Impact of the COVID-19 Pandemic on Fecal Immunochemical Testing, Colonoscopy Services, and Colorectal Neoplasia Detection in a Large United States Community-based Population.

BACKGROUND & AIMS: The COVID-19 pandemic has affected clinical services globally, including colorectal cancer (CRC) screening and diagnostic testing. We investigated the pandemic's impact on fecal immunochemical test (FIT) screening, colonoscopy utilization, and colorectal neoplasia detection across 21 medical centers in a large integrated health care organization. METHODS: We performed a retrospective cohort study in Kaiser Permanente Northern California patients ages 18 to 89 years in 2019 and 2020 and measured changes in the numbers of mailed, completed, and positive FITs; colonoscopies; and cases of colorectal neoplasia detected by colonoscopy in 2020 vs 2019. RESULTS: FIT kit mailings ceased in mid-March through April 2020 but then rebounded and there was an 8.7% increase in kits mailed compared with 2019. With the later mailing of FIT kits, there were 9.0% fewer FITs completed and 10.1% fewer positive tests in 2020 vs 2019. Colonoscopy volumes declined 79.4% in April 2020 compared with April 2019 but recovered to near pre-pandemic volumes in September through December, resulting in a 26.9% decline in total colonoscopies performed in 2020. The number of patients diagnosed by colonoscopy with CRC and advanced adenoma declined by 8.7% and 26.9%, respectively, in 2020 vs 2019. CONCLUSIONS: The pandemic led to fewer FIT screenings and colonoscopies in 2020 vs 2019; however, after the lifting of shelter-in-place orders, FIT screenings exceeded, and colonoscopy volumes nearly reached numbers from those same months in 2019. Overall, there was an 8.7% reduction in CRC cases diagnosed by colonoscopy in 2020. These data may help inform the development of strategies for CRC screening and diagnostic testing during future national emergencies.

Disseminating MSSA Infection in a Preterm Infant With Rare Finding of Spinal Epidural Abscess: A Case Report.

BACKGROUND: Methicillin-susceptible Staphylococcus aureus (MSSA) occurs more frequently in the neonatal intensive care unit (NICU) than methicillin-resistant S. aureus (MRSA) and can result in comparable morbidity and mortality in the neonatal population. MSSA infection may present as pustulosis or cellulitis and evolve into bacteremia, pneumonia, endocarditis, brain abscesses, and osteomyelitis. There is a paucity of literature regarding the treatment and long-term outcomes in the premature infant. CLINICAL FINDINGS: A 32-week twin developed MSSA sepsis with presentation of pain, decreased movement of upper extremities, and global hypotonia. Blood cultures remained positive despite antibiotic coverage. PRIMARY DIAGNOSIS: The infant was admitted to the level IV NICU with the diagnosis of MSSA bacteremia, with concern for dissemination and osteomyelitis. INTERVENTIONS: Diagnostic studies included laboratory testing for sepsis evaluation, radiologic studies to evaluate for dissemination, immunologic testing to rule out complement deficiency, and hematology testing to rule out hypercoagulable conditions. OUTCOMES: Diagnostic testing showed extensive cellulitis, osteomyelitis, multiple liver abscesses, and epidural abscesses suggestive of spinal epidural abscess (SEA). Abscess debridement and irrigation on the left distal femur, left elbow, and right tibia were performed. The infant completed 8 weeks of IV antibiotic therapy. Immunologic and hematology testing was within normal limits. PRACTICE RECOMMENDATIONS: Prompt recognition and follow-up for clinical signs of sepsis are vital when caring for premature infants. Inclusion of pediatric subspecialist recommendations to assure all diagnostic studies and treatments are completed can significantly impact the patient's outcome. Long-term follow-up is needed for premature infants with the diagnosis of SEA.

Phase I/II trial of nano-camptothecin CRLX101 with capecitabine and radiotherapy as neoadjuvant treatment for locally advanced rectal cancer.

CRLX101 is a nanoparticle-drug conjugate with a camptothecin payload. We assessed the toxicity and pathologic complete response (pCR) rate of CRLX101 with standard neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer. A single-arm study was conducted with a 3 + 3 dose escalation phase Ib followed by phase II at the maximum tolerated dose (MTD). Thirty-two patients were enrolled with 29 (91%) patients having T3/4 and 26 (81%) N1/2 disease. In phase Ib, no patient experienced a dose limiting toxicity (DLT) with every other week dosing, while 1/9 patients experienced a DLT with weekly dosing. The weekly MTD was identified as 15 mg/m2. The most common grade 3-4 toxicity was lymphopenia, with only 1 grade 4 event. pCR was achieved in 6/32 (19%) patients overall and 2/6 (33%) patients at the weekly MTD. CRLX101 at 15 mg/m2 weekly with neoadjuvant CRT is a feasible combination strategy with an excellent toxicity profile. Clinicaltrials.gov registration NCT02010567.

A Triplication of 6q24 and Meconium Pseudocyst: A Case Report.

With the rise in genetic screening both pre- and postnatally, new variances in genes are being recognized. Some are of unknown significance, while other known genetic expressions have obvious phenotypical expressions. Transient neonatal diabetes mellitus is a result of the duplication of chromosome 6q24, but little is known about the phenotypic expression of a triplication of chromosome 6q24. This case study presents an infant with a postnatally diagnosed triplication of chromosome 6q24, meconium pseudocyst, and multiple congenital anomalies with unknown genetic significance.

A phase I trial of mFOLFOX6 combined with the oral PI3K inhibitor BKM120 in patients with advanced refractory solid tumors.

PURPOSE: The oral PI3K inhibitor BKM120 has been reported as safe and well tolerated in early phase clinical trials of advanced cancer patients. We performed a phase I trial of BKM120 plus mFOLFOX6 (5-FU/LV + oxaliplatin), a common chemotherapeutic backbone in GI malignancies, to establish the maximum tolerated dose (MTD) and characterize the safety and tolerability of the combination. METHODS: Patients with advanced solid tumors received oral BKM120 daily combined with standard doses of mFOLFOX6 every 2 weeks of a 28 day cycle. The study utilized a standard 3 + 3 dose escalation schema. RESULTS: A total of 17 patients received treatment with BKM120, 13 of which were evaluate for dose limited toxicity (DLT). The most common tumor types were colorectal cancer, cholangiocarcinoma, pancreatic cancer and hepatocellular carcinoma. DLT included grade 3 hyperglycemia, grade 3 AST/ALT elevation, grade 4 neutropenia and grade 4 thrombocytopenia. A total of 76 % of patients experienced treatment related grade 3/4 adverse events (AEs), the most common of which were neutropenia, fatigue, leukopenia, hyperglycemia and thrombocytopenia. One patient demonstrated an unconfirmed partial response and three patients had stable disease. DISCUSSION: The MTD of BKM120 in combination with standard doses of mFOLFOX6 was 40 mg daily, which is well below the 100 mg daily dose proven effective and tolerable both as a single agent and in combination with other chemotherapeutics. In addition, the regimen of BKM120 with mFOLFOX6 in patients with refractory solid tumors resulted in increased toxicity than would be expected from either the PI3K inhibitor or the chemotherapy backbone alone.

Decoding cell lineage from acquired mutations using arbitrary deep sequencing.

Because mutations are inevitable, the genome of each cell in a multicellular organism becomes unique and therefore encodes a record of its ancestry. Here we coupled arbitrary single primer PCR with next-generation DNA sequencing to catalog mutations and deconvolve the phylogeny of cultured mouse cells. This study helps pave the way toward construction of retrospective cell-fate maps based on mutations accumulating in genomes of somatic cells.

Increased frequency of complement C4B deficiency in rheumatoid arthritis.

OBJECTIVE: To assess the copy number variation of complement C4A and C4B genes in patients with rheumatoid arthritis (RA). METHODS: DNA samples were obtained from 299 patients and controls and analyzed for copy number variation of total complement C4, C4A, and C4B genes. The results were compared by chi-square analysis, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Chi-square analysis revealed similar distribution patterns of total C4 alleles in RA patients (n = 160), non-RA patients (n = 88), and healthy controls (n = 51). There was no trend toward C4A deficiency as in lupus. Significant differences in C4B distribution were observed in RA patients, in whom an ∼2-fold increase in the frequency of homozygous and/or heterozygous C4B deficiency (0 or 1 allele) (40%) was present relative to non-RA patients or healthy controls (both 21.6%). C4B deficiency was more frequent in seropositive RA patients than in seronegative RA patients (44% versus 31%). The odds of C4B deficiency were 2.99 (95% CI 1.58-5.65) (P = 0.0006) in seropositive RA patients relative to non-RA controls. These findings were confirmed in a larger healthy control cohort, yielding an OR of 1.83 (95% CI 1.21-2.76) (P = 0.0056). The association of the shared epitope with C4B deficiency was significantly greater in seropositive RA patients than in non-seropositive RA controls (96% versus 54.5%) (P < 0.0001), suggesting that C4B deficiency interacts with the shared epitope in the development of seropositive RA. CONCLUSION: Our findings indicate a relationship between C4B copy number variation and RA that approximates that seen between C4A copy number variation and lupus. The concurrence of C4B deficiency and the shared epitope in seropositive RA may have broad implications for our understanding of RA pathogenesis.

Challenges in Phase 4 post-licensure safety studies using real world data in the United States: Hepatitis B vaccine example.

Post-licensure vaccine safety studies are essential to identify adverse events that may not have been detected in pre-licensure clinical trials and to address questions that arose during the pre-licensure phase. These studies are increasingly conducted using real-world data collected as part of routine health care delivery. However, design of post-licensure vaccine safety studies involves many pragmatic and scientific decisions, which must be made while balancing diverse stakeholder opinions. Challenges include selecting exposure and comparison groups, deciding on the most appropriate outcome, determining sample size and length of follow-up time, and other analytic considerations. As an example of this process and to inform other post-licensure vaccine safety studies in real-world settings, we discuss our experience with design of an FDA-required Phase 4 post-licensure safety study of a hepatitis B vaccine in a large integrated health care organization in the United States.

Secondary surfactant deficiency in neonates.

Surfactant treatment has become the standard of care in premature infants with respiratory distress syndrome (RDS). Pulmonary hemorrhage, pulmonary edema, pneumonia, and atelectasis have been shown to liberate inflammatory mediators and plasma proteins, which damage type II pneumocytes and inactivate surfactant. These disease processes may, therefore, lead to a secondary surfactant inactivation or deficiency, which can be an unrecognized cause of respiratory decompensation after initial recovery from RDS in this vulnerable population. This is a descriptive report of three cases, which had acute respiratory decompensation between 1 and 3 weeks of age. All three infants demonstrated a response to secondary doses of surfactant. We submit that the diagnosis and treatment of secondary surfactant deficiency in the critically ill premature neonate warrants further study.

Gait assessment during the initial fitting of an ankle foot orthosis in individuals with stroke.

PURPOSE: To evaluate if the measurement of gait parameters, examined during the fitting of an Ankle Foot Orthosis (AFO), has a beneficial effect on the gait pattern of individuals who were affected by a stroke. Also, this study seeks to provide evidence regarding the use of the portable GaitRite system in a clinical setting. METHOD: Before-after trial conducted at a stroke outpatient orthotic clinic of a freestanding rehabilitation hospital. Thirteen individuals with acute and 27 individuals with chronic stroke participated in the assessment of gait velocity, cadence, step length and stance phase. RESULTS: AFO use significantly improves gait velocity, cadence, step, and stride length in individuals with hemiparesis due to stroke. CONCLUSION: The results of the current study indicate that the assessment of temporo-spatial characteristics of gait can be incorporated into a clinical routine. This will be useful for patient education, justification of medical necessity of paying, monitoring progress, and in the decision-making process of weaning patients off orthoses.

Restoration of a functional open reading frame by homologous recombination between two adenoviral vectors.

In this study, we examined the ability of adenoviral (Ad) vectors to undergo homologous recombination. The lacZ gene was divided between two parental, first-generation vectors such that neither encoded a functional product but both shared 494 bp in common. The open reading frame could only be restored by homologous recombination. We observed beta-galactosidase activity only upon co-infection of both parental vectors and after the onset of viral DNA replication, creating a delay in expression of 24-36 hours in HeLa cells. At peak efficiency, this recombination vector system resulted in beta-galactosidase activity levels 100x above background and just 18x less than a conventional, first-generation vector in HeLa cells. After recombination, the resultant progeny vector genomes containing reconstituted expression cassettes were devoid of all viral genes and contained two packaging signals. These progeny genomes were efficiently packaged, could be separated from their parental vectors based on their lighter buoyant densities in CsCl gradients, and were subsequently used as functional gene transfer vectors. This novel recombination vector system should be useful for transferring large transgenes (because the carrying capacity of two Ad vectors can be exploited) or expressing any cytotoxic or Ad replication inhibitory protein (because the parental vectors exhibit no background expression).

An adenoviral expression system for AAV rep78 using homologous recombination.

The construction and amplification of adenoviral (Ad) vectors expressing biologically active transgenes that are cytotoxic or inhibit Ad replication can be extremely difficult, if not impossible. In this study, we harnessed the ability of Ad genomes to undergo efficient homologous recombination to reconstitute the adeno-associated virus (AAV) rep78 gene, a cytotoxic gene that strongly inhibits Ad replication, which was divided between two parental, first-generation Ad vectors. A functional open reading frame was generated by recombination only upon co-infection of both parental vectors and after the onset of viral DNA replication. We were able to amplify both parental rep78 vectors to normal titers without any signs of inhibition or toxicity and could use them to generate progeny vectors containing a functional rep78 gene without any Ad genes. Using this vector recombination system in AAV rescue assays demonstrated that no Ad protein was essential for Rep78 mediated rescue of AAV ITR flanked DNA from plasmid or Ad backbones; the amount of rescue product generated was substantially greater in the presence of Ad infection; neither cellular nor viral DNA replication was necessary for rescue to occur; and progeny vector genomes were efficiently co-replicated along with conventional, first-generation Ad vectors.

A high-capacity, capsid-modified hybrid adenovirus/adeno-associated virus vector for stable transduction of human hematopoietic cells.

To achieve stable gene transfer into human hematopoietic cells, we constructed a new vector, DeltaAd5/35.AAV. This vector has a chimeric capsid containing adenovirus type 35 fibers, which conferred efficient infection of human hematopoietic cells. The DeltaAd5/35.AAV vector genome is deleted for all viral genes, allowing for infection without virus-associated toxicity. To generate high-capacity DeltaAd5/35.AAV vectors, we employed a new technique based on recombination between two first-generation adenovirus vectors. The resultant vector genome contained an 11.6-kb expression cassette including the human gamma-globin gene and the HS2 and HS3 elements of the beta-globin locus control region. The expression cassette was flanked by adeno-associated virus (AAV) inverted terminal repeats (ITRs). Infection with DeltaAd5/35.AAV allowed for stable transgene expression in a hematopoietic cell line after integration into the host genome through the AAV ITR(s). This new vector exhibits advantages over existing integrating vectors, including an increased insert capacity and tropism for hematopoietic cells. It has the potential for stable ex vivo transduction of hematopoietic stem cells in order to treat sickle cell disease.