Recent trends in incidence, survival and treatment of multiple myeloma in Finland - a nationwide cohort study.

This study aimed to determine the incidence and prevalence of multiple myeloma (MM) in Finland in 2015-2019, to characterize adult patients newly diagnosed with MM, and to follow-up their overall survival (OS) and treatment patterns until the end of 2020. We sourced the data on inpatient and outpatient diagnoses, outpatient medication use, and date of death from comprehensive, nationwide registers. We identified 2037 incident patients with MM in 2015-2019. On average, the annual crude incidence was 8.8 and the age-standardized incidence (World Standard Population) was 3.3 per 100,000. The crude prevalence at the end of 2019 was 32.7 cases per 100,000 inhabitants ≥ 18 years of age. Median age of the patients at first diagnosis (index date) was 71 years, and 48% were female, the median follow-up being 2.4 years. The median OS was estimated at 4.5 years. The proportion of the patients receiving autologous stem cell transplantation (ASCT) within one year since the index date was 24%, with little variation across study years. Conversely, the proportion of all patients receiving lenalidomide within one year since the index date increased from 27 to 48% overall, and from 39 to 81% among ASCT recipients. The estimated median relapse-free survival after ASCT was 2.9 years. Information on in-hospital MM medication administrations was available for a subset of the study cohort. In this subset, 85.8% of the patients received immunomodulatory drugs and/or proteasome inhibitors within the first year after the index date.

Observational study on the evolution of systemic treatments for advanced renal cell carcinoma in Southwest Finland between 2010 and 2021.

Background: Novel receptor tyrosine kinase inhibitors and immune checkpoint inhibitors have been introduced to the treatment of advanced renal cell carcinoma (aRCC) during the past decade. However, the adoption of novel treatments into clinical practice has been unknown in Finland. Objectives: Our aim was to evaluate the use of systemic treatments and treatment outcomes of aRCC patients in Southwest Finland during 2010-2021. Design and Methods: Clinical characteristics, treatments for aRCC, healthcare resource utilization, and overall survival (OS) were retrospectively obtained from electronic medical records. Patients were stratified using the International Metastatic RCC Database Consortium (IMDC) risk classification. Results: In total, 1112 RCC patients were identified, 336 (30%) patients presented with aRCC, and 57% of them (n = 191) had received systemic treatment. Pre-2018, sunitinib (79%) was the most common first-line treatment, and pazopanib (17%), axitinib (17%), and cabozantinib (5%) were frequently used in the second-line. Post-2018, sunitinib (52%), cabozantinib (31%), and the combination of ipilimumab and nivolumab (10%) were most commonly used in the first-line, and cabozantinib (23%) in the second-line. Median OS for patients with favorable, intermediate, and poor risk were 61.9, 28.6, and 8.1 months, respectively. A total of 73%, 74%, and 35% of the patients with favorable, intermediate, and poor risk had received second-line systemic treatment. In poor-risk patients, the number of hospital inpatient days was twofold higher compared to intermediate and fourfold higher compared to favorable-risk patients. Conclusion: New treatment options were readily adopted into routine clinical practice after becoming reimbursed in Finland. OS and the need for hospitalization depended significantly on the IMDC risk category. Upfront combination treatments are warranted for poor-risk patients as the proportion of patients receiving second-line treatment is low. Registration: Clinical trial identifier: ClinicalTrials.gov NCT05363072.

Observational study on the evolution of systemic treatments for advanced renal cell carcinoma in Southwest Finland between 2010 and 2021 The aim of the study was to evaluate the use of novel medical treatments for advanced kidney cancer in routine clinical practice in Southwest Finland from 2010 to 2021 and to study the impact of IMDC risk factors on patients' survival and healthcare resource utilization. Before 2018, sunitinib (79%) was the most common first-line treatment for advanced kidney cancer, and pazopanib (17%), axitinib (17%), and cabozantinib (5%) were frequently used in the second-line. After 2018, sunitinib (52%), cabozantinib (31%), and the combination of ipilimumab and nivolumab (10%) were most commonly used in the first-line, and cabozantinib (23%) in the second-line treatment. The IMDC risk category predicted the patient's prognosis accurately as the median overall survival times for patients with favorable, intermediate, and poor risk were 61.9 months, 28.6 months, and 8.1 months, respectively. 73­74% of the patients with favorable and intermediate risk had received second-line medical treatment for advanced disease, whereas only 35% of the patients with poor risk had received second-line treatment after disease progression on the first-line treatment. Among patients with poor risk, the number of hospital inpatient days was twofold higher compared to intermediate and fourfold higher compared to favorable-risk patients. This study demonstrated that new treatment options for advanced kidney cancer were readily adopted into clinical practice and IMDC risk scoring was a valuable tool in determining patient prognosis and healthcare resource utilization.

COVID-19 hospitalisations and all-cause mortality by risk group in Finland.

Ever since COVID-19 was announced as a global pandemic in March 2020, healthcare systems around the world have struggled with the burden of the disease. Vaccinations and other preventive measures have decreased this burden, but severe forms of COVID-19 leading to hospitalizations and even deaths still effect certain risk groups, such as the elderly and patients with multiple comorbidities. The objective of this retrospective observational study was to identify which risk groups are at the highest risk for a severe COVID-19 infection in Finland using national registry data ranging from January 2021 to June 2022. The data was analysed in three time periods, enabling comparisons in high-risk groups between epidemiological waves caused by different variants of SARS-CoV-2. The summary level data were stratified according to predefined groups based on two criteria: age (≥18 years, 18-59 years, and ≥60 years) and risk group. The results include analysis of infection hospitalisation rate (IHR), case fatality rate (CFR) and average length of stay (LOS) in both primary and specialty care for each risk group and age group. Our results confirm that despite the decrease in COVID-19 hospitalisations and deaths observed during the study period, a significant proportion of patients are still hospitalised, and deaths occur especially in the 60+ population. Also, even though the average length of stay of hospitalised COVID-19 patients has decreased, it is still long compared to specialty care hospitalisations in general. Old age is a significant risk factor for severe COVID-19 in all patient groups and certain risk factors such as chronic kidney disease clearly increase the risk for severe COVID-19 outcomes. Early treatment should be considered with a low threshold for risk group patients and for elderly patients in order to avoid severe disease courses, and to ease the burden on hospitals where resources are currently very strained.

The burden of hip and knee osteoarthritis in Finnish occupational healthcare.

BACKGROUND: Osteoarthritis (OA) is a leading cause of disability and pain especially among older adults, but it is also known to affect working age individuals, often leading to reduced productivity and increased healthcare usage. The aim of this study was to determine the burden of hip and knee OA in Finnish occupational healthcare. METHODS: This was a retrospective registry study utilizing the electronic medical records of the largest private and occupational healthcare provider in Finland. All consented patients with hip or knee OA were identified. A subcohort of occupational healthcare (OCH) patients was then compared to an age- and gender-matched control group without OA. Patient demographics including comorbidities were determined and healthcare contacts, medication prescriptions, and sick leaves were compared between the two groups. The study period was from January 1st, 2012 to April 30th, 2020. RESULTS: 51,068 patients with hip or knee OA were identified (all OA cohort) and 35,109 of these formed the occupational healthcare subcohort. Most of the OA patients were female and belonged to the age group 50-59 years. The point prevalence of hip/knee OA at the end of the study period was 5.6% for the occupational healthcare subcohort. OA patients had 2.2 times more healthcare contacts and 2.8 times more overall sick leave days compared to the age- and gender-matched control cohort. Etoricoxib was the most commonly prescribed medication at OA-related visits (21.8% of patients). Opioids were prescribed to 10.6% of patients at OA-related visits and the most prescribed opioid was a combination of codeine and paracetamol (4.8% of patients). 5054 OA patients (14.4%) had a contraindication for non-steroidal anti-inflammatory drugs (NSAIDs). CONCLUSIONS: This retrospective registry study utilizing real-world data provides new evidence on the disease burden of hip or knee osteoarthritis from the electronic medical records of Finnish occupational healthcare customers. OA patients had more comorbidities, more healthcare contacts, more sick leave days, and more analgesic prescriptions compared to an age- and gender-matched control cohort without OA.

Carbonic anhydrase seven bundles filamentous actin and regulates dendritic spine morphology and density.

Intracellular pH is a potent modulator of neuronal functions. By catalyzing (de)hydration of CO2 , intracellular carbonic anhydrase (CAi ) isoforms CA2 and CA7 contribute to neuronal pH buffering and dynamics. The presence of two highly active isoforms in neurons suggests that they may serve isozyme-specific functions unrelated to CO2 -(de)hydration. Here, we show that CA7, unlike CA2, binds to filamentous actin, and its overexpression induces formation of thick actin bundles and membrane protrusions in fibroblasts. In CA7-overexpressing neurons, CA7 is enriched in dendritic spines, which leads to aberrant spine morphology. We identified amino acids unique to CA7 that are required for direct actin interactions, promoting actin filament bundling and spine targeting. Disruption of CA7 expression in neocortical neurons leads to higher spine density due to increased proportion of small spines. Thus, our work demonstrates highly distinct subcellular expression patterns of CA7 and CA2, and a novel, structural role of CA7.

A physiologically validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia.

OBJECTIVE: Birth asphyxia (BA) is often associated with seizures that may exacerbate the ensuing hypoxic-ischemic encephalopathy. In rodent models of BA, exposure to hypoxia is used to evoke seizures, that commence already during the insult. This is in stark contrast to clinical BA, in which seizures are typically seen upon recovery. Here, we introduce a term-equivalent rat model of BA, in which seizures are triggered after exposure to asphyxia. METHODS: Postnatal day 11-12 male rat pups were exposed to steady asphyxia (15 min; air containing 5% O2  + 20% CO2 ) or to intermittent asphyxia (30 min; three 5 + 5-min cycles of 9% and 5% O2 at 20% CO2 ). Cortical activity and electrographic seizures were recorded in freely behaving animals. Simultaneous electrode measurements of intracortical pH, Po2 , and local field potentials (LFPs) were made under urethane anesthesia. RESULTS: Both protocols decreased blood pH to <7.0 and brain pH from 7.3 to 6.7 and led to a fall in base excess by 20 mmol·L-1 . Electrographic seizures with convulsions spanning the entire Racine scale were triggered after intermittent but not steady asphyxia. In the presence of 20% CO2 , brain Po2 was only transiently affected by 9% ambient O2 but fell below detection level during the steps to 5% O2 , and LFP activity was nearly abolished. Post-asphyxia seizures were strongly suppressed when brain pH recovery was slowed down by 5% CO2 . SIGNIFICANCE: The rate of brain pH recovery has a strong influence on post-asphyxia seizure propensity. The recurring hypoxic episodes during intermittent asphyxia promote neuronal excitability, which leads to seizures only after the suppressing effect of the hypercapnic acidosis is relieved. The present rodent model of BA is to our best knowledge the first one in which, consistent with clinical BA, behavioral and electrographic seizures are triggered after and not during the BA-mimicking insult.

Surge of Peripheral Arginine Vasopressin in a Rat Model of Birth Asphyxia.

Mammalian birth is accompanied by a period of obligatory asphyxia, which consists of hypoxia (drop in blood O2 levels) and hypercapnia (elevation of blood CO2 levels). Prolonged, complicated birth can extend the asphyxic period, leading to a pathophysiological situation, and in humans, to the diagnosis of clinical birth asphyxia, the main cause of hypoxic-ischemic encephalopathy (HIE). The neuroendocrine component of birth asphyxia, in particular the increase in circulating levels of arginine vasopressin (AVP), has been extensively studied in humans. Here we show for the first time that normal rat birth is also accompanied by an AVP surge, and that the fetal AVP surge is further enhanced in a model of birth asphyxia, based on exposing 6-day old rat pups to a gas mixture containing 4% O2 and 20% CO2 for 45 min. Instead of AVP, which is highly unstable with a short plasma half-life, we measured the levels of copeptin, the C-terminal part of prepro-AVP that is biochemically much more stable. In our animal model, the bulk of AVP/copeptin release occurred at the beginning of asphyxia (mean 7.8 nM after 15 min of asphyxia), but some release was still ongoing even 90 min after the end of the 45 min experimental asphyxia (mean 1.2 nM). Notably, the highest copeptin levels were measured after hypoxia alone (mean 14.1 nM at 45 min), whereas copeptin levels were low during hypercapnia alone (mean 2.7 nM at 45 min), indicating that the hypoxia component of asphyxia is responsible for the increase in AVP/copeptin release. Alternating the O2 level between 5 and 9% (CO2 at 20%) with 5 min intervals to mimic intermittent asphyxia during prolonged labor resulted in a slower but quantitatively similar rise in copeptin (peak of 8.3 nM at 30 min). Finally, we demonstrate that our rat model satisfies the standard acid-base criteria for birth asphyxia diagnosis, namely a drop in blood pH below 7.0 and the formation of a negative base excess exceeding -11.2 mmol/l. The mechanistic insights from our work validate the use of the present rodent model in preclinical work on birth asphyxia.

Vasopressin excites interneurons to suppress hippocampal network activity across a broad span of brain maturity at birth.

During birth in mammals, a pronounced surge of fetal peripheral stress hormones takes place to promote survival in the transition to the extrauterine environment. However, it is not known whether the hormonal signaling involves central pathways with direct protective effects on the perinatal brain. Here, we show that arginine vasopressin specifically activates interneurons to suppress spontaneous network events in the perinatal hippocampus. Experiments done on the altricial rat and precocial guinea pig neonate demonstrated that the effect of vasopressin is not dependent on the level of maturation (depolarizing vs. hyperpolarizing) of postsynaptic GABAA receptor actions. Thus, the fetal mammalian brain is equipped with an evolutionarily conserved mechanism well-suited to suppress energetically expensive correlated network events under conditions of reduced oxygen supply at birth.

Serum copeptin and neuron specific enolase are markers of neonatal distress and long-term neurodevelopmental outcome.

The objective of this study was to evaluate the early changes in serial serum levels of copeptin and neuron-specific enolase (NSE) in neonates diagnosed with birth asphyxia, and to determine whether these biomarkers measured in the first 168 hours after birth are predictive of long-term neurodevelopmental outcome. Copeptin and NSE levels were measured from serum samples collected 6, 12, 24, 48, 72, and 168 hours after birth from 75 term neonates diagnosed with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia for 72 hours. In addition, serum copeptin levels after birth were measured from 10 HIE diagnosed neonates, who were randomized to the normothermic arm of the TOBY cohort. All neonates underwent neurodevelopmental assessment using the Bayley Scales of Infant and Toddler Development-II at two years of age. Copeptin levels were highest at 6 hours after birth and steadily decreased, whereas the highest NSE levels were measured at 24 hours after birth. The biomarker levels correlated with blood-gas parameters (base excess, pH and lactate) at 6 and 12 hours after birth. Copeptin and NSE levels in the early postnatal period were significantly higher in neonates with poor outcome compared to those with favorable outcome at two years of age. Furthermore, in the TOBY cohort, copeptin levels were significantly lower in hypothermic compared to normothermic neonates. To conclude, copeptin and NSE measured in the early postnatal period are potential prognostic biomarkers of long-term neurodevelopmental outcome in term neonates diagnosed with HIE and treated with therapeutic hypothermia.

Comparison of Umbilical Serum Copeptin Relative to Erythropoietin and S100B as Asphyxia Biomarkers at Birth.

BACKGROUND: Birth asphyxia, estimated to account for a million neonatal deaths annually, can cause a wide variety of neurodevelopmental impairments. There is a need to develop new, swift methods to identify those neonates who would benefit from neuroprotective treatments such as hypothermia. OBJECTIVES: To examine the utility of cord serum copeptin, a stable byproduct of arginine vasopressin release, as a biomarker of birth asphyxia based on a comparison with 2 biomarkers of hypoxia and brain trauma: erythropoietin and S100B. METHODS: The study population consisted of 140 singleton, term neonates: 113 controls and 27 with birth asphyxia (2/3 criteria met: umbilical artery pH <7.10, base excess ≤12 mmol/L, and 5-min Apgar score <7). All deliveries were planned vaginal, but 51 neonates were born by emergency cesarean section. Copeptin, S100B, and erythropoietin levels in umbilical artery samples were measured by immunoassays. RESULTS: Copeptin correlated in the entire study population more strongly with umbilical artery base excess than S100B and erythropoietin, and only copeptin correlated with arterial pH. Furthermore, only copeptin levels were significantly higher in cases of birth asphyxia, and in vaginally born neonates they were found to increase as a function of labor duration. Copeptin was elevated in neonates born via vacuum extraction, whereas erythropoietin levels showed a slight increase after emergency cesarean section. CONCLUSIONS: In this study population, S100B and erythropoietin were not valid biomarkers of birth asphyxia. In contrast, our work suggests that copeptin has high potential to become a routinely used biomarker for acute birth asphyxia and neonatal distress.

Kinetics of PKCε activating and inhibiting llama single chain antibodies and their effect on PKCε translocation in HeLa cells.

Dysregulation of PKCε is involved in several serious diseases such as cancer, type II diabetes and Alzheimer's disease. Therefore, specific activators and inhibitors of PKCε hold promise as future therapeutics, in addition to being useful in research into PKCε regulated pathways. We have previously described llama single chain antibodies (VHHs) that specifically activate (A10, C1 and D1) or inhibit (E6 and G8) human recombinant PKCε. Here we report a thorough kinetic analysis of these VHHs. The inhibiting VHHs act as non-competitive inhibitors of PKCε activity, whereas the activating VHHs have several different modes of action, either increasing V(max) and/or decreasing K(m) values. We also show that the binding of the VHHs to PKCε is conformation-dependent, rendering the determination of affinities difficult. Apparent affinities are in the micromolar range based on surface plasmon resonance studies. Furthermore, the VHHs have no effect on the activity of rat PKCε nor can they bind the rat form of the protein in immunoprecipitation studies despite the 98% identity between the human and rat PKCε proteins. Finally, we show for the first time that the VHHs can influence PKCε function also in cells, since an activating VHH increases the rate of PKCε translocation in response to PMA in HeLa cells, whereas an inhibiting VHH slows down the translocation. These results give insight into the mechanisms of PKCε activity modulation and highlight the importance of protein conformation on VHH binding.