Exploring pharmacists' perspectives about substandard and falsified medical products through interviews.

Background: The problem with substandard and falsified (SF) medical products may grow in high-income countries when e-commerce of medicines increases. Unauthorized websites offer medicines of insufficient quality. This underscores the importance of evaluating how the problem with SF medical products can be prevented from escalating. However, little is known about what knowledge and experience professionals working primarily with medicines have about the phenomenon. Objective: This study was conducted to explore purposively selected pharmacists' experience and knowledge about SF medical products. Methods: Twelve individual interviews were conducted with purposively selected pharmacists between May 2021 and September 2021. An interview guide was used with specific questions about e-commerce, which focused on exploring pharmacists' experience and knowledge about SF medical products. The interviews lasted, on average, 49 min and were analyzed using inductive qualitative content analysis. Results: A main theme 'Pharmacists as guardians of safe medicines' emerged. This theme consisted of three categories pinpointing 'risk factors', 'protective factors', and 'opportunities for improvement' regarding SF medical products. Findings suggest that pharmacists can play a role in preventing the problem with SF medical products from escalating. Participants emphasized they were in this line of work to help patients and increase patient safety. Conclusions: Pharmacists have the opportunity to empower the public with knowledge about SF medical products since they discuss medicines with many people every day. Awareness of risk factors for SF medical products enables pharmacists to guide patients to avoid risky purchases from unauthorized websites. To do this, better communication, and cooperation with patients and other healthcare professionals are needed.

The Role of Macula Densa Nitric Oxide Synthase 1 Beta Splice Variant in Modulating Tubuloglomerular Feedback.

Abnormalities in renal electrolyte and water excretion may result in inappropriate salt and water retention, which facilitates the development and maintenance of hypertension, as well as acid-base and electrolyte disorders. A key mechanism by which the kidney regulates renal hemodynamics and electrolyte excretion is via tubuloglomerular feedback (TGF), an intrarenal negative feedback between tubules and arterioles. TGF is initiated by an increase of NaCl delivery at the macula densa cells. The increased NaCl activates luminal Na-K-2Cl cotransporter (NKCC2) of the macula densa cells, which leads to activation of several intracellular processes followed by the production of paracrine signals that ultimately result in a constriction of the afferent arteriole and a tonic inhibition of single nephron glomerular filtration rate. Neuronal nitric oxide (NOS1) is highly expressed in the macula densa. NOS1ß is the major splice variant and accounts for most of NO generation by the macula densa, which inhibits TGF response. Macula densa NOS1ß-mediated modulation of TGF responses plays an essential role in control of sodium excretion, volume and electrolyte hemostasis, and blood pressure. In this article, we describe the mechanisms that regulate macula densa-derived NO and their effect on TGF response in physiologic and pathologic conditions. © 2023 American Physiological Society. Compr Physiol 13:4215-4229, 2023.

Swedish community pharmacy employees' knowledge and experience of substandard and falsified medical products: a cross-sectional descriptive survey.

OBJECTIVES: Substandard and falsified medical products are, according to the World Health Organization, a global threat to public health. To evaluate if community pharmacy employees can guide the public to safer medication purchases, their knowledge and experience about SF medical products was examined. METHODS: A digital questionnaire was distributed to the five dominating pharmacy companies in Sweden, representing 97% of the community pharmacies (1391/1433), giving the theoretical possibility of reaching 6200 employees. Three companies published a link to the questionnaire on their intranets, one distributed the link via e-mail to the responsible pharmacist for quality and knowledge, respectively. The fifth company did not pass on, due to technical problems. Employees aged 18 years or older with customer contact were invited to participate. KEY FINDINGS: The questionnaire was available for 74% of all community pharmacies (1067/1433), having approximately 4900 employees with customer contact. The response rate was 5% (228/4900). Of the respondents, 89% were pharmacists (203/228), 84% were women (191/228) and 43% were 35-49 years (98/228). The respondents worked in pharmacies of different size, located both in rural and urban areas. The definition of substandard and falsified medical products was known by 182 of the 228 respondents (80%) and the main source of knowledge was media (61%, 111/228). The common European logo for authorized online pharmacies was not recognized by 74% (169/228). CONCLUSIONS: For pharmacy employees to guide the public to safer medication purchases, knowledge about substandard and falsified medical products needs to be enhanced specially about legal international e-commerce.

A data management framework for strategic urban planning using blue-green infrastructure.

Spatial planning of Blue-Green Infrastructure (BGI) should ideally be based on well-evaluated and context specific solutions. One important obstacle to reach this goal relates to adequate provisioning of data to ensure good governance of BGI, i.e., appropriate planning, design, construction, and maintenance. This study explores the gap between data availability and implementation of BGI in urban planning authorities in Sweden. A multi method approach including brainstorming, semi-structured interviews with urban planners and experts on BGI and Geographical Information System (GIS), and validating workshops were performed to develop a framework for structured and user-friendly data collection and use. Identified challenges concern data availability, data management, and GIS knowledge. There is a need to improve the organisation of data management and the skills of trans-disciplinary cooperation to better understand and interpret different types of data. Moreover, different strategic goals require different data to ensure efficient planning of BGI. This calls for closer interactions between development of strategic political goals and data collection. The data management framework consists of three parts: A) Ideal structure of data management in relation to planning process, data infrastructure and organisational structure, and B) A generic list of data needed, and C) The development of structures for data gathering and access. We conclude that it is essential to develop pan-municipal data management systems that bridge sectors and disciplines to ensure efficient management of the urban environment, and which is able to support the involvement of citizens to collect and access relevant data. The framework can assist in such development.

IMAGE QUALITY AND POTENTIAL DOSE REDUCTION USING ADVANCED MODELED ITERATIVE RECONSTRUCTION (ADMIRE) IN ABDOMINAL CT - A REVIEW.

Traditional filtered back projection (FBP) reconstruction methods have served the computed tomography (CT) community well for over 40 years. With the increased use of CT during the last decades, efforts to minimise patient exposure, while maintaining sufficient or improved image quality, have led to the development of model-based iterative reconstruction (MBIR) algorithms from several vendors. The usefulness of the advanced modeled iterative reconstruction (ADMIRE) (Siemens Healthineers) MBIR in abdominal CT is reviewed and its noise suppression and/or dose reduction possibilities explored. Quantitative and qualitative methods with phantom and human subjects were used. Assessment of the quality of phantom images will not always correlate positively with those of patient images, particularly at the higher strength of the ADMIRE algorithm. With few exceptions, ADMIRE Strength 3 typically allows for substantial noise reduction compared to FBP and hence to significant (≈30%) patient dose reductions. The size of the dose reductions depends on the diagnostic task.

High-Protein Diet-Induced Glomerular Hyperfiltration Is Dependent on Neuronal Nitric Oxide Synthase ß in the Macula Densa via Tubuloglomerular Feedback Response.

It is well known that high protein intake increases glomerular filtration rate. Evidence from several studies indicated that NO and tubuloglomerular feedback (TGF) mediate the effect. However, a recent study with a neuronal NO synthase-α knockout model refuted this mechanism and concluded that neither neuronal NO synthase nor TGF response is involved in the protein-induced hyperfiltration. To examine the discrepancy, this study tested a hypothesis that neuronal NO synthase-ß in the macula densa mediates the high-protein diet-induced glomerular hyperfiltration via TGF mechanism. We examined the effects of high protein intake on NO generation at the macula densa, TGF response, and glomerular filtration rate in wild-type and macula densa-specific neuronal NO synthase KO mice. In wild-type mice, high-protein diet increased kidney weight, glomerular filtration rate, and renal blood flow, while reduced renal vascular resistance. TGF response in vivo and in vitro was blunted, and NO generation in the macula densa was increased following high-protein diet, associated with upregulations of neuronal NO synthase-ß expression and phosphorylation at Ser1417. In contrast, these high-protein diet-induced changes in NO generation at the macula densa, TGF response, renal blood flow, and glomerular filtration rate in wild-type mice were largely attenuated in macula densa-specific neuronal NO synthase KO mice. In conclusion, we demonstrated that high-protein diet-induced glomerular hyperfiltration is dependent on neuronal NO synthase ß in the macula densa via TGF response.

Nationwide study of appendicitis in children.

BACKGROUND: Paediatric surgical care is increasingly being centralized away from low-volume centres, and prehospital delay is considered a risk factor for more complicated appendicitis. The aim of this study was to determine the incidence of paediatric appendicitis in Sweden, and to assess whether distance to the hospital was a risk factor for complicated disease. METHODS: A nationwide cohort study of all paediatric appendicitis cases in Sweden, 2001-2014, was undertaken, including incidence of disease in different population strata, with trends over time. The risk of complicated disease was determined by regression methods, with travel time as the primary exposure and individual-level socioeconomic determinants as independent variables. RESULTS: Some 38 939 children with appendicitis were identified. Of these, 16·8 per cent had complicated disease, and the estimated risk of paediatric appendicitis by age 18 years was 2·5 per cent. Travel time to the treating hospital was not associated with complicated disease (adjusted odds ratio (OR) 1·00 (95 per cent c.i. 0·96 to 1·05) per 30-min increase; P = 0·934). Level of education (P = 0·177) and family income (P = 0·120) were not independently associated with increased risk of complicated disease. Parental unemployment (adjusted OR 1·17, 95 per cent c.i. 1·05 to 1·32; P = 0·006) and having parents born outside Sweden (1 parent born in Sweden: adjusted OR 1·12, 1·01 to 1·25; both parents born outside Sweden: adjusted OR 1·32, 1·18 to 1·47; P < 0·001) were associated with an increased risk of complicated appendicitis. CONCLUSION: Every sixth child diagnosed with appendicitis in Sweden has a more complicated course of disease. Geographical distance to the surgical facility was not a risk factor for complicated appendicitis.

ANTECEDENTES: La atención quirúrgica pediátrica está cada vez más centralizada lejos de los centros de bajo volumen, y el retraso pre-hospitalario se considera un factor de riesgo para las apendicitis más complicadas. El objetivo de este estudio fue determinar la incidencia de apendicitis pediátrica en Suecia y evaluar si la distancia al hospital era un factor de riesgo para una enfermedad complicada. MÉTODOS: Se analizó un estudio de cohortes a nivel nacional que incluyó todos los casos de apendicitis pediátrica en Suecia durante el periodo 2001-2014, incluida la incidencia de la enfermedad en diferentes estratos de la población y las tendencias a lo largo del tiempo. El riesgo de enfermedad complicada se determinó mediante métodos de regresión, con el tiempo de viaje como exposición primaria y los determinantes socioeconómicos a nivel individual como variables independientes. RESULTADOS: Se identificaron 38.939 casos de apendicitis pediátrica. De estos, el 17% eran complicados y el riesgo estimado de apendicitis pediátrica a los 18 años era del 2,5%. El tiempo de viaje al hospital de tratamiento no se asoció con una enfermedad complicada (razón de oportunidades, odds ratio OR ajustada 1,00 (i.c. del 95%: 0,96 a 1,05) por aumentos de 30 minutos, P = 0,93). El nivel de educación (P = 0,18) y los ingresos familiares (P = 0,120) no se asociaron de forma independiente con un aumento del riesgo de enfermedad complicada. El desempleo de los padres (OR ajustada 1,17 (1,05 a 1,32), P = 0,006) y tener padres nacidos fuera de Suecia se asociaron con un mayor riesgo de apendicitis complicada (P < 0,001; un progenitor nacido en Suecia: OR ajustada 1,12 (1,01 a 1,25), ambos progenitores nacidos fuera de Suecia: OR ajustada 1,32 (1,18 a 1,47)). CONCLUSIÓN: Uno de cada seis niños diagnosticados de apendicitis en Suecia sufre un curso de enfermedad más complicado. La distancia geográfica al hospital donde se llevó a cabo la cirugía no fue un factor de riesgo para la apendicitis complicada.

Drivers of changing urban flood risk: A framework for action.

This study focuses on drivers for changing urban flood risk. We suggest a framework for guiding climate change adaptation action concerning flood risk and manageability in cities. The identified key drivers of changing flood hazard and vulnerability are used to provide an overview of each driver's impact on flood risk and manageability at the city level. We find that identified drivers for urban flood risk can be grouped in three different priority areas with different time horizon. The first group has high impact but is manageable at city level. Typical drivers in this group are related to the physical environment such as decreasing permeability and unresponsive engineering. The second group of drivers is represented by public awareness and individual willingness to participate and urbanization and urban sprawl. These drivers may be important and are manageable for the cities and they involve both short-term and long-term measures. The third group of drivers is related to policy and long-term changes. This group is represented by economic growth and increasing values at risk, climate change, and increasing complexity of society. They have all high impact but low manageability. Managing these drivers needs to be done in a longer time perspective, e.g., by developing long-term policies and exchange of ideas.

Dietary Nitrate Reduces Blood Pressure in Rats With Angiotensin II-Induced Hypertension via Mechanisms That Involve Reduction of Sympathetic Hyperactivity.

Several experimental and clinical studies have shown that dietary nitrate supplementation can increase nitric oxide bioavailability. In the oral cavity, commensal bacteria reduce nitrate to nitrite, which is subsequently absorbed into the circulation where reduction to nitric oxide by enzymatic systems occur. Although it is well-known that boosting the nitrate-nitrite-nitric oxide pathway can improve cardiovascular, renal, and metabolic functions and that sympathoexcitation contributes to the development of the same disorders, the potential effects of dietary nitrate on sympathetic activity remain to be elucidated. In this study, we hypothesized that treatment with inorganic nitrate could prevent the increase in sympathetic nerve activity in an experimental model of Ang II (angiotensin II)-induced hypertension. Multiple in vivo approaches were combined, that is, Wistar rats orally treated with the nitric oxide synthase inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester, 0.5 g/L) and implanted with subcutaneous osmotic minipump for continuous delivery of Ang II (120 ng/kg per minute; 14 days). Simultaneously, rats were supplemented with sodium nitrate (10 mmol/L) or placebo (sodium chloride; 10 mmol/L) in the drinking water. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded. In placebo-treated rats, Ang II+L-NAME treatment-induced arterial hypertension, which was linked with reduced spontaneous baroreflex sensitivity and increased renal sympathetic nerve activity, as well as upregulation of AT1Rs (Ang II type-1 receptors) in the rostral ventrolateral medulla. Supplementation with nitrate normalized the expression of AT1Rs in rostral ventrolateral medulla and reduced sympathetic nerve activity, which was associated with attenuated development of hypertension. In conclusion, chronic dietary nitrate supplementation blunted the development of hypertension via mechanisms that involve reduction of sympathetic outflow.

High Resolution Intravital Imaging of the Renal Immune Response to Injury and Infection in Mice.

We developed an experimental set up that enables longitudinal studies of immune cell behavior in situ in the challenged as well as unchallenged kidney of anesthetized mice over several hours. Using highly controlled vacuum to stabilize the kidney, the superficial renal cortex could continuously be visualized with minimal disruption of the local microenvironment. No visible changes in blood flow or neutrophils and macrophages numbers were observed after several hours of visualizing the unchallenged kidney, indicating a stable tissue preparation without apparent tissue damage. Applying this set up to monocyte/macrophage (CX3CR1GFP/+) reporter mice, we observed the extensive network of stellate-shaped CX3CR1 positive cells (previously identified as renal mononuclear phagocytes). The extended dendrites of the CX3CR1 positive cells were found to bridge multiple capillaries and tubules and were constantly moving. Light induced sterile tissue injury resulted in rapid neutrophil accumulation to the site of injury. Similarly, microinfusion of uropathogenic Escherichia coli into a single nephron induced a rapid and massive recruitment of neutrophils to the site of infection, in addition to active bacterial clearance by neutrophils. In contrast, the kidney resident mononuclear phagocytes were observed to not increase in numbers or migrate toward the site of injury or infection. In conclusion, this model allows for longitudinal imaging of responses to localized kidney challenges in the mouse.

Changes of arterial pressure following relief of obstruction in adults with hydronephrosis.

BACKGROUND: As much as 20% of all cases of hypertension are associated with kidney malfunctions. We have previously demonstrated in animals and in pediatric patients that hydronephrosis causes hypertension, which was attenuated by surgical relief of the ureteropelvic junction (UPJ) obstruction. This retrospective cohort study aimed to investigate: (1) the proposed link between hydronephrosis, due to UPJ obstruction, and elevated arterial pressure in adults; and (2) if elevated blood pressure in patients with hydronephrosis might be another indication for surgery. MATERIALS AND METHODS: Medical records of 212 patients undergoing surgical management of hydronephrosis, due to UPJ obstruction, between 2000 and 2016 were assessed. After excluding patients with confounding conditions and treatments, paired arterial pressures (i.e. before/after surgery) were compared in 49 patients (35 years old; 95% CI 29-39). Split renal function was evaluated by using mercaptoacetyltriglycine (MAG3) renography before surgical management of the hydronephrotic kidney. RESULTS: Systolic (-11 mmHg; 95% CI 6-15 mmHg), diastolic (-8 mmHg; 95% CI 4-11 mmHg), and mean arterial (-9 mmHg; 95% CI 6-12) pressures were significantly reduced after relief of the obstruction (p < 0.001). Split renal function of the hydronephrotic kidney was 39% (95% CI 37-41). No correlations were found between MAG3 and blood pressure level before surgery or between MAG3 and the reduction of blood pressure after surgical management of the UPJ obstruction. CONCLUSIONS: In adults with hydronephrosis, blood pressure was reduced following relief of the obstruction. Our findings suggest that elevated arterial pressure should be taken into account as an indication to surgically correct hydronephrosis.

Urban residential greenness and adiposity: A cohort study in Stockholm County.

BACKGROUND: Increasing evidence suggests that exposure to residential greenness is associated with positive health outcomes among urban populations. However, few studies have considered effects on adiposity development in a longitudinal setting. OBJECTIVES: This study aimed to explore the association between long-term exposure to urban residential greenness and markers of adiposity. METHODS: A cohort of 5126 adults from five municipalities in Stockholm County was examined clinically at baseline (1992-1998) and follow-up (2002-2006) after on average nine years. Time-weighted average exposure to urban greenness was estimated by Normalized Difference Vegetation Index (NDVI) within 100 m, 250 m, and 500 m buffers around the residential addresses of each participant. Multiple linear and Poisson regression models were used to estimate associations between greenness and change in weight and waist circumference as well as risk of overweight, obesity and central obesity. Co-exposures to air pollution, traffic noise and distance to water were also examined. RESULTS: In women, higher levels of residential greenness were associated with a reduced increase in waist circumference during follow-up (ß = -0.11 cm/year, 95% CI -0.14; -0.08 per one interquartile range increase in NDVI) and decreased risk for central obesity (IRR = 0.88: 95% CI 0.79; 0.99) in the 500 m buffer. No associations were observed for men or with regard to weight development or the risk of developing overweight or obesity. Exposure to low NDVI levels in combination with high NOx from road traffic and transportation noise as well as long distance to water rendered statistically significant increases in waist circumference in both sexes. CONCLUSION: Higher long-term exposure to greenness was associated with a reduced increase in waist circumference and lower risk of central adiposity in women but not in men. In both sexes, low NDVI exposure in combination with other environmental risk factors appeared particularly harmful.

Short-term external counterpulsation augments cerebral blood flow and tissue oxygenation in chronic cerebrovascular occlusive disease.

BACKGROUND AND PURPOSE: External counterpulsation improves cerebral perfusion velocity in acute stroke and may stimulate collateral artery growth. However, whether (non-acute) at-risk patients with high-grade carotid artery disease may benefit from counterpulsation needs to be validated. METHODS: Twenty-eight patients (71 ± 6.5 years, five women) with asymptomatic unilateral chronic severe internal carotid artery stenosis (>70%) or occlusion were randomized to receive 20 min active counterpulsation followed by sham treatment or vice versa. Cerebral blood flow velocity (CBFV) (measured bilaterally by transcranial middle cerebral artery Doppler), tissue oxygenation index (TOI) (measured over the bilateral prefrontal cortex by near-infrared spectroscopy) and cerebral hemodynamic parameters, such as relative pulse slope index (RPSI), were monitored. RESULTS: Ipsilateral mean CBFV (ΔVmean +3.5 ± 1.2 cm/s) and tissue oxygenation (ΔTOI +2.86 ± 0.8) increased significantly during active counterpulsation compared to baseline, whilst the sham had little effect (ΔVmean +1.13 ± 1.1 cm/s; ΔTOI +1.25 ± 0.65). On contralateral sides, neither counterpulsation nor sham control had any effect on either parameter. During counterpulsation, early dynamic changes in ΔRPSI of the ipsilateral CBFV signal predicted improved tissue oxygenation during counterpulsation (odds ratio 1.179, 95% confidence interval 1.01-1.51), whilst baseline cerebrovascular reactivity to hypercapnia failed to show an association. CONCLUSIONS: In patients with high-grade carotid disease, ipsilateral cerebral oxygenation and blood flow velocity are increased by counterpulsation. This is a necessary condition for the stimulation of regenerative collateral artery growth and thus a therapeutic concept for the prevention of cerebral ischaemia. This study provides a rationale for further clinical investigations on the long-term effects of counterpulsation on cerebral hemodynamics and collateral growth.

Changes in arterial pressure and markers of nitric oxide homeostasis and oxidative stress following surgical correction of hydronephrosis in children.

OBJECTIVE: Recent clinical studies have suggested an increased risk of elevated arterial pressure in patients with hydronephrosis. Animals with experimentally induced hydronephrosis develop hypertension, which is correlated to the degree of obstruction and increased oxidative stress. In this prospective study we investigated changes in arterial pressure, oxidative stress, and nitric oxide (NO) homeostasis following correction of hydronephrosis. METHODS: Ambulatory arterial pressure (24 h) was monitored in pediatric patients with hydronephrosis (n = 15) before and after surgical correction, and the measurements were compared with arterial pressure measurements in two control groups, i.e. healthy controls (n = 8) and operated controls (n = 8). Markers of oxidative stress and NO homeostasis were analyzed in matched urine and plasma samples. RESULTS: The preoperative mean arterial pressure was significantly higher in hydronephrotic patients [83 mmHg; 95% confidence interval (CI) 80-88 mmHg] than in healthy controls (74 mmHg; 95% CI 68-80 mmHg; p < 0.05), and surgical correction of ureteral obstruction reduced arterial pressure (76 mmHg; 95% CI 74-79 mmHg; p < 0.05). Markers of oxidative stress (i.e., 11-dehydroTXB2, PGF2α, 8-iso-PGF2α, 8,12-iso-iPF2α-VI) were significantly increased (p < 0.05) in patients with hydronephrosis compared with both control groups, and these were reduced following surgery (p < 0.05). Interestingly, there was a trend for increased NO synthase activity and signaling in hydronephrosis, which may indicate compensatory mechanism(s). CONCLUSION: This study demonstrates increased arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls, which can be restored to normal levels by surgical correction of the obstruction. Once reference data on ambulatory blood pressure in this young age group become available, we hope cut-off values can be defined for deciding whether or not to correct hydronephrosis surgically.

Extravasal albumin concentration modulates contractile responses of renal afferent arterioles.

AIM: Afferent arterioles (AA) hold a key position in the regulation of renal blood flow and glomerular filtration rate. Being the effector site of tubuloglomerular feedback, the afferent arteriole contributes to the renal handling of sodium and fluid. Dehydration goes along with increased renal interstitial protein concentration. Here, the hypothesis was tested that extravasal protein concentration directly modulates afferent arteriolar tone, a mechanism which may contribute to body fluid volume control. METHOD: The effect of increased extravasal albumin concentration on the vascular reactivity was investigated in renal AA and interlobar arteries of mice, in rat renal AA and in pancreatic islet arterioles. RESULTS: Albumin (2 and 4% in the bath solution) significantly potentiated the contractile response of renal afferent arterioles induced by angiotensin II and adenosine, as well as their combination, compared to the control situation (0.1% albumin). Albumin did not influence the contractility of larger renal vessels or pancreatic islet arterioles. Mimicking the increase in the osmolality induced by 4% albumin by applying mannitol to the bath solution also increased the response of renal arterioles to Ang II. However, the effect was smaller compared to that of albumin. The nitric oxide bioavailability, measured by DAF-FM fluorescence, was reduced in afferent arterioles exposed to 4% albumin. CONCLUSION: The protein-induced modulation of AA tone is mediated by the increased osmolality as well as by NO scavenging. The results suggest a possible contribution of these mechanisms to the control of extracellular fluid volume via adjustment of renal blood flow and glomerular filtration rate.