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Gurleen Mann,1 Sonia Shirin,2,3 Sewon Bann,2– 4 Paul J Yong,2,3,5 Dharani Kalidasan,2 Azita Goshtasebi,2,3 Jerilynn C Prior2– 4,6 1University of British Columbia, Vancouver, British Columbia, Canada; 2Centre for Menstrual Cycle and Ovulation Research, University of British Columbia, Vancouver, British Columbia, Canada; 3British Columbia Women’s Health Research Institute, Vancouver, British Columbia, Canada; 4Division of Endocrinology and Metabolism, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; 5Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada; 6School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, CanadaCorrespondence: Jerilynn C Prior, Diamond Healthcare Centre – Division of Endocrinology and Metabolism, 2775 Laurel Street, Suite 4111, Vancouver, British Columbia, V5Z 1M9, Canada, Tel +1-604 875-5927, Email jerilynn.prior@ubc.caPurpose: It is asserted that primary dysmenorrhea/menstrual cramps only occur in ovulatory menstrual cycles. Our first objective was to present detailed menstrual cramps information in normally ovulatory versus anovulatory cycles from a single-cycle cohort study during the SARS-CoV-2 Pandemic. Secondly, we reviewed the literature for cohort studies documenting both menstrual cramps and ovulation.Participants and Methods: The Menstruation and Ovulation Study 2 recruited 108 women ages 19– 35 years to a prospective, observational single-cycle study, recording cramps daily (0– 4 scale) in the Menstrual Cycle Diary© and assessing normal ovulation (luteal length ≥ 10 days) by the validated Quantitative Basal Temperature© (Mean Temperature Method). We searched databases for « primary dysmenorrhea » / » menstrual cramps »; « menstrual cycles »; « anovulation », finding four valid publications.Results: In 75 women/cycles during the Pandemic, mean age was 28.5, body mass index 23.5, and higher education (16 years); 40 normally ovulatory and 35 anovulatory cycles had similar lengths (29.5– 30.0 days), respectively (P= 0.571). However, anovulatory cycles recorded significantly worse menstrual cramps versus normally ovulatory cycles; anovulatory median intensity was 1.9 versus 1.6, and Cramp Score was 8 versus 6 in normally ovulatory cycles (P=0.017). Four publications in 273 women (991 cycles) showed cramps in both anovulatory and ovulatory cycles; three were in adolescent/young adult women, one of which documented a significantly greater percentage of cramps in ovulatory cycles. The 694 cycles in premenopausal women (20– 41 years) showed similar percentages of symptomatic cramps in cycles of both ovulatory types. Meta-analysis documented significantly higher cramp prevalence in ovulatory cycles (OR 2.10; 95% CI 1.31, 3.37; P=0.002).Conclusion: This is the first documentation of more intense and frequent cramps in anovulatory cycles. However, meta-analysis showing the presence of symptomatic cramps in both ovulatory and anovulatory cycles documented they were twice as prevalent in ovulatory menstrual cycles.Plain Language Summary: “Worse Menstrual Cramps in Anovulatory Cycles”. Medicine has long believed that menstrual cramps only occur in ovulatory menstrual cycles that release an egg and have high progesterone levels that decrease before the next period. The notion was that dropping progesterone levels triggered release of prostaglandins that cause the pain and uterus muscle contractions of menstrual cramps. This research studied 75 community women aged 19– 35 years for a single cycle during COVID-19. Forty women had normally ovulatory cycles and 35 had anovulatory cycles with a similar mean cycle length of 29.7 days. Women in both groups were similar in age, weight, education and other reproductive characteristics. Women recorded Menstrual Cycle Diary© daily experiences for cramp presence and intensity (scored 0– 4). Ovulation was documented by daily first morning temperatures analyzed by the valid Quantitative Basal Temperature© method. Results showed menstrual cramps occurred in both normally ovulatory and anovulatory cycles. Surprisingly, anovulatory compared with ovulatory cycles had cramps that lasted longer (4 rather than 3 days), were more intense (1.9 versus 1.6) and with significantly higher Cramp Scores (of 8 versus 6). We also found four other published studies showing cramps occurred in both anovulatory and ovulatory cycles. A meta-analysis of these, however, showed that cramps were twice as frequent in ovulatory cycles. These results matter because they stimulate the search for more accurate understandings of why menstrual cramps occur. They will likely stimulate more effective therapies for the rare, intense menstrual cramps that currently are not effectively treated by anti-inflammatory medicines such as ibuprofen.Keywords: primary dysmenorrhea, menstrual pain, menstrual cycles, ovulation, adolescent, premenopause

Loblolly pine (Pinus taeda L.) is one of the most planted forest species in the Americas. Since few studies have comprehensively assessed loblolly pine responses to fertilization, the present study performed a meta-analysis of the Americas based on 44 publications (1970-2022) of loblolly pine fertilization under field conditions. In general, fertilization increased root dry matter (+33%), litter (+21%), plant height (+6%), trunk diameter (+9%), wood yield (+30%), and needle concentrations of P (+9%), K (+36%), Ca (+17%), Mg (+14%), and S (+12%). Wood production was higher with residue fertilization, primarily with use of composite residues (cellulosic sludge + ash), compared to mineral fertilization. In regards to mineral applications, wood production was higher when multiple nutrients were added from fertilization and liming operations. Applications at planting (< 1 year) or on established trees (2-8 years), showed similar increases in wood production with higher responses occurring on sandy soils. These factors generally increased needle nutrient concentrations, except for no alteration or slight decreases in N under most conditions. The present study revealed loblolly pine responses to contrasting application strategies, which can help identify efficient fertility management practices for this commercially significant tree species.

Camilla F Christiansen,1,2 Anders Løkke,1,2 Vibeke Bregnballe,3 Thomas Skovhus Prior,4 Ingeborg Farver-Vestergaard1,2 1Department of Medicine, Lillebaelt Hospital, Vejle, Denmark; 2Department of Regional Health Research, University of Southern Denmark, Odense, Denmark; 3Faculty of Health, Aarhus University, Aarhus, Denmark; 4Center for Rare Lung Diseases, Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Ingeborg Farver-Vestergaard, Department of Medicine, Lillebaelt Hospital, Beriderbakken 4, Vejle, 7100, Denmark, Tel +45 79 40 98 32, Email ingeborg.farver@rsyd.dkBackground: Anxiety in patients with chronic obstructive pulmonary disease (COPD) is prevalent but often unidentified and therefore not adequately managed. Clinicians find it difficult to detect anxiety symptoms and to differentiate subclinical anxiety from anxiety disorders, because of the considerable overlap between symptoms of COPD and anxiety.Purpose: We synthesized existing qualitative research on patients’ experiences of COPD-related anxiety with the purpose of gaining a richer understanding and proposing a model of the construct.Methods: Searches for qualitative studies of patients’ experiences of COPD-related anxiety were conducted independently by two authors in the databases of PubMed (MEDLINE), CINAHL (EBSCO), and PsycInfo (APA). English-language studies including patients diagnosed with COPD were reviewed, and data were analyzed using thematic analysis.Results: A total of 41 studies were included in the review. Four themes related to COPD-related anxiety were identified: initial events; internal maintaining factors; external maintaining factors; and behavioral maintaining factors. Based on the identified four themes, a conceptual model of COPD-related anxiety from the patient perspective was developed.Conclusion: A conceptual model of COPD-related anxiety from the patient perspective is now available, with the potential to inform future attempts at improving identification and management of COPD-related anxiety. Future research should focus on the development of a COPD-specific anxiety questionnaire containing domains that are relevant from the patient perspective.Keywords: qualitative studies, psychological symptoms, chronic disease management, psychological distress, mental health, respiratory illness, chronic obstructive pulmonary disease

Henrik Schou Pedersen,1,2 Kaj Sparle Christensen,1,2 Anders Prior1,2 1Research Unit for General Practice, Aarhus, Denmark; 2Department of Public Health, Aarhus University, Aarhus, DenmarkCorrespondence: Henrik Schou Pedersen, Research Unit for General Practice, Bartholins Allé 2, Aarhus, 8000, Denmark, Email henrikp@ph.au.dkObjective: Most mental disorders are diagnosed and treated in general practice. Psychometric tests may help the general practitioner diagnose and treat mental disorders like dementia, anxiety, and depression. However, little is known about the use of psychometric tests in general practice and their impact on further treatment. We aimed to assess the use of psychometric tests in Danish general practice and to estimate whether variation in use is associated with the provided treatment and death by suicide in patients.Methods: This nationwide cohort study included registry data on all psychometric tests performed in Danish general practice in 2007– 2018. We used Poisson regression models adjusted for sex, age, and calendar time to assess predictors of use. We used fully adjusted models to estimate the standardized utilization rates for all general practices.Results: A total of 2,768,893 psychometric tests were used in the study period. Considerable variations were observed among general practices. A positive association was seen between a general practitioner’s propensity to use psychometric testing and talk therapy. Patients listed with a general practitioner with low use had an increased rate of redeemed prescriptions for anxiolytics [incidence rate ratio (95% confidence interval):1.39 (1.23;1.57)]. General practitioners with high use had an increased rate of prescriptions for antidementia drugs [1.25 (1.05;1.49)] and first-time antidepressants [1.09 (1.01;1.19)]. High test use was seen for females [1.58 (1.55; 1.62)] and patients with comorbid diseases. Low use was seen for populations with high income [0.49 (0.47; 0.51)] and high educational level [0.78 (0.75; 0.81)].Conclusion: Psychometric tests were used mostly for women, individuals with a low socioeconomic status, and individuals with comorbid conditions. The use of psychometric tests depends on general practice and is associated with talk therapy, redemptions for anxiolytics, antidementia drugs, and antidepressants. No association was found between general practice rates and other treatment outcomes.Keywords: psychometric tests, registries, general practice, mental disorders, treatment variation

Prenatal genetic diagnosis of monogenic diseases is a process involving the use of a variety of molecular techniques for the molecular characterization of a potential monogenic disease in the fetus during pregnancy. Prenatal genetic diagnosis can be performed through invasive and non-invasive methods. A distinction must be made between “NIPD” (non-invasive prenatal diagnosis), which is considered to be diagnostic, from “NIPT” (non-invasive prenatal test), which is a screening test that requires subsequent confirmation by invasive methods. The different techniques currently available aim at detecting either, previously characterized pathogenic mutations in the family, the risk haplotype associated with the familial mutation, or potential pathogenic mutation(s) in a gene associated with a diagnostic suspicion. An overview is provided of relevant aspects of prenatal genetic diagnosis of monogenic diseases. The objective of this paper is to describe the main molecular techniques currently available and used in clinical practice. A description is provided of the indications, limitations and analytical recommendations regarding these techniques, and the standards governing genetic counseling. Continuous rapid advances in the clinical applications of genomics have provided increased access to comprehensive molecular characterization. Laboratories are struggling to keep in pace with technology developments.

El diagnóstico genético prenatal de enfermedades monogénicas es un proceso que engloba el conjunto de técnicas moleculares dirigidas a caracterizar molecularmente una posible enfermedad monogénica en el feto durante el embarazo. Actualmente, el diagnóstico genético prenatal puede realizarse de manera invasiva o no invasiva. Debemos diferenciar “NIPD” (del inglés: non invasive prenatal diagnosis) que se considera diagnóstico de “NIPT” (del inglés: non invasive prenatal test) que se considera prueba de cribado y tendrá que confirmarse por técnicas invasivas. Las diferentes metodologías disponibles y empleadas pueden ir dirigidas a la detección de variante/s genética/s causal/es previamente caracterizada/s en la familia, la detección del haplotipo de riesgo asociado a la mutación familiar y/o la búsqueda de posibles variante/s patogénicas en un gen asociado a una sospecha diagnóstica. Se revisarán los aspectos relevantes del diagnóstico genético prenatal de las enfermedades monogénicas. El objetivo es la exposición de las principales técnicas moleculares disponibles y empleadas en la actualidad, detallando sus indicaciones, limitaciones y recomendaciones analíticas, así como la normativa que regula el asesoramiento genético. La evolución permanente y exponencial en la aplicación asistencial de las técnicas genómicas, facilita progresivamente el acceso a una caracterización molecular exhaustiva, obligando a una constante actualización homogénea de los laboratorios.

Cathrine Bell,1 Anders Prior,2 Anne Frølich,3,4 Charlotte Weiling Appel,1 Peter Vedsted1,2 1Diagnostic Centre - University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Department of Clinical Medicine, Aarhus University, Silkeborg, Denmark; 2Research Unit for General Practice, Aarhus, Denmark; 3Innovation and Research Centre for Multimorbidity, Slagelse Hospital, Region Zealand, Denmark; 4Centre for General Practice, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Cathrine Bell, Diagnostic Centre - University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Department of Clinical Medicine, Aarhus University, Denmark, Tel +45 7841 7884, Email catbel@rm.dkBackground: Multimorbidity is a global health challenge. Individuals with multimorbidity are frequent users of healthcare services, and many experience fragmented healthcare. We assessed the number of outpatient trajectories and contacts with hospital outpatient clinics for individuals with multimorbidity and explored different time intervals for the occurrence of concurrent outpatient trajectories.Methods: A population-based cohort of 1.3 million residents, ≥ 18 years, with multimorbidity was identified through Danish national health registries. Multimorbidity was defined as having two or more of 39 specific chronic conditions. Nine disease system categories were used to categorize outpatient contacts in 2018 into outpatient trajectories and trajectory-related contacts. We defined an “outpatient trajectory” as two contacts within 12 consecutive months for the same medical condition. All outpatient contacts and trajectories with related contacts were counted for 2018. The impact of different time intervals on the number of concurrent trajectories was analyzed.Results: On 1 January 2019, 29% of the adult Danish population was classified as multimorbid. During 2018, 68% of them had ≥ 1 outpatient contact (median: 2 (IQI: 0– 4)). Twenty-six percent had ≥ 1 outpatient trajectory. The median number of trajectory contacts was 3 (IQI: 2– 5). The 4% of individuals with ≥ 2 outpatient trajectories accounted for 28% of trajectory contacts. During the 6-week period from the latest outpatient contact, 33% of all patients with ≥ 2 trajectories in 2018 experienced concurrent trajectories with outpatient contact.Conclusion: Two-thirds of adult Danes with multimorbidity attended an outpatient clinic in 2018, and one-fourth had at least one outpatient trajectory. Individuals with two or more trajectories represented 4% and comprised 28% of the trajectory contacts; 33% had concurrent trajectories within a 6-week period. It appears that a small proportion place demands on outpatient clinics because of frequent attendance. A more uniform way of organizing outpatient trajectories for these patients merits consideration.Keywords: outpatient, hospital, multimorbidity, prevalence, healthcare utilization, trajectory

Melissa C Keinath,1 Devin E Prior,2 Thomas W Prior1 1Pathology, University Hospitals Center for Human Genetics, Cleveland, OH, USA; 2Neurology, Mount Auburn Hospital, Cambridge, MA, USACorrespondence: Thomas W Prior Email Thomas.Prior@UHhospitals.orgAbstract: Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder that causes degeneration of the alpha motor neurons from anterior horn cells in the spinal cord, which causes severe progressive hypotonia and muscular weakness. With a carrier frequency of 1 in 40– 50 and an estimated incidence of 1 in 10,000 live births, SMA is the second most common autosomal recessive disorder. Affected individuals with SMA have a homozygous loss of function of the survival motor neuron gene SMN1 on 5q13 but keep the modifying SMN2 gene. The most common mutation causing SMA is a homozygous deletion of the SMN1 exon 7, which can be readily detected and used as a sensitive diagnostic test. Because SMN2 produces a reduced number of full-length transcripts, the number of SMN2 copies can modify the clinical phenotype and as such, becomes an essential predictive factor. Population-based SMA carrier screening identifies carrier couples that may pass on this genetic disorder to their offspring and allows the carriers to make informed reproductive choices or prepare for immediate treatment for an affected child. Three treatments have recently been approved by the Food and Drug Administration (FDA). Nusinersen increases the expression levels of the SMN protein using an antisense oligonucleotide to alter splicing of the SMN2 transcript. Onasemnogene abeparvovec is a gene therapy that utilizes an adeno-associated virus serotype 9 vector to increase low functional SMN protein levels. Risdiplam is a small molecule that alters SMN2 splicing in order to increase functional SMN protein. Newborn screening for SMA has been shown to be successful in allowing infants to be treated before the loss of motor neurons and has resulted in improved clinical outcomes. Several of the recommendations and guidelines in the review are based on studies performed in the United States.Keywords: spinal muscular atrophy, carrier screening, newborn screening, SMA treatment

Localized surface plasmon resonances of individual sub-wavelength cavities milled in metallic films can couple to each other to form a collective behavior. This coupling leads to a delocalization of the plasmon field at the film surface and drastically alters both the linear and nonlinear optical properties of the sample. In periodic arrays of nanocavities, the coupling results in the formation of propagating surface plasmon polaritons (SPP), eigenmodes extending across the array. When artificially introducing dislocations, defects and imperfections, multiple scattering of these SPP modes can lead to hot-spot formation, intense and spatially confined fluctuations of the local plasmonic field within the array. Here, we study the underlying coupling effects by probing plasmonic modes in well-defined individual triangular dimer cavities and in arrays of triangular cavities with and without artificial defects. Nonlinear confocal spectro-microscopy is employed to map the second harmonic (SH) radiation from these systems. Pronounced spatial localization of the SPP field and significant enhancements of the SH intensity in certain, randomly distributed hot spots by more than an order of magnitude are observed from the triangular arrays as compared to a bare silver film by introducing a finite degree of disorder into the array structure. Hot-spot formation and the resulting enhancement of the nonlinear efficiency are correlated with an increase in the lifetime of the localized SPP modes. By using interferometric SH autocorrelation measurements, we reveal lifetimes of hot-spot resonances in disordered arrays that are much longer than the few-femtosecond lifetimes of the localized surface plasmon resonances of individual nanocavity dimers. This suggests that hot spot lifetime engineering provides a path for manipulating the linear and nonlinear optical properties of nanosystems by jointly exploiting coherent couplings and tailored disorder.

Forest floor litter can influence biogeochemical cycling and root growth in Pinus taeda systems, especially on low soil fertility sites. The impact of fertilization and liming on forest floor litter (quantity, elemental composition and root presence) was evaluated in a Pinus taeda stand in southern Brazil. A nutrient omission experiment was initiated in November 2008 on an 11 year-old Pinus taeda plantation. The experiment was a randomized block design with seven treatments and four blocks. The treatments were: complete (macro + micro + lime); minus macronutrients; minus micronutrients; minus K; minus Zn; minus lime; and control. In 2012, forest floor litter samples were collected, divided by layer (new litter, old litter, coarse fragmented forest layer > 2mm, fine fragment forest floor < 2mm, and fine roots) and analyzed for concentrations of Na, Al, and total nutrients. Results indicated that lime increased Ca and Mg concentrations, reduced Al toxicity, and improved fine root growth. An increase in fine roots was observed in treatments without K. There were large increases in Fe and Al as a function of litter age and increased Mn in fragmented litter when lime was applied. There was little variation in forest floor litter accumulation in all treatments. Elemental abundance was C>N>Fe>P>Ca>K>Mg>Mn under control conditions and C>N>Ca>Mg>P>Fe>Mn>K for the complete treatment. Occurrence of needle chlorosis, similar to that reported for Mg, and low growth under lime omission indicate that Mg was a major factor limiting growth. Fertilization and liming affected the bio-cycling of nutrients, Al toxicity, and root growth.

Ulrike Dapunt,1 Birgit Prior,2 Jan Philippe Kretzer,3 Thomas Giese,4 Yina Zhao1 1Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Heidelberg 69118, Germany; 2Department of Anesthesiology, Heidelberg University Hospital, Heidelberg 69120, Germany; 3Laboratory of Biomechanics and Implant Research, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Heidelberg 69118, Germany; 4Institute for Immunology, Heidelberg University, Heidelberg 69120, GermanyCorrespondence: Ulrike DapuntCenter for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, Heidelberg 69118, GermanyTel + ± 49-6221-56-25000Email Ulrike.Dapunt@med.uni-heidelberg.dePurpose: Aseptic implant loosening is still a feared complication in the field of orthopaedics. Presumably, a chronic inflammatory response is induced by wear particles, which leads to osteoclast generation, bone degradation and hence loosening of the implant. Since it has been demonstrated in the literature that most implants are in fact colonized by bacteria, the question arises whether aseptic implant loosening is truly aseptic. The aim of this study was to investigate a possibly enhanced inflammatory response to metal wear particles in the context of subclinical infection.Patients and Methods: Tissue samples were collected intra-operatively from patients undergoing implant-exchange surgery due to aseptic loosening. Histopathological analysis was performed, as well as gene expression analysis for the pro-inflammatory cytokine Interleukin-8. By a series of in vitro experiments, the effect of metal wear particles on human monocytes, polymorphonuclear neutrophiles and osteoblasts was investigated. Additionally, minor amounts of lipoteichoic acid (LTA) and the bacterial heat shock protein GroEL were added.Results: Histopathology of tissue samples revealed an accumulation of metal wear particles, as well as a cellular infiltrate consisting predominately of mononuclear cells. Furthermore, high expression of IL-8 could be detected in tissue surrounding the implant. Monocytes and osteoblasts in particular showed an increased release of IL-8 after stimulation with metal wear particles and in particular after stimulation with bacterial components and wear particles together.Conclusion: We were able to show that minor amounts of bacterial components and metal wear particles together induce an enhanced inflammatory response in human monocytes and osteoblasts. This effect could significantly contribute to the generation of bone-resorbing osteoclasts and hence implant-loosening.Keywords: aseptic loosening, metal wear particles, biofilm, implant-associated infection, Interleukin-8

The winter storm of late 2022 caused difficulties for many US-based airlines, but none more so than Southwest Airlines. Like other airlines, Southwest canceled flights in the early stages of the storm. Their attempted recoveries failed due to procedural and technology issues. The airline was unable to cope with the magnitude of canceled flights, aircraft and crews in the wrong places, disrupted passenger plans, and luggage separated from its owners. Over the next several days, Southwest canceled tens of thousands of flights, called in thousands of additional staff to support manual operations, and flew a reduced schedule for a time before returning to normal operations. The case provides numerous scenarios for you to analyze and research, to strengthen your understanding of the underlying concepts.