Fine Mapping the Spatial Distribution and Concentration of Unlabeled Drugs within Tissue Micro-Compartments Using Imaging Mass Spectrometry

Readouts that define the physiological distributions of drugs in tissues are an unmet challenge and at best imprecise, but are needed in order to understand both the pharmacokinetic and pharmacodynamic properties associated with efficacy. Here we demonstrate that it is feasible to follow the in vivo transport of unlabeled drugs within specific organ and tissue compartments on a platform that applies MALDI imaging mass spectrometry to tissue sections characterized with high definition histology. We have tracked and quantified the distribution of an inhaled reference compound, tiotropium, within the lungs of dosed rats, using systematic point by point MS and MS/MS sampling at 200 µm intervals. By comparing drug ion distribution patterns in adjacent tissue sections, we observed that within 15 min following exposure, tiotropium parent MS ions (mass-to-charge; m/z 392.1) and fragmented daughter MS/MS ions (m/z 170.1 and 152.1) were dispersed in a concentration gradient (80 fmol-5 pmol) away from the central airways into the lung parenchyma and pleura. These drug levels agreed well with amounts detected in lung compartments by chemical extraction. Moreover, the simultaneous global definition of molecular ion signatures localized within 2-D tissue space provides accurate assignment of ion identities within histological landmarks, providing context to dynamic biological processes occurring at sites of drug presence. Our results highlight an important emerging technology allowing specific high resolution identification of unlabeled drugs at sites of in vivo uptake and retention

Natural course and long-term prognosis in idiopathic Normal Pressure Hydrocephalus - the effect of delayed surgery and clinical factors on outcome and survival

Idiopathic Normal Pressure Hydrocephalus, iNPH, causes gait and balance difficulties, urinary incontinence and cognitive decline in mainly older persons and is treatable by insertion of a cerebrospinal fluid diverting shunt. The effects of postponing treatment in these patients have have been largely unknown and the benefits of treatment in the long-term, mortality and causes of death have not been reported in any large cohort of patients. The aims of this thesis were to study the natural course in untreated iNPH patients, and the effect of postponed treatment, with regard to outcome and survival. Moreover, the aim was to study the long-term outcome and survival in a large unselected cohort of iNPH patients treated all over Sweden, registered in the Swedish Hydrocephalus Quality Registry, SHQR. A group of patients diagnosed with iNPH who due to capacity problems had to wait median 13 months for shunt surgery, was studied and compared to a group of patients operated without delay. Symptoms progressed during the wait. Once treated, these patients improved, but outcome was less beneficial than in the patients operated without delay (paper I). Their mortality was more than two-fold increased (paper II). In 979 iNPH patients from the SHQR, around 60% stated being improved 2 to 6 years after shunt surgery. Re-operations were necessary in 26% but did not influence the long-term outcome, and vascular comorbidity had only minor effects (paper III). Survival was reduced compared to the general population, and shorter in patients with more pronounced symptoms or with heart diseases. Patients with the most beneficial treatment effects, survived similarly as the general population. Death due to cerebrovascular diseases was more common in iNPH patients, while death due to malignancy was less common, than in the general population (paper IV). This thesis indicates that the natural course of iNPH is progression of symptoms which are only partially reversible and in order to optimize treatment benefits and survival, surgery should be performed without delay. The majority of this aged patient group, also those with vascular comorbidities, have favourable long-term effects and should also be offered treatment. Complications are common, but do not seem to hamper the long-term results. Treatment improves the symptoms and increases survival in iNPH

Adherence to anti-seizure medications in the Swedish Prospective Regional Epilepsy Database and Biobank for Individualized Clinical Treatment (PREDICT)

The aim of this study was to describe the extent of, and risk factors for, non-adherence to anti-seizure medications (ASMs) in adult people with epilepsy (PWE) in Sweden.A cross-sectional multi-centre study was performed of PWEs in western Sweden, with data from medical records, and a questionnaire filled in by the participants including self-reports on how often ASM doses had been forgotten during the past year. Participants were categorized into adherent if they forgot at 0–1 occasion, and non-adherent if they forgot at 2–10 or >10 occasions. Demographic and clinical factors were compared by Chi2- or Fisher’s test and a logistic regression model was used to find risk factors for non-adherence.In the cohort of 416 PWE aged median 43, IQR 29–62 years, 398 patients were prescribed ASM treatment at inclusion, and 39 % (n = 154) were in the non-adherent group. Significant factors in the multivariable analysis were: younger age, seizure freedom the past year, valproate treatment and experiencing side effects.The rate of self-reported non-adherence was high, illustrating a need for continuous focus on fundamental aspects of epilepsy care. The identified risk factors could enable quality improvement projects and patient education to be directed to those at risk of non-adherence

One size does not fit all : Perspectives from Swedish midwives on fetal movement counselling

PROBLEM: Migration continues to play a role in determining health outcomes related to pregnancy and childbirth in Sweden. BACKGROUND: Migrant women have, compared to Swedish-born women, increased risks of adverse birth outcomes. Previous research suggests that migrant women seek care for decreased fetal movements less than Swedish-born women. Given these documented risks, understanding midwives' perspectives in this context is crucial to address maternal health inequities. AIM: To explore midwives' experiences conveying information about fetal movement to migrant women in antenatal healthcare settings. METHODS: Semi-structured, individual interviews with midwives (n=15) experienced in providing information about fetal movements to migrant women. The interviews were analysed using reflexive thematic analysis. FINDINGS: The midwives' efforts to compensate for the deficiencies within the antenatal healthcare organisation and to ensure that all women received access to information and care regarding fetal movements are described in four themes: (a) building a trusting relationship; (b) empowering women through guidance and support; (c) overcoming communication challenges; and d) navigating safety measures. DISCUSSION: Our findings suggest that the standard antenatal care programme does not support midwives to provide holistic and individualised care that aligns with midwifery care philosophy. CONCLUSION: To reduce health inequities for migrant women, this study highlights the need for more flexible guidelines within the standard antenatal care programme. These guidelines should prioritise the individual woman's needs over institutional protocols, acknowledge the midwife-woman relationship as the core of midwifery practice and support midwives to build a partnership with women through continuity of care

Survival in treated idiopathic normal pressure hydrocephalus

Objective: To describe survival and causes of death in 979 treated iNPH patients from the Swedish Hydrocephalus Quality Registry (SHQR), and to examine the influence of comorbidities, symptom severity and postoperative outcome. Methods: All 979 patients operated for iNPH 2004-2011 and registered in the SHQR were included. A matched control group of 4890 persons from the general population was selected by Statistics Sweden. Data from the Swedish Cause of Death Registry was obtained for patients and controls. Results: At a median 5.9 (IQR 4.2-8.1) year follow-up, 37% of the iNPH patients and 23% of the controls had died. Mortality was increased in iNPH patients by a hazard ratio of 1.81, 95% CI 1.61-2.04, p < 0.001. More pronounced symptoms in the preoperative ordinal gait scale and the Mini-mental State Examination were the most important independent predictors of mortality along with the prevalence of heart disease. Patients who improved in both the gait scale and in the modified Rankin Scale postoperatively (n = 144) had a similar survival as the general population (p = 0.391). Deaths due to cerebrovascular disease or dementia were more common in iNPH patients, while more controls died because of neoplasms or disorders of the circulatory system. Conclusions: Mortality in operated iNPH patients is 1.8 times increased compared to the general population, a lower figure than previously reported. The survival of iNPH patients who improve in gait and functional independence is similar to that of the general population, indicating that shunt surgery for iNPH, besides improving symptoms and signs, can normalize survival

Miscommunication influences how women act when fetal movements decrease an interview study with Swedish Somali migrant women

OBJECTIVE: To explore how Swedish Somali migrant women perceive fetal movements, process information about fetal movements, and take actions if decreased fetal activity occurs. DESIGN: A qualitative study based on individual semi-structured interviews. The interviews were analysed using content analysis. SETTING: The study was conducted in Sweden. PARTICIPANTS: Swedish Somali migrant women (n=15) pregnant in their third trimester or recently given birth. FINDINGS: The analysis led to the main category: tailored information about fetal movements enhances the possibility to seek care if the movements decrease. The results are described in the generic categories: explanatory models determine action; and understand and interpret information. KEY CONCLUSIONS: Miscommunication on fetal movements can be a hurdle for Swedish Somali migrant women that may have impact on stillbirth prevention and the quality of care. Improved communication and information tailored to individual needs is essential to achieve equality for women and their newborns. IMPLICATIONS FOR PRACTICE: The midwife can be used as a hub for reassuring that adequate information about fetal movements reaches each individual woman in antenatal care. Individualised information on fetal movements based on the women's own understanding is suggested to increase the possibility that the pregnant woman will seek care if the movements decrease. Somali women's verbal communication can be used to spread accurate information in the Somali community on the importance of seeking care if fetal movements decrease

Long-term effects of complications and vascular comorbidity in idiopathic normal pressure hydrocephalus : a quality registry study

Background: There is little knowledge about the factors influencing the long-term outcome after surgery for idiopathic normal pressure hydrocephalus (iNPH). Objective: To evaluate the effects of reoperation due to complications and of vascular comorbidity (hypertension, diabetes, stroke and heart disease) on the outcome in iNPH patients, 2–6 years after shunt surgery. Methods: We included 979 patients from the Swedish Hydrocephalus Quality Registry (SHQR), operated on for iNPH during 2004–2011. The patients were followed yearly by mailed questionnaires, including a self-assessed modified Rankin Scale (smRS) and a subjective comparison between their present and their preoperative health condition. The replies were grouped according to the length of follow-up after surgery. Data on clinical evaluations, vascular comorbidity, and reoperations were extracted from the SHQR. Results: On the smRS, 40% (38–41) of the patients were improved 2–6 years after surgery and around 60% reported their general health condition to be better than preoperatively. Reoperation did not influence the outcome after 2–6 years. The presence of vascular comorbidity had no negative impact on the outcome after 2–6 years, assessed as improvement on the smRS or subjective improvement of the health condition, except after 6 years when patients with hypertension and a history of stroke showed a less favorable development on the smRS. Conclusion: This registry-based study shows no negative impact of complications and only minor effects of vascular comorbidity on the long-term outcome in iNPH

Essential tactics of tissue preparation and matrix nano-spotting for successful compound imaging mass spectrometry

The ultimate goal of MALDI-Imaging Mass Spectrometry (MALDI-IMS) is to achieve spatial localization of analytes in tissue sections down to individual tissue compartments or even at the level of a few cells. With compound tissue imaging, it is possible to track the transportation of an unlabelled, inhaled reference compound within lung tissue, through the application of MALDI-IMS. The procedure for isolation and preparation of lung tissues is found to be crucial in order to preserve the anatomy and structure of the pulmonary compartments. To avoid delocalization of analytes within lung tissue compartments we have applied an in-house designed nano-spotter, based on a microdispenser mounted on XY-table, of which movement and spotting functionality were fully computer controlled. We demonstrate the usefulness of this platform in lung tissue sections isolated from rodent in vivo model, applied to compound tissue imaging as exemplified with the determination of the spatial distribution of (1α,2β,4β,7β)-7-[(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane, also known as tiotropium. We provide details on tissue preparation protocols and sample spotting technology for successful identification of drug in mouse lung tissue by using MALDI-Orbitrap instrumentation