Deep sequencing detects human papillomavirus (HPV) in cervical cancers negative for HPV by PCR.

BACKGROUND: Human papillomavirus (HPV) is a necessary cause of cervical cancer, although some invasive cervical cancers may test negative by HPV PCR. We previously requested all invasive cervical cancers in Sweden during 10 years and subjected them to PCR. We also optimised methods for deep sequencing of formalin-fixed paraffin-embedded samples. METHODS: Using Novaseq 6000, we simultaneously sequenced total DNA and cDNA from 392 HPV PCR-negative cervical cancers. Non-human reads were queried against all known HPVs. The complete database now contains PCR and/or deep sequencing data on 2850 invasive cervical cancers. RESULTS: HPV sequences were detected in 169/392 of HPV PCR-negative cervical cancers. Overall, 30 different HPV types were detected, but only 5 types were present in proportions above 3% of cancers. More than 92% of tumours were HPV-positive in PCR and/or sequencing (95% confidence interval: 91.1-93.1%). Exploring possible reasons for failure to previously detect HPV suggest that more sensitive type-specific PCRs for HPV 31, 33, 45 and 73 targeting retained regions of HPV would have detected most of these (117/392). CONCLUSIONS: Unbiased deep sequencing provides comprehensive data on HPV types in cervical cancers and appears to be an important tool for quality assurance of HPV screening.

Adverse cardiac events after vascular surgery are prevalent despite negative results of preoperative stress testing.

OBJECTIVE: Cardiac risk assessment is a critical component of vascular disease management before surgical intervention. The predictive risk reduction of a negative cardiac stress test result remains poorly defined. The objective of this study was to compare the incidence of postoperative cardiac events among patients with negative stress test results vs those who did not undergo testing. METHODS: We reviewed all patients who underwent elective open abdominal aortic aneurysm repair, suprainguinal bypass, endovascular aneurysm repair (EVAR), carotid endarterectomy (CEA), and infrainguinal bypass within the Vascular Study Group of New England from 2003 to 2017. We excluded patients with positive stress test results (n = 3312) and studied two mutually exclusive groups: elective surgery patients with a negative stress test result and elective surgery patients with no stress test (total n = 26,910). The primary outcome was a composite of in-hospital postoperative cardiac events (dysrhythmia, heart attack, heart failure) or death. RESULTS: A preoperative stress test was obtained in 66.3% of open repairs, 42.8% of suprainguinal bypasses, 37.1% of EVARs, 36.0% of CEAs, and 31.2% of infrainguinal bypasses. The proportion of patients receiving a preoperative stress test varied widely across centers, from 37.1% to 80.0%. The crude odds ratio of in-hospital postoperative cardiac event or death was 1.37 (95% confidence interval [CI], 1.07-1.76) for open repair and 1.52 (CI, 1.13-2.03) for suprainguinal bypass, indicating that patients with negative stress test results before these procedures were 37% and 52% more likely to suffer a postoperative event or die compared with patients selected to proceed directly to surgery without testing. Conversely, the crude odds ratio was 0.92 (CI, 0.66-1.29) for EVAR, 0.92 (CI, 0.70-1.21) for CEA, and 1.13 (CI, 0.90-1.40) for infrainguinal bypass, indicating that patients undergoing these procedures had a similar likelihood of sustaining an event whether they had a negative stress test result or proceeded directly to surgery without a stress test. CONCLUSIONS: The use of cardiac stress testing before vascular surgery varies widely throughout New England. Whereas patients are often appropriately selected to proceed directly to surgery, a negative preoperative stress test result should not assuage the concern for an adverse outcome as these patients retain a substantial likelihood of cardiac events, especially after large-magnitude procedures.

An omnibus test for the global null hypothesis.

Global hypothesis tests are a useful tool in the context of clinical trials, genetic studies, or meta-analyses, when researchers are not interested in testing individual hypotheses, but in testing whether none of the hypotheses is false. There are several possibilities how to test the global null hypothesis when the individual null hypotheses are independent. If it is assumed that many of the individual null hypotheses are false, combination tests have been recommended to maximize power. If, however, it is assumed that only one or a few null hypotheses are false, global tests based on individual test statistics are more powerful (e.g. Bonferroni or Simes test). However, usually there is no a priori knowledge on the number of false individual null hypotheses. We therefore propose an omnibus test based on cumulative sums of the transformed p-values. We show that this test yields an impressive overall performance. The proposed method is implemented in an R-package called omnibus.

"Stoneless" or Negative Ureteroscopy: A Reality in the Endourologic Routine or Avoidable Source of Frustration? Estimating the Risk Factors for a Negative Ureteroscopy.

INTRODUCTION: A "Negative" ureteroscopy (URS) is defined as a URS in which no stone is found during the procedure. It may occur when the stone has already been passed spontaneously or when it is located outside the collecting system. The aim of the study was to outline risk factors for Negative-URS. MATERIALS AND METHODS: We retrospectively analyzed the possible risk factors for Negative-URS from a database of 341 URS cases. In every case where presumptive ureteral stone was not found, a formal nephroscopy as well as a whole collecting system revision was completed. The Negative-URS group was compared with the non-Negative-URS group, in terms of patient and stone characteristics. RESULTS: The database of 341 URS cases included 448 different stone instances, of which 17 (3.8%) were negative and 431 (96.2%) were therapeutic. There was no statistical significant difference between the two groups concerning age, body mass index, stone location in the ureter, stone laterality, and whether the patient was prestented. The stepwise multiple logistic regression revealed three important risk factors, namely CT stone surface area (p < 0.0001), radiopacity of the stone at kidney, ureter, and bladder radiograph (KUB; p = 0.0004), and gender (p = 0.0011) with an area under the curve of 0.91. Women were found to have more possibilities to have a negative procedure by four- to sevenfold than men depending on the model. A nonradio-opaque stone at KUB is more likely to be correlated with a Negative-URS by 9.5- to 11-fold more than a radiopaque stone at KUB. For each increase of 1 U in CT stone surface area, there is an increase of 10%-12% to be non-negative. CONCLUSIONS: Female gender, a nonradio-opaque stone at KUB, and a smaller stone surface were statistically significantly different in the Negative-URS population.

Relationship Between Pelvic Organ Prolapse and Non-Human Papillomavirus Pap Smear Abnormalities.

OBJECTIVE: The aim of this study was to determine the association between pelvic organ prolapse (POP) and non-human papillomavirus (HPV) Papanicolaou (Pap) smear abnormalities. METHODS: This was a retrospective cohort study of women aged 40 to 70 years who presented for consultation at our institution between 2010 and 2015 and had results of a Pap smear and HPV test available within 5 years of their visit. We extracted demographic information, medical and social history, Pap smear, and HPV results from the electronic medical record. Associations between the presence of POP and non-HPV Pap smear abnormalities were estimated using univariable and multivariable analyses. RESULTS: We reviewed 1590 charts and excluded 980 women, leaving 610 women in the study: 183 with POP and 427 without POP. Women with POP were significantly older (58.2 ± 7.2 vs 55.6 ± 6.6, P < 0.01) and more likely to have a remote (>10 year) history of abnormal Pap smear (24.0% vs 14.8%, P < 0.01). The rate of non-HPV-associated abnormal Pap smears was higher in the POP group than in the non-POP group (12/183 [6.6%] vs 12/427 [2.8%], P = 0.029). In the POP group, the rate of non-HPV Pap smear abnormality was significantly associated with increasing prolapse stage (stage 1: 0/16 [0%], stage 2: 5/77 [6.5%], stage 3: 3/73 [4.1%], stage 4: 4/17 [23.5%]; P = 0.02). After controlling for age and remote history of abnormal Pap smear, the odds ratio for non-HPV Pap smear abnormalities in the POP group remained significant (2.49; 95% confidence interval, 1.08-5.79). CONCLUSIONS: Human papillomavirus-negative Pap smear abnormalities may be related to POP. Our findings have important implications for surgeons seeking to leave the cervix in situ in women with POP.