozygous insertion in SNAP29 (c.486insA) in two sibs presenting with ichthyosis and dysgenesis of the corpus callosum. In vitro transfection experiments indicated that this mutation results in SNAP29 loss-of-function. Further substantiating this notion, we could replicate histological features typical for CEDNIK syndrome in three-dimensional primary human keratinocyte organotypic cell cultures downregulated for SNAP29. CONCLUSIONS: The identification of a second mutation in SNAP29 in the present study definitely establishes a causal relationship between defective function of SNAP29 and the pleiotropic manifestations of CEDNIK syndrome. Our present and previous data position SNAP29 as an essential component of the epidermal differentiation machinery.

Minimally invasive surgery for splenic malignancies.

While minimally invasive surgery, i.e. laparoscopy, has become well-accepted in the treatment algorithm for malignancies of the gastrointestinal tract and gynecologic tumors, the role of laparoscopy for malignancies involving the spleen is less clear. Initially described in 1992 for benign hematologic disease, laparoscopic splenectomy (LS) for splenic malignancy was avoided secondary to the severe hematologic disease, profound cytopenia, and massive splenomegaly frequently seen in these patients. As experience with LS grew and larger data were generated, it became clear that hematologic malignancy and splenomegaly could be safely managed laparoscopically. In experienced hands, LS can be used for the diagnosis and treatment of both lymphoproliferative and myeloproliferative disorders affecting spleen, in addition to splenic tumors of both primary and metastatic origin. LS can be performed from a lateral or anterior approach, and hand-assisted laparoscopic splenectomy can provide significant benefit in cases of massive splenomegaly. Preoperative imaging for accurate splenic measurement is invaluable to guide surgical planning. Triple vaccination should be given to all patients prior to surgery, and splenic artery embolization before surgery should be considered in patients with massive splenomegaly to reduce intraoperative bleeding. LS can be performed safely for nearly all cases of malignancy involving the spleen, and potentially offers significant advantages of decreased pain and recovery time while maintaining equivalent complications and survival compared to open splenectomy.

Antenatal mitochondrial disease caused by mitochondrial ribosomal protein (MRPS22) mutation.

Three patients born to the same set of consanguineous parents presented with antenatal skin oedema, hypotonia, cardiomyopathy and tubulopathy. The enzymatic activities of multiple mitochondrial respiratory chain complexes were reduced in muscle. Marked reduction of 12s rRNA, the core of the mitochondrial small ribosomal subunit, was found in fibroblasts. Homozygosity mapping led to the identification of a mutation in the MRPS22 gene, which encodes a mitochondrial ribosomal protein. Transfection of the patient cells with wild-type MRPS22 cDNA increased the 12s rRNA content and normalised the enzymatic activities. Quantification of mitochondrial transcripts is advisable in patients with multiple defects of the mitochondrial respiratory chain.