Rapid progression of cervical squamous cell carcinoma with delayed treatment in pregnancy.

•Delayed treatment of cervical cancer in pregnancy can result in progression.•Surveillance of cervical cancer in pregnancy with pelvic MRIs every 6 weeks.•Comprehensive multidisciplinary care is essential in setting of treatment delays.

Association of second trimester uterine artery Doppler parameters with maternal hypertension 2-7 years after delivery.

BACKGROUND: Reduced uterine artery compliance is associated with adverse pregnancy outcomes (APOs) and may indicate underlying maternal cardiovascular pathology. We investigated associations between second trimester uterine artery Doppler (UAD) parameters and incident maternal hypertension 2-7 years after delivery. METHODS: A cohort of 10,038 nulliparous US participants was recruited early in pregnancy. A subgroup of 3739, without baseline hypertension and with complete follow-up visits 2-7 years after delivery, were included in this analysis. We investigated UAD indicators of compliance including: 1) early diastolic notch; 2) resistance index (RI); and 3) pulsatility index (PI). We defined hypertension as systolic blood pressure ≥130 mmHg, diastolic ≥80 mmHg, or antihypertensive medication use. We calculated odds ratios (OR) and 95 % confidence intervals (95%CI) for associations between UAD parameters and hypertension, adjusting for age, obesity, race/ethnicity, insurance, smoking, and APOs. RESULTS: A total of 187 (5 %) participants developed hypertension after the index pregnancy. Presence of early diastolic notch on UAD was not associated with incident hypertension. Increased RI and PI correlated with higher odds of hypertension (RI: adjusted OR 1.15 [95 % CI 1.03-1.30]; PI: adjusted OR 1.03 [95%CI 1.01-1.05] for each 0.1 unit increase). Maximum RI above 0.84 or maximum PI above 2.3 more than doubled the odds of incident hypertension (RI: adjusted OR 2.49, 95%CI 1.45-4.26; PI: adjusted OR 2.36, 95%CI 1.45-3.86). CONCLUSION: Higher resistance and pulsatility indices measured on second trimester UAD were associated with increased odds of incident hypertension 2-7 years later, and may be biomarkers of higher maternal cardiovascular risk.

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis.

BACKGROUND: The cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear. METHODS: We evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited. RESULTS: In 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases. CONCLUSIONS: In this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.).

Rejuvenation of RBCs: validation of a manufacturing method suitable for clinical use.

BACKGROUND: Rejuvenation of stored red blood cells (RBCs) increases levels of adenosine 5'-triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) to those of fresh cells. This study aimed to optimize and validate the US-approved process to a UK setting for manufacture and issue of rejuvenated RBCs for a multicenter randomized controlled clinical trial in cardiac surgery. STUDY DESIGN AND METHODS: Rejuvenation of leukoreduced RBC units involved adding a solution containing pyruvate, inosine, phosphate, and adenine (Rejuvesol, Zimmer Biomet), warming at 37°C for 60 minutes, then "manual" washing with saline adenine glucose mannitol solution. A laboratory study was conducted on six pools of ABO/D-matched units made the day after donation. On Days 7, 21, and 28 of 4 ± 2°C storage, one unit per pool was rejuvenated and measured over 96 hours for volume, hematocrit, hemolysis, ATP, 2,3-DPG, supernatant potassium, lactate, and purines added (inosine) or produced (hypoxanthine) by rejuvenation. Subsequently, an operational validation (two phases of 32 units each) was undertaken, with results from the first informing a trial component specification applied to the second. Rejuvenation effects were also tested on crossmatch reactivity and RBC antigen profiles. RESULTS: Rejuvenation raised 2,3-DPG to, and ATP above, levels of fresh cells. The final component had potassium and hemolysis values below those of standard storage Days 7 and 21, respectively, containing 1.2% exogenous inosine and 500 to 1900 µmoles/unit of hypoxanthine. The second operational validation met compliance to the trial component specification. Rejuvenation did not adversely affect crossmatch reactivity or RBC antigen profiles. CONCLUSION: The validated rejuvenation process operates within defined quality limits, preserving RBC immunophenotypes, enabling manufacture for clinical trials.

Nonimmune hydrops fetalis: identifying the underlying genetic etiology.

PURPOSE: Numerous etiologies may lead to nonimmune hydrops fetalis (NIHF), and the underlying cause often remains unclear. We aimed to determine the proportion of NIHF cases in which the etiology was clearly determined in a large, contemporary, and diverse cohort, as well as to describe the etiologies with a focus on genetic causes. METHODS: Retrospective review of NIHF cases between 2015 and 2017 from the five University of California Fetal-Maternal Consortium sites. Singleton pregnancies with prenatally diagnosed NIHF were included, and cases with maternal alloimmunization were excluded. Cases were categorized as being of confirmed, suspected, or unknown etiology. RESULTS: Sixty-five NIHF cases were identified. Forty-six percent (30/65) remained of unknown etiology, while 9.2% (6/65) had a suspected etiology and 44.6% (29/65) were of confirmed etiology. Among confirmed cases, 11 resulted from aneuploidy; 7 from fetal structural anomalies; 2 each from fetal arrhythmia, Noonan syndrome, and generalized lymphatic dysplasia; and 1 each from arthrogryposis, parvovirus, neonatal alloimmune thrombocytopenia, fetal goiter, and Kasabach-Merritt syndrome. CONCLUSION: In this contemporary, multicenter study, the cause of prenatally diagnosed NIHF was confirmed in only 44% of cases, and a genetic etiology was found in only 25% of those that received standard of care genetic testing.

Conservative Management of Invasive Placentation: Two Cases with Different Surgical Approaches.

Background When placenta accreta complicates a delivery, the typical management is to perform a cesarean hysterectomy. Other management strategies, including leaving the placenta in situ, have been attempted and supported in some cases. This may allow for an interval hysterectomy, which can potentially decrease average blood loss and/or allow a minimally invasive approach to the hysterectomy. Cases We present two cases of women with invasive placentation managed conservatively with interval hysterectomy. One woman was managed with robotic-assisted laparoscopic surgery and the other with an open surgical approach. Conclusion These cases highlight the successful use of conservative management for invasive placentation in two stable patients and showcase the novel use of a robotic-assisted laparoscopic surgery for management of invasive placentation.

Paraesophageal hernia repair in the emergency setting: is laparoscopy with the addition of a fundoplication the new gold standard?

BACKGROUND: Laparoscopic repair of paraesophageal hernia (PEH) with fundoplication is currently the preferred elective strategy, but emergent cases are often done open without an anti-reflux (AR) procedure. This study examined PEH repair in elective and urgent/emergent settings and investigated patient characteristic influence on the use of adjunctive techniques, such as AR procedures or gastrostomy tube (GT) placement. METHODS: Utilizing the University HealthSystem Consortium Clinical Database Resource Manager, selected discharge data were retrieved using International Classification of Disease 9 diagnosis codes for PEH and procedure specific codes. Chi-squared and paired t tests were applied (α = 0.05). RESULTS: Discharge data from October 2010 through June 2014 indicated 7950 patients (≥18 years) underwent PEH surgery, 84.7 % were performed laparoscopically and 15.3 % open. 24.6 % of cases were classified urgent/emergent upon admission, and almost 70 % of these were completed laparoscopically. Open paraesophageal hernia repairs (OHR) represented a higher proportion of urgent/emergent cases but were only 30 % of this total. Laparoscopic paraesophageal hernia repair (LHR) patients were more likely to receive an AR procedure in all situations (54.9 % LHR vs. 26.3 % OHR). Almost 90 % of elective PEH repairs in this cohort were laparoscopic. Elective cases were more commonly associated with AR procedures than emergent cases which frequently incorporated GT placement. CONCLUSION: We demonstrate that laparoscopic PEH repair has become accepted in emergent cases. Open PEH repair is often reserved for emergent surgeries and less commonly includes an AR procedure. Laparoscopy with an AR procedure is clearly the standard of care in elective surgery. The decision to perform an open or laparoscopic surgery, with or without adjunctive techniques, may be based more on the physician's comfort with laparoscopic surgery and surgical practices than the patient's condition. Long-term follow-up studies are needed to determine the functional outcomes of these strategies.

Resident involvement in laparoscopic procedures does not worsen clinical outcomes but may increase operative times and length of hospital stay.

BACKGROUND: Surgical procedures have a learning curve regarding the number of cases required for proficiency. Consequently, involvement of less experienced resident surgeons may impact patients and the healthcare system. This study examines basic and advanced laparoscopic procedures performed between 2010 and 2011 and evaluates the resident surgeon participation effect. METHODS: Basic laparoscopic procedures (BL), appendectomy (LA), cholecystectomy (LC), and advanced Nissen fundoplication (LN) were queried from the American College of Surgeons National Surgical Quality Improvement Program database. Cases were identified using Current Procedural Terminology codes. Analyses were performed using IBM SPSS Statistics v.22, α-level = 0.05. Multiple logistic regression was used, accounting for age, race, gender, admission status, wound classification, and ASA classification. RESULTS: In total, 71,819 surgeries were reviewed, 66,327 BL (37,636 LC and 28,691 LA) and 5492 LN. Median age was 48 years for LC and 37 years for LA. In sum, 72.2 % of LC and 49.5 % of LA patients were female. LN median age was 59 years, and 67.7 % of patients were female. For BL, resident involvement was not significantly associated with mortality, morbidity, and return to the OR. Readmission was not related to resident involvement in LC. In LA, resident-involved surgeries had increased readmission and longer OR time, but decreased LOS. In LC, resident involvement was associated with longer LOS and OR time. Resident involvement was not a significant factor in the odds of mortality, morbidity, return to OR, or readmission in LN. Surgeries involving residents had increased odds of having longer LOS, and of lengthier surgery time. CONCLUSIONS: We demonstrate resident involvement is safe and does not result in poorer patient outcomes. Readmissions and LOS were higher in BL, and operative times were longer in all surgeries. Resident operations do appear to have real consequences for patients and may impact the healthcare system financially.

Paraesophageal hernia.

The treatment of PEHs is challenging. They tend to occur in patients in their 60s and 70s with multiple medical problems and a variety of associated symptoms. Detailed preoperative evaluation is crucial to determining a safe and effective strategy for repair in the operating room. Laparoscopic PEH repair has shown to be advantageous compared with conventional open repair with regard to hospital stay, recovery time, and decreased complications. Although some results indicate there are higher recurrence rates in laparoscopic PEH repair, the clinical significance of these recurrences has not yet been determined. In order to maximize the efficacy of this procedure, modifications have emerged, such as performing a fundoplication and using an absorbable mesh onlay to reinforce the cruroplasty. Althoughmoreprospective, randomized studies are needed to support the superior results of these surgical adjuncts, laparoscopic PEH repair with an antireflux procedure and absorbable mesh should be the current standard of care.

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis.

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

The relationship between previous treatment for cervical dysplasia and preterm delivery in twin gestations.

OBJECTIVE: To describe the impact of previous cervical surgery on preterm birth prior to 34 weeks in twins. METHODS: A retrospective review of twin pregnancies delivered between January 1998 and December 2005 at two institutions was performed. Women with a prior cold knife cone (CKC), loop electrosurgical excision procedure (LEEP), or ablative procedure were compared to a control group of women who had not undergone a previous treatment for cervical dysplasia. The primary outcome was delivery before 34 weeks of gestation. RESULTS: A total of 876 women met inclusion criteria. Of these, 110 (12.6%) had previous surgical procedures for cervical dysplasia, including CKC (n = 10), LEEP (n = 36), cryotherapy (n = 59) and CO2 laser treatment (n = 5). Delivery prior to 34 weeks was more common in women with a previous CKC compared to women with no prior treatment (40% versus 11.3%; odds ratio [OR], 3.6; 95% confidence interval [CI], 1.7-8.0). Delivery prior to 34 weeks was not more common in women with a previous LEEP (8.3%; OR, 0.8; 95% CI, 0.3-2.3) or ablative procedure (9.4%; OR, 0.9; 95% CI, 0.4-1.9) in comparison to the untreated group. Adjusting for the potential confounders of age, tobacco use, infertility treatments and previous preterm birth did not change the results. CONCLUSIONS: Previous CKC is associated with delivery prior to 34 weeks while LEEP and ablative procedures are not. CKC should be carefully considered and avoided when possible in reproductive age women.

Single-incision versus conventional laparoscopic adjustable gastric banding.

BACKGROUND AND OBJECTIVES: Laparoscopic adjustable gastric banding is an effective and popular bariatric surgery for weight loss in obese patients that traditionally involves up to 5 incisions. Recently, a more minimally invasive single-incision technique has been developed. In this retrospective study, we compare conventional and single-incision laparoscopic adjustable gastric banding with regard to weight loss and complication rates in a cohort of demographically similar patients. METHODS: From February 2009 to February 2010, 59 patients underwent laparoscopic adjustable gastric banding by one surgeon at an outpatient surgery center. All patients were compared by age, sex, preoperative body mass index, 30-day complication rates, and excess weight loss. Thirty-seven operations were performed by a conventional, 5-incision technique, whereas 22 patients underwent the single-incision technique. The success of these techniques was determined by comparing complication rates and average percentage excess weight loss at 6-month follow-up intervals. RESULTS: Patients who underwent conventional laparoscopic adjustable gastric banding had a mean age of 41.2 years and preoperative body mass index of 48.2 kg/m(2) compared with 43.9 years and 40.3 kg/m(2), respectively, for the single-incision patients. The mean operative time in the single-incision group was longer than that in the conventional group: 47.1 minutes versus 37.4 minutes (P = .0027). The overall percentage excess weight loss was not statistically different between the 2 groups for each follow-up period. There were no complications or deaths in either group. CONCLUSION: Although patients undergoing bariatric surgery may choose the single-incision technique for cosmetic purposes, this retrospective review comparing single-incision and conventional laparoscopic adjustable gastric banding shows longer operative times with equivalent weight loss and morbidity.

Hospital readmission for fluid and electrolyte abnormalities following ileostomy construction: preventable or unpredictable?

BACKGROUND: Ileostomy creation has complications, including rehospitalization for fluid and electrolyte abnormalities. Although studies have identified predictors of this morbidity, readmission rates remain high. METHODS: The researchers conducted a retrospective chart review of all patients with ileostomy creation at a tertiary institution from January 2008 to June 2011. RESULTS: One hundred fifty-four patients (154) were included in this study; 71 (46.1 %) were female. Mean age was 49 ± 17.64 (range 16-91), and mean BMI was 26.9 ± 6.44 (range 13-52). The readmission rate for fluid and electrolyte abnormalities was 20.1 % for the study population; of those readmitted for all diagnoses, dehydration accounted for 40.7 % of all readmissions. Cancer was associated with readmission (χ(2) = 4.73, p = 0.03) as was neoadjuvant therapy (χ(2) = 9.20, p = 0.01). After multivariate analysis, only the use of anti-diarrheals and neoadjuvant therapy remained significant. High stoma output, adjuvant treatment, and postoperative complications were not significant. CONCLUSIONS: Our study found that the use of anti-diarrheals and neoadjuvant therapy for rectal cancer were associated with readmission. Our findings imply that the use of anti-diarrheals may be a marker for patients at risk for fluid and electrolyte abnormalities; these patients should be strictly monitored at home. Our study also suggests consideration of avoidance of ileostomy creation or different discharge criteria for at-risk patients. Prospective studies focused on stoma monitoring after discharge may help reduce rehospitalizations for fluid and electrolyte abnormalities after ileostomy creation.

Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome.

The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.

A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function.

Mean platelet volume (MPV) and platelet count (PLT) are highly heritable and tightly regulated traits. We performed a genome-wide association study for MPV and identified one SNP, rs342293, as having highly significant and reproducible association with MPV (per-G allele effect 0.016 +/- 0.001 log fL; P < 1.08 x 10(-24)) and PLT (per-G effect -4.55 +/- 0.80 10(9)/L; P < 7.19 x 10(-8)) in 8586 healthy subjects. Whole-genome expression analysis in the 1-MB region showed a significant association with platelet transcript levels for PIK3CG (n = 35; P = .047). The G allele at rs342293 was also associated with decreased binding of annexin V to platelets activated with collagen-related peptide (n = 84; P = .003). The region 7q22.3 identifies the first QTL influencing platelet volume, counts, and function in healthy subjects. Notably, the association signal maps to a chromosome region implicated in myeloid malignancies, indicating this site as an important regulatory site for hematopoiesis. The identification of loci regulating MPV by this and other studies will increase our insight in the processes of megakaryopoiesis and proplatelet formation, and it may aid the identification of genes that are somatically mutated in essential thrombocytosis.

A HaemAtlas: characterizing gene expression in differentiated human blood cells.

Hematopoiesis is a carefully controlled process that is regulated by complex networks of transcription factors that are, in part, controlled by signals resulting from ligand binding to cell-surface receptors. To further understand hematopoiesis, we have compared gene expression profiles of human erythroblasts, megakaryocytes, B cells, cytotoxic and helper T cells, natural killer cells, granulocytes, and monocytes using whole genome microarrays. A bioinformatics analysis of these data was performed focusing on transcription factors, immunoglobulin superfamily members, and lineage-specific transcripts. We observed that the numbers of lineage-specific genes varies by 2 orders of magnitude, ranging from 5 for cytotoxic T cells to 878 for granulocytes. In addition, we have identified novel coexpression patterns for key transcription factors involved in hematopoiesis (eg, GATA3-GFI1 and GATA2-KLF1). This study represents the most comprehensive analysis of gene expression in hematopoietic cells to date and has identified genes that play key roles in lineage commitment and cell function. The data, which are freely accessible, will be invaluable for future studies on hematopoiesis and the role of specific genes and will also aid the understanding of the recent genome-wide association studies.

Pregnancy management after cervical surgery.

PURPOSE OF REVIEW: An amplified risk of adverse pregnancy outcomes after excisional cervical surgery has been identified. Procedures such as cold-knife conization, laser conization, loop electrosurgical excision procedure, and trachelectomy increase the risk of preterm delivery and preterm premature rupture of membranes. Few studies have evaluated prenatal care considerations after these procedures. This review discusses pregnancy management after cervical surgery. RECENT FINDINGS: Data showing an association between excisional and ablative procedures of the cervix and subsequent preterm delivery or preterm premature rupture of membranes are increasing and include more recent information from larger case series and meta-analyses. The need for appropriate and evidence-based management strategies during subsequent pregnancy has arisen. Screening for genital tract infection, sonographic cervical length surveillance, and progesterone administration for cervical shortening may lead to improved pregnancy outcomes in women at high risk for preterm delivery, including women who have undergone cervical surgery. Modifiable risk factors such as depth of conization and procedure-to-pregnancy time interval should be recognized and clinicians should avoid overtreatment for preinvasive cervical lesions. SUMMARY: A number of procedures performed for a variety of indications can be considered excisional cervical surgery. As a result, no standard recommendations for pregnancy management following cervical surgery exist. Given the increased risk of pregnancy complications, certain screening tests or interventions may be appropriate for these women.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.