The association between farming activities,precipitation, and the risk of acute gastrointestinal illness in rural municipalities of Quebec,Canada: a cross-sectional study

Background  

Increasing livestock density and animal manure spreading, along with climate factors such as heavy rainfall, may increase the risk of acute gastrointestinal illness (AGI). In this study we evaluated the association between farming activities, precipitation and AGI.     

Human chorionic gonadotropin serum levels following ovulation triggering and IVF cycle outcome

Purpose

The clinical significance of serum hCG levels after ovulation triggering was studied previously with conflicting results. Our aim was to study the correlation of hCG levels on the day after ovulation triggering using recombinant hCG (r-hCG) with treatment outcome.

Methods

A prospective observational study of all fresh IVF/ICSI cycles in a single medical center, between January 2015 and June 2016, was performed. hCG serum levels were obtained 10–12 h following ovulation triggering with 250 mcg r-hCG. Clinical and laboratory outcome parameters were compared between cycles with serum hCG above and below median level. A multivariate regression analysis was performed in order to study the association between hCG levels and live birth rate, after controlling for confounders.

Results

Overall, 326 cycles were included. Median serum hCG level was 91.35 IU/L. hCG levels were lower as age and BMI were higher (p?=?0.004, p?<?0.001, respectively). The study groups did not differ with regard to clinical pregnancy rate (p?=?0.14), live birth rate (p?=?0.09), fertilization rate (p?=?0.45), or metaphase II oocyte rate (p?=?0.68). On multivariate regression analysis, hCG level was not associated with live birth (aOR 0.99, 95% CI 0.98–1.005), after controlling for patient’s age and BMI.

Conclusions

hCG levels on the day after ovulation triggering with 250 mcg r-hCG are inversely correlated with patient age and BMI. However, they are not correlated with any clinical or laboratory outcome parameter. Therefore, testing for hCG levels after ovulation induction seems futile and cannot be recommended.

     

Cumulative pregnancy and live birth rates through assisted reproduction in women 44–45 years of age: is there any hope?

Purpose

The purpose of the study is to calculate the cumulative pregnancy rate and cumulative live birth rate in women undergoing in vitro fertilization (IVF) at ages 44–45.

Methods

The study calculated cumulative live pregnancy rate and cumulative live birth rate of 124 women aged 44 to 45 years old who commenced IVF treatment.

Main outcome measures

The main outcome measures are cumulative live pregnancy rate and cumulative live birth rate.

Results

Cumulative live pregnancy rates following 1, 2, 3, and 4 cycles were 5.6, 11, 17, and 20%, respectively, with no additional pregnancies in further cycles. Cumulative live birth rates following 1, 2, and 3 cycles were 1.6, 3, and 7%, respectively, with no additional live births in further cycles.

Conclusions

The cumulative pregnancy rate rises during the first 4 cycles and cumulative live birth rate rises during the first 3 cycles, with no additional rise in pregnancies or deliveries thereafter, suggesting that it is futile to offer more than 3 cycles of treatment to 44–45-year-old women.

     

Refractive surgery in Israel Defense Forces recruits

PURPOSE: To determine the prevalence of refractive surgery history in recruits for military service in the Israel Defense Forces (IDF) between 1998 to 2005 and to evaluate the effect of surgery on the recruits' fitness to serve in combat units. SETTING: Surgeon General's HQ, Medical Corps, Israel Defense Forces. METHODS: The computerized medical records of all ametropic Israeli army inductees were reviewed. They included spectacle-wearing, contact lens-wearing, and post refractive-surgery individuals who were examined in the recruitment office before their compulsory military service. The extracted data from the personal files consisted of the assignment to combat units of those who had refractive surgery and those who wore corrective eyewear and the first and last military position of all ametropic recruits who were assigned to combat units. RESULTS: Five hundred ninety-seven inductees (513 men, 84 women) had refractive surgery before their military service during the study period. The prevalence of recruits who had refractive surgery increased from 0.8/1000 ametropes in 1998 to 4.9/1000 ametropes in 2005. Significantly more recruits who had surgery (73.5%) than recruits who wore corrective eyewear were assigned to combat units (P<.001). The dropout rate from combat units of the former was significantly lower than that of the latter (13.1% versus 29.2%) (P<.001). CONCLUSIONS: More corrective eyewear users had refractive surgery before their IDF military service, and relatively more of them applied for combat duty. The high percentage of recruits who had refractive surgery who serve uninterruptedly in combat units indicates that the procedure has no deleterious effect on the recruits' fitness.     

Temporary Regulatory Deviations and the Coronavirus Disease 2019 (COVID-19) PCR Labeling Update Study Indicate What Laboratory-Developed Test Regulation by the US Food and Drug Administration (FDA) Could Look Like

The coronavirus disease 2019 (COVID-19) response necessitated innovations and a series of regulatory deviations that also affected laboratory-developed tests (LDTs). To examine real-world consequences and specify regulatory paradigm shifts, legislative proposals were aligned on a common timeline with Emergency Use Authorization (EUA) of LDTs and the US Food and Drug Administration (FDA)-orchestrated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) labeling update study. The initial EUA adoption by LDT developers shows that the FDA can have oversight over LDTs. We used efficiency-corrected microcosting of our EUA PCR assay to estimate the national cost of the labeling update study to $0.3 to $1.4 million US dollars. Labeling update study performance data showed lower average detection limits in commercial in vitro diagnostic (IVD) assays versus LDTs (32,000 ± 75,000 versus 71,000 ± 147,000 nucleic acid amplification tests/mL; P = 0.04); however, comparison also shows that FDA review of IVD assays and LDTs did not prevent differences between initial and labeling update performance (IVD assay, P < 0.0001; LDT, P = 0.003). The regulatory shifts re-emphasized that both commercial tests and LDTs rely heavily on laboratory competence and procedures; however, lack of performance data on authorized tests, when clinically implemented, precludes assessment of the benefit related to regulatory review. Temporary regulatory deviations during the pandemic and regulatory science tools (ie, reference material) have generated valuable real-world evidence to inform pending legislation regarding LDT regulation.

One of the unanticipated consequences of the coronavirus disease 2019 (COVID-19) pandemic is that it forced the ongoing debate of diagnostic test regulation into the public consciousness (Health Affairs Blog, https://www.healthaffairs.org/doi/10.1377/hblog20200814.376610, last accessed August 29, 2021).1, 2, 3, 4 Specifically, the regulatory oversight of laboratory-developed procedures, known as laboratory-developed tests (LDTs), has been a contentious issue in the United States (Association for Molecular Pathology, https://www.amp.org/advocacy/advocacy-resources/laboratory-developedtesting-procedures-ldps, last accessed August 29, 2021; Diagnostics World, https://www.diagnosticsworldnews.com/news/2019/10/22/mixed-opinions-on-how-to-regulate-laboratory-developed-tests, last accessed August 29, 2021).5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 LDTs are assays that are assembled, validated, and performed within a clinical laboratory.^{16,27,29,34,35} The laboratories are not required to submit data on the test for US Food and Drug Administration (FDA) review. Instead, laboratories must follow the regulations of the Clinical Laboratory Improvement Amendments (CLIA) of 1988. In contrast, test systems that are developed and sold by a manufacturer (ie, those that are distributed in interstate commerce) are regulated by the FDA under the Federal Food, Drug, and Cosmetic Act.³⁴ Once FDA authorized and sold, these in vitro diagnostic (IVD) devices are implemented, after appropriate verification of performance, in a CLIA-certified laboratory.^14,15,20,31 Changes to the nuanced regulatory balance between CLIA and FDA may critically affect US patient access to testing.^{4,13,24,29,32,34,}36, 37, 38 An ideal regulatory framework for oversight of tests and procedures must balance the need for accuracy and safety with ensuring that new tests are made available to patients within a rapid time frame.^{4,13,19,32,34,37,38} Congress has not expanded the FDA''s authority to regulate LDTs; however, shortly following the introduction of the Verifying Accurate Leading-Edge IVCT (in vitro clinical test) Development Act (VALID Act) on March 5, 2020 (https://www.congress.gov/bill/116th-congress/senate-bill/3404/text, last accessed June 19, 2021), the United States plunged into the COVID-19 pandemic.Diagnostic oversight took center stage in March 2020 because the FDA published guidance regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostics.1, 2, 3, 4 In contrast with the prevailing paradigm that CLIA-certified laboratories can develop and validate LDTs to perform clinical testing without FDA oversight, the FDA outlined eligibility criteria for the use and authorization of LDTs (FDA, https://www.fda.gov/medical-devices, last accessed June 19, 2021). The basis for this decision was the public health emergency declaration (85 FR 17335) by the US Department of Health and Human Services that triggered section 564 of the Federal Food, Drug, and Cosmetic Act.^1,2 Although later rescinded (US Department of Health and Human Services, https://www.hhs.gov/coronavirus/testing/covid-19-diagnostic-data-reporting/index.html, last accessed June 19, 2021; College of American Pathologists, https://www.cap.org/covid-19, last accessed June 19, 2021), the FDA guidance documents effectively asserted authority over LDTs; and LDT developers had to undergo Emergency Use Authorization (EUA). In the early phase of the COVID-19 pandemic, this authority allowed the FDA to “help strengthen the nation''s public health protections” (FDA, https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#abouteuas, last accessed June 19, 2021). The resulting scenario is interesting: the pandemic mandated diagnostic innovation to tackle disease identification, whereas the EUA requirement attempted to establish common ground regarding performance and accuracy of deployed systems. In an echo of the proposed legislation,^14,39,40 this temporary assertion of authority marked the first time that the FDA took practical steps to regulate LDTs.In August 2020, parallel to US Department of Health and Human Services enabling laboratories to administer COVID-19 tests without FDA authorization, the FDA sent out agency-verified reference materials along with a study protocol to conduct an interlaboratory study (labeling update study). Practically speaking, all laboratories that received EUA for SARS-CoV-2 molecular diagnostics received an FDA notice:

“As part of the condition of authorization under the EUA it was listed that you will evaluate the analytical limit of detection and assess traceability of your product with any FDA-recommended reference material(s). After submission to FDA and DMD/OHT7-OIR/OPEQ/CDRH''s review of and concurrence with the data, you will update labeling to reflect the additional testing. Such labeling updates will be made in consultation with, and require concurrence of, DMD/OHT7- OIR/OPEQ/CDRH. Through collaboration with CBER/FDA, a suitable reference panel is now available, and we are requesting you to test it."(EUA communication from the FDA, https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas-molecular-diagnostic-tests-sars-cov-2#individual-molecular)

The COVID-19 pandemic resulted in two specific regulatory deviations: First, the temporary EUA requirement for COVID-19 diagnostics by the FDA represents a deviation from current practice of LDT regulation (ie, no FDA oversight). Second, the subsequent labeling update study represents a large-scale comparator study across manufacturers and LDT developers. Together, these temporary deviations provide a unique chance to examine what regulatory oversight of LDTs by the FDA could practically look like. To our knowledge, an examination of these LDT-related regulatory deviations has not been performed.Herein, we review the timeline of regulating LDTs in the specific context of COVID-19, describe the regulatory deviations, and examine the labeling update study protocol, cost, and results. The COVID-19 pandemic required balancing innovation with patient safety and has led to several, temporary regulatory deviations. Ignoring the lessons from these regulatory paradigm shifts can be considered a missed opportunity. As Congress will debate legislative proposals to modernize diagnostic test regulation, an evidence-informed dialogue will be essential to align legislative intent with practical feasibility.     

Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients

Renal involvement as part of systemic lymphoma (LY) is quite frequent, however, primary extranodal renal non-Hodgkin's lymphoma (NHL) is extremely rare, and only about 65 cases have been reported in the world literature. In a retrospective study of renal manifestations in 700 patients with documented LY and chronic lymphocytic leukemia (CLL) seen at our hospital during 1986-95, 83 patients had signs of acute renal failure. Only five of these had proven renal infiltration, but none of them satisfied the criteria for primary renal LY. Glomerulonephritis (GN) has also rarely been reported in association with LY and CLL, and only 37 glomerular lesions in NHL and 42 in CLL have been documented, respectively. GN may precede, coexist, or follow the diagnosis of LY by several years. Of the 42 cases of CLL reported worldwide, 36 had nephrotic syndrome. Renal failure was seen in about one third. The most common glomerular lesion reported is membranoproliferative GN, followed by membranous GN. In our study, we found only five biopsy-proven cases with GN amongst the 700 patients seen. In this report we also briefly describe some rare interesting associated renal syndromes in CLL and NHL.