Cost-Effectiveness of Newborn Screening for Phenylketonuria and Congenital Hypothyroidism.

OBJECTIVE: To evaluate the long-term costs and health effects of the Swedish newborn screening program for classic phenylketonuria (PKU) alone and in combination with congenital hypothyroidism compared with no screening. STUDY DESIGN: A decision-analytic model was developed to estimate and compare the long-term (80 years) costs and health effects of newborn screening for PKU and congenital hypothyroidism. Data were obtained from the literature and translated to Swedish conditions. A societal perspective was taken, including costs falling on health care providers, municipal care and services, as well as production loss due to morbidity. RESULTS: Screening 100 000 newborns for PKU resulted in 73 gained quality-adjusted life-years (QALYs) compared with no screening. When adding congenital hypothyroidism, the number of gained QALYs was 232 compared with PKU alone, adding up to a total of 305 QALYs gained. Corresponding cost estimates were $80.8, $70.3, and $10.05 million USD for no screening, PKU screening, and PKU plus congenital hypothyroidism screening, respectively, indicating that screening for PKU plus congenital hypothyroidism was more effective and less costly compared with the other strategies. The majority of cost savings with PKU plus congenital hypothyroidism screening was due to reductions in productivity losses and municipal care and services costs. CONCLUSION: The Swedish newborn screening program for PKU and congenital hypothyroidism saves substantial costs for society while generating additional QALYs, emphasizing the importance of public investments in early diagnosis and treatment.

Stability of Proteins in Dried Blood Spot Biobanks.

An important motivation for the construction of biobanks is to discover biomarkers that identify diseases at early, potentially curable stages. This will require biobanks from large numbers of individuals, preferably sampled repeatedly, where the samples are collected and stored under conditions that preserve potential biomarkers. Dried blood samples are attractive for biobanking because of the ease and low cost of collection and storage. Here we have investigated their suitability for protein measurements. Ninety-two proteins with relevance for oncology were analyzed using multiplex proximity extension assays (PEA) in dried blood spots collected on paper and stored for up to 30 years at either +4 °C or -24 °C.Our main findings were that (1) the act of drying only slightly influenced detection of blood proteins (average correlation of 0.970), and in a reproducible manner (correlation of 0.999), (2) detection of some proteins was not significantly affected by storage over the full range of three decades (34 and 76% of the analyzed proteins at +4 °C and -24 °C, respectively), whereas levels of others decreased slowly during storage with half-lives in the range of 10 to 50 years, and (3) detectability of proteins was less affected in dried samples stored at -24 °C compared with at +4 °C, as the median protein abundance had decreased to 80 and 93% of starting levels after 10 years of storage at +4 °C or -24 °C, respectively. The results of our study are encouraging as they suggest an inexpensive means to collect large numbers of blood samples, even by the donors themselves, and to transport, and store biobanked samples as spots of whole blood dried on paper. Combined with emerging means to measure hundreds or thousands of protein, such biobanks could prove of great medical value by greatly enhancing discovery as well as routine analysis of blood biomarkers.

Intra-abdominal pressure increases peri-operatively in patients undergoing deep inferior epigastric perforator flap reconstruction: A prospective study linking high intra-abdominal pressure to non-fatal lung embolism within one patient.

BACKGROUND: The deep inferior epigastric perforator (DIEP) flap is the gold standard for autologous breast reconstruction. The procedure and peri-operative period are associated with the risk of severe post-operative complications, like venous thromboembolic events (VTE) and lung embolism. Whether the intra-abdominal pressure (IAP) increases after the closure of the abdominal defect, thereby potentially affecting the venous backflow and the risk of VTE, is currently not known. AIM: The primary aim is to test if the closure of the abdominal donor site increases the IAP in women undergoing secondary DIEP flap breast reconstruction. MATERIALS AND METHOD: By using a Unometer, we measured the intravesical pressure as a surrogate marker for the IAP, at baseline, immediately after, and 24 h after abdominal skin closure, for 13 patients. RESULTS: The mean IAP increased from 6.1 mmHg (95% CI 4.6-7.7) at baseline to 9.0 mmHg (95% CI 8.0-10.0) immediately after skin closure [mean diff. 2.9 (95% CI 1.0-4.8) (p = 0.007)] and further up to 11.7 mmHg (95% CI 9.0-14.5) 24 h after closure [mean diff. 5.3 (95% CI 1.4-9.1) (p = 0.012)]. We found that IAP varies among the patients, regardless of the tightness of abdominal closure or rectus plication (n = 3). Immediately after closure, none of the isolated patients showed abnormal levels of IAP (>12 mmHg), while eight out of 12 isolated patients (67%) showed IAP levels above the normal range after 24 h. One patient developed a non-fatal lung embolism. CONCLUSION: The mean IAP increases significantly over the post-operative period after DIEP flap reconstruction, although abnormal IAP values are only seen 24 h after the closure of the skin.

Age-associated mosaic respiratory chain deficiency causes trans-neuronal degeneration.

Heteroplasmic mitochondrial DNA (mtDNA) mutations (mutations present only in a subset of cellular mtDNA copies) arise de novo during the normal ageing process or may be maternally inherited in pedigrees with mitochondrial disease syndromes. A pathogenic mtDNA mutation causes respiratory chain deficiency only if the fraction of mutated mtDNA exceeds a certain threshold level. These mutations often undergo apparently random mitotic segregation and the levels of normal and mutated mtDNA can vary considerably between cells of the same tissue. In human ageing, segregation of somatic mtDNA mutations leads to mosaic respiratory chain deficiency in a variety of tissues, such as brain, heart and skeletal muscle. A similar pattern of mutation segregation with mosaic respiratory chain deficiency is seen in patients with mitochondrial disease syndromes caused by inherited pathogenic mtDNA mutations. We have experimentally addressed the role of mosaic respiratory chain deficiency in ageing and mitochondrial disease by creating mouse chimeras with a mixture of normal and respiratory chain-deficient neurons in cerebral cortex. We report here that a low proportion (>20%) of respiratory chain-deficient neurons in the forebrain are sufficient to cause symptoms, whereas premature death of the animal occurs only if the proportion is high (>60-80%). The presence of neurons with normal respiratory chain function does not only prevent mortality but also delays the age at which onset of disease symptoms occur. Unexpectedly, respiratory chain-deficient neurons have adverse effect on normal adjacent neurons and induce trans-neuronal degeneration. In summary, our study defines the minimal threshold level of respiratory chain-deficient neurons needed to cause symptoms and also demonstrate that neurons with normal respiratory chain function ameliorate disease progression. Finally, we show that respiratory chain-deficient neurons induce death of normal neurons by a trans-neuronal degeneration mechanism. These findings provide novel insights into the pathogenesis of mosaic respiratory chain deficiency in ageing and mitochondrial disease.

Complications in skin grafts when continuing antithrombotic therapy prior to cutaneous surgery requiring skin grafting: an observational study.

Use of anticoagulants is common and practice regarding continuation or discontinuation of the medication peri-operatively for cutaneous surgery lacks evidence-based consensus. Therefore, we aimed to do a prospective observational study with patients who were referred to cutaneous surgery and needed full thickness or split skin grafting and using antitrombotic or non-antitrombotic therapies. Data on patients characteristics, diagnosis, location of surgery and surgery performed, antithrombotic medication and complications in skin grafts were collected. Skin grafts were traced on a transparent film and areas of unhealed skin graft were marked. All patients were routinely followed-up on days 5-7 postoperative. Chi-square test, Fisher's exact test or Mann-Whitney U-test were used to compare patients taking antitrombotic medication with patients receiving no antitrombotic therapy. In addition, associations were calculated for treatment with the different antithrombotic therapies. No severe bleeding requiring blood transfusion or re-operation was observed in this study. The results showed no statistically significant difference between patients who continued treatment with antithrombotic therapy compared with patients having no antithrombotic treatment regarding sub graft hematomas or graft take. Continuing antithrombotic monotheraphy with acetylsalicylic, clopidogrel, warfarin or fish oil in relations to cutaneous surgery do not seem to increase risk of haematoma or graft lost.

Expanded Screening of One Million Swedish Babies with R4S and CLIR for Post-Analytical Evaluation of Data.

Sweden has one neonatal screening laboratory, receiving 115 to 120 thousand samples per year. Among the one million babies screened by tandem mass spectrometry from November 2010 until July 2019, a total of 665 babies were recalled and 311 verified as having one of the diseases screened for with this methodology, giving a positive predictive value (PPV) of 47% and an incidence of 1:3200. The PPV was high (41%) already in the first year after start of screening, thanks to the availability of the collaborative project Region 4 Stork database. The PPV is presently 58%. This improvement was achieved by the implementation of second-tier analyses in the screening for methylmalonic aciduria, propionic aciduria, isovaleric aciduria, and homocystinuria, and the employment of various post analytical tools of the Region 4 Stork, and its successor the collaborative laboratory integrated reports.

[Reconstruction of ritual female genital mutilation].

This review discusses female genital mutilation (FGM), which is a culturally founded ritual of unknown origin. The definition is intentional altering or injuring the female genitals for non-medical reasons. The WHO estimates, that more than 200 million women have sequelae from FGM. Acute compli-ca-tions range from haemorrhage and infection to death, while the most common chronic complications are vulvar pain, problems with micturition and childbirth, recurrent infec-tions, dysmenorrhoea, and dyspareunia. Favourable surgical techniques are available. Hitherto, these techniques are limited to certain types of FGM.

[Local anaesthetics].

Local anaesthetics are widely used in clinical practice. They comprise a group of weak organic bases, which selectively block sodium channels in the nerve cell membrane, thus blocking transmission of nociception by impeding depolarisation of the nerve. Local anaesthetics are generally safe and readily used and provide reduction of pain during biopsies, invasive procedures and surgery. This is an updated review of pharmacology and utilisation of local anaesthetics, as well as an overview of adjuvants, allergies, and adverse effects.

Laypersons' understanding of relative risk reductions: randomised cross-sectional study.

BACKGROUND: Despite increasing recognition of the importance of involving patients in decisions on preventive healthcare interventions, little is known about how well patients understand and utilise information provided on the relative benefits from these interventions. The aim of this study was to explore whether lay people can discriminate between preventive interventions when effectiveness is presented in terms of relative risk reduction (RRR), and whether such discrimination is influenced by presentation of baseline risk. METHODS: The study was a randomised cross-sectional interview survey of a representative sample (n = 1,519) of lay people with mean age 59 (range 40-98) years in Denmark. In addition to demographic information, respondents were asked to consider a hypothetical drug treatment to prevent heart attack. Its effectiveness was randomly presented as RRR of 10, 20, 30, 40, 50 or 60 percent, and half of the respondents were presented with quantitative information on the baseline risk of heart attack. The respondents had also been asked whether they were diagnosed with hypercholesterolemia or had experienced a heart attack. RESULTS: In total, 873 (58%) of the respondents consented to the hypothetical treatment. While 49% accepted the treatment when RRR = 10%, the acceptance rate was 58-60% for RRR>10. There was no significant difference in acceptance rates across respondents irrespective of whether they had been presented with quantitative information on baseline risk or not. CONCLUSION: In this study, lay people's decisions about therapy were only slightly influenced by the magnitude of the effect when it was presented in terms of RRR. The results may indicate that lay people have difficulties in discriminating between levels of effectiveness when they are presented in terms of RRR.

Risk-based analysis of the Danish pork Salmonella program: past and future.

The Danish pork Salmonella control program was initiated in 1993 in response to a prominent pork-related outbreak in Copenhagen. It involved improved efforts at slaughter hygiene (postharvest) and on-farm (preharvest) surveillance and control. After 10 years, 95 million Euros, significant reductions in seropositive herds, Salmonella positive carcasses, and pork-attributable human cases (PAHC), questions have arisen about how best to continue this program. The objective of this study was to provide some analysis and information to address these questions. The methods used include a computer simulation model constructed of a series of Excel workbooks, one for each simulated year and scenario (http://www.ifss.iastate/DanSalmRisk). Each workbook has three modules representing the key processes affecting risk: seropositive pigs leaving the farm (Production), carcass contamination after slaughter (Slaughter), and PAHC of Salmonella (Attribution). Parameter estimates are derived from an extensive farm-to-fork database collected by industry and government and managed by the Danish Zoonosis Centre (http://www.food.dtu.dk). Retrospective (1994-2003) and prospective (2004-2013) simulations were evaluated. The retrospective simulations showed that, except for the first few years (1994-1998), the on-farm program had minimal impact in reducing the number of positive carcasses and PAHC. Most of the reductions in PAHC up to 2003 were, according to this analysis, due to various improvements in abattoir processes. Prospective simulations showed that minimal reductions in human health risk (PAHC) could be achieved with on-farm programs alone. Carcass decontamination was shown as the most effective means of reducing human risk, reducing PAHC to about 10% of the simulated 2004 level.

Implementation of a rational pharmacotherapy intervention for inpatients at a psychiatric department.

The objective of the study was to develop, implement and evaluate two treatment algorithms for schizophrenia and depression at a psychiatric hospital department. The treatment algorithms were based on available literature and developed in collaboration between psychiatrists, clinical pharmacologists and a clinical pharmacist. The treatment algorithms were introduced at a meeting for all psychiatrists, reinforced by the project psychiatrists in the daily routine and used for educational purposes of young doctors and medical students. A quantitative pre-post evaluation was conducted using data from medical charts, and qualitative information was collected by interviews. In general, no significant differences were found when comparing outcomes from 104 charts from the baseline period with 96 charts from the post-intervention period. Most of the patients (65% in the post-intervention period) admitted during the data collection periods did not receive any medication changes. Of the patients undergoing medication changes in the post-intervention period, 56% followed the algorithms, and 70% of the patients admitted to the psychiatric hospital department for the first time had their medications changed according to the algorithms. All of the 10 interviewed doctors found the algorithms useful. The treatment algorithms were successfully implemented with a high degree of satisfaction among the interviewed doctors. The majority of patients admitted to the psychiatric hospital department for the first time had their medications changed according to the algorithms.

[Post-operative infections after cosmetic tourism].

Cosmetic tourism is defined as patient mobility across borders, typically constituted by patients seeking cosmetic surgery at lower costs abroad. The most common procedures are abdominoplasty, fat grafting and breast augmentation. Very little is known about the complication rates after cosmetic tourism, and there is a paucity of evidence in all aspects of cosmetic tourism. In this review, we focus on post-operative complications i.e. post-operative infections, in particular with rare microorganisms such as mycobacteria.

[Mycobacterium abscessus infection after cosmetic breast surgery in India].

A 36-year-old Danish woman underwent cosmetic breast surgery in India. Post-operatively, she presented with infection and ulcers under the breasts, and dicloxacillin was administered. The patient did not return for follow-up. Two years later the ulcer under the right breast had not healed, and the patient returned to hospital, where a wound culture was done. The result showed Mycobacterium abscessus. Hence, cephalexin administration was instituted, but the ulcer did not heal, and it was excised. The subsequent healing was rapid. Mycobacterial infections in Denmark are rare, serious, and often resistant to antibiotics.

User driven, evidence based experimental design; a new method for interface design used to develop an interface for clinical overview of patient records.

A novel method of interface design--user driven, evidence based experimental design--was developed which approximates the usual clinical way of maturing science and technology in the healthcare domain. The method is user-driven and the clinician remains in control of gathering and evaluating evidence of relevance to the project--as well as specifying the details of the user interface. Information not obtainable from the literature was gained experimentally and used to achieve a deeper understanding of the problem before the design phase. The design was subsequently validated experimentally by ordinary users with no connection to the software or design team. After applying this method to the problem of gaining a satisfactory clinical overview of a single patient's record, we recommend that clinical IT interfaces have clinical logic, sufficient complexity, and are well structured. Developers should use computer power to support "building blocks" such as anatomical problem lists and summaries of history, status and treatment, personal notes, and should support clinical browsing using text and graphics.

Complications in skin grafts when continuing antithrombotic therapy prior to cutaneous surgery requiring skin grafting: A systematic review.

The risk of postoperative bleeding and wound healing complications in skin grafts among anticoagulated patients undergoing cutaneous surgery has not been firmly established. The objective was to examine the literature and assess the risk of postoperative bleeding or wound healing complications in skin grafts among anticoagulated patients, compared with patients who discontinue or patients who are not receiving antithrombotic therapy prior to cutaneous surgery requiring skin grafting. A systematic review examining the effect of antithrombotic therapy on cutaneous surgery was performed according to the PRISMA-guidelines. PubMed and Embase databases were primarily searched for relevant literature in the period from the start date of each database to 2014. A total of eight studies representing 443 patients met criteria for inclusion. No randomised controlled trials were found; the included studies were of prospective and retrospective design. Most of the reviewed studies suggest that the use of antithrombotic therapy can increase the risk of bleeding complications in skin grafts. These complications are only wound threatening and not life threatening. Therefore, this is of concern mostly in terms of hemostasis by the surgeon and good pressure dressings. Care should be taken when operating on anticoagulated patients undergoing cutaneous surgery requiring skin grafting. However, graft failure is rare and, given the risk of thrombotic events, the reviewed studies recommend continuing all medically necessary antithrombotic therapy. The limitations of this study are the small sample sizes and the level of evidence; hence, more research is needed to substantiate these preliminary findings.

Effect of active site-inactivated factor VIIa on ischaemia/reperfusion injury in a porcine flap model.

In free flap surgery, restored blood flow following a lengthy ischaemic period may lead to necrosis as a result of ischaemia/reperfusion (IR) injury. This injury comprises both proinflammatory and prothrombotic events, where the tissue factor/factor VIIa complex probably has a key role. Active site-inactivated factor VIIa (FFR-rFVIIa) exerts an antithrombotic effect by binding to tissue factor without initiating coagulation. In this study we have evaluated the potential protective effects of FFR-rFVIIa in IR injury. Bilateral musculocutaneous latissimus dorsi flaps in 16 pigs were made ischaemic for eight hours, then given 1 mg/kg/flap of FFR-rFVIIa or vehicle intra-arterially, and reperfused for 10 hours. The viable:necrotic tissue ratio, and accumulation of radiolabelled leucocytes, fibrinogen, and platelets were measured. There was no effect on tissue survival, but radiolabelled components in viable tissue were increased, though not significantly so. We conclude that FFR-rFVIIa did not prevent IR injury, indicating that tissue factor-mediated coagulation is not an important determinant of IR injury in this setting.

The day-to-day acute effect of wake therapy in patients with major depression using the HAM-D6 as primary outcome measure: results from a randomised controlled trial.

BACKGROUND: This paper reports day-to-day data for from a one-week intervention phase, part of a 9-weeks randomised parallel study with patient having major depression (data from weekly visits have been reported). Wake therapy (sleep deprivation) has an established antidepressant effect with onset of action within hours. Deterioration on the following night's sleep is, however, common, and we used daily light therapy and sleep time stabilisation as a preventive measure. In particular, we evaluated the day-to-day acute effect of and tolerance to sleep deprivation and examined predictors of response. METHODS: Patients were assessed at psychiatric inpatient wards. In the wake group (n = 36), patients did three wake therapies in combination with light therapy each morning together with sleep time stabilisation. In the exercise group (n = 38), patients did daily exercise. Hamilton subscale scores were primary outcome (not blinded), secondary outcome was self-assessment data from the Preskorn scale and sleep. RESULTS: Patients in the wake therapy group had an immediate, large, stable, and statistically significant better antidepressant effect than patients in the exercise group with response rates at day5 of 75.0%/25.1% and remission rates of 58.6%/6.0%, respectively. The response and remission rates were diminished at day8 with response rates of 41.9%/10.1% and remission rates of 19.4%/4.7%, respectively. Patients and ward personnel found the method applicable with few side effects. Positive diurnal variation (mood better in the evening) predicted a larger response to wake therapy. In the wake group napping on days after intervention predicted greater deterioration on day8. CONCLUSIONS: The intervention induced an acute antidepressant response without relapse between wake nights but with a diminishing effect after intervention. Development is still needed to secure maintenance of response. Avoiding napping in the days after wake therapy is important. TRIAL REGISTRATION: Clinical trials.gov NCT00149110.

Integrating ergonomics in design processes: a case study within an engineering consultancy firm.

This paper reports on a case study within an engineering consultancy firm, where engineering designers and ergonomists were working together on the design of a new hospital sterile processing plant. The objective of the paper is to gain a better understanding of the premises for integrating ergonomics into engineering design processes and how different factors either promote or limit the integration. Based on a grounded theory approach a model illustrating these factors is developed and different hypotheses about how these factors either promote and/or limit the integration of ergonomics into design processes is presented along with the model.

A 9-week randomized trial comparing a chronotherapeutic intervention (wake and light therapy) to exercise in major depressive disorder patients treated with duloxetine.

OBJECTIVE: The onset of action of antidepressants often takes 4 to 6 weeks. The antidepressant effect of wake therapy (sleep deprivation) comes within hours but carries a risk of relapse. The objective of this study was to investigate whether a new chronotherapeutic intervention combining wake therapy with bright light therapy and sleep time stabilization could induce a rapid and sustained augmentation of response and remission in major depressive disorder. METHOD: 75 adult patients with DSM-IV major depressive disorder, recruited from psychiatric wards, psychiatric specialist practices, or general medical practices between September 2005 and August 2008, were randomly assigned to a 9-week chronotherapeutic intervention using wake therapy, bright light therapy, and sleep time stabilization (n = 37) or a 9-week intervention using daily exercise (n = 38). Patients were evaluated at a psychiatric research unit. The study period had a 1-week run-in phase in which all patients began treatment with duloxetine. This phase was followed by a 1-week intervention phase in which patients in the wake therapy group did 3 wake therapies in combination with daily morning light therapy and sleep time stabilization and patients in the exercise group began daily exercise. This phase was followed by a 7-week continuation phase with daily light therapy and sleep time stabilization or daily exercise. The 17-item Hamilton Depression Rating Scale was the primary outcome measure, and the assessors were blinded to patients' treatment allocation. RESULTS: Both groups responded well to treatment. Patients in the wake therapy group did, however, have immediate and clinically significantly better response and remission compared to the exercise group. Thus, immediately after the intervention phase (week 2), response was obtained in 41.4% of wake therapy patients versus 12.8% of exercise patients (odds ratio [OR] = 4.8; 95% CI, 1.7-13.4; P = .003), and remission was obtained in 23.9% of wake therapy patients versus 5.4% of exercise patients (OR = 5.5; 95% CI, 1.7-17.8; P = .004). These superior response and remission rates obtained by the wake therapy patients were sustained for the whole study period. At week 9, response was obtained in 71.4% of wake therapy patients versus 47.3% of exercise patients (OR = 2.8; 95% CI, 1.1-7.3; P = .04), and remission was obtained in 45.6% of wake therapy patients and 23.1% of exercise patients (OR = 2.8; 95% CI, 1.1-7.3, P = .04). All treatment elements were well tolerated. CONCLUSIONS: Patients treated with wake therapy in combination with bright light therapy and sleep time stabilization had an augmented and sustained antidepressant response and remission compared to patients treated with exercise, who also had a clinically relevant antidepressant response. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00149110.

[Identification of non-compliant hypertensive patients]. / Identificering af nonkompliante patienter med hypertension.

INTRODUCTION: The purpose was to contribute to the development of a validated instrument for identification of patients with poor compliance in the use of hypertension medicine in primary health care. MATERIAL AND METHODS: The analysis included questionnaire data from 1,421 hypertensive patients, data from the Danish register "Patient Medical Profile" (PEM, n = 182) and electronic medicine containers (MEMS, n = 33). The analysis included preliminary scale validation resulting in five scales. The scales were used in a subsequent multivariate regression analysis which involved a total of 29 variables. The key variables were established via the correlations between variables in the graphic model and included in the instrument. RESULTS: The scale "Unintentional non-compliance" (concerning the patient's self-assessed tendency to forget to take the medicine) is central in the graphic network in terms of its relation to the scales "Intentional non-compliance" (when patients opt not to follow the prescriptions) and "Medical concern" (concerns related to medicine intake). "Unintentional non-compliance", moreover, correlates with PEM. The item concerning the patient's systolic blood pressure proved to be crucial because of its correlation with both PEM and MEMS. The scales "Medical concern" and "Intentional non-compliance" are, moreover, assessed to measure different dimensions of compliance. CONCLUSION: A group of items has been developed and validated. Collectively they can identify hypertensive patients with poor compliance in primary health care.