Cost-effectiveness of implementing a digital psychosocial intervention for patients with psychotic spectrum disorders in low- and middle-income countries in Southeast Europe: Economic evaluation alongside a cluster randomised trial.

BACKGROUND: DIALOG+ is a digital psychosocial intervention aimed at making routine meetings between patients and clinicians therapeutically effective. This study aimed to evaluate the cost-effectiveness of implementing DIALOG+ treatment for patients with psychotic disorders in five low- and middle-income countries in Southeast Europe alongside a cluster randomised trial. METHODS: Resource use and quality of life data were collected alongside the multi-country cluster randomised trial of 468 participants with psychotic disorders. Due to COVID-19 interruptions of the trial's original 12-month intervention period, adjusted costs and quality-adjusted life years (QALYs) were estimated at the participant level using a mixed-effects model over the first 6 months only. We estimated the incremental cost-effectiveness ratio (ICER) with uncertainty presented using a cost-effectiveness plane and a cost-effectiveness acceptability curve. Seven sensitivity analyses were conducted to check the robustness of the findings. RESULTS: The average cost of delivering DIALOG+ was €91.11 per participant. DIALOG+ was associated with an incremental health gain of 0.0032 QALYs (95% CI -0.0015, 0.0079), incremental costs of €84.17 (95% CI -8.18, 176.52), and an estimated ICER of €26,347.61. The probability of DIALOG+ being cost-effective against three times the weighted gross domestic product (GDP) per capita for the five participating countries was 18.9%. CONCLUSION: Evidence from the cost-effectiveness analyses in this study suggested that DIALOG+ involved relatively low costs. However, it is not likely to be cost-effective in the five participating countries compared with standard care against a willingness-to-pay threshold of three times the weighted GDP per capita per QALY gained.

Improving treatment of patients with psychosis in low-and-middle-income countries in Southeast Europe: Results from a hybrid effectiveness-implementation, pragmatic, cluster-randomized clinical trial (IMPULSE).

BACKGROUND: In Southeast Europe (SEE) standard treatment of patients with psychosis is largely based on pharmacotherapy with psychosocial interventions rarely available. DIALOG+ is a digital psychosocial intervention designed to make routine care therapeutically effective. This trial simultaneously examined effectiveness of DIALOG+ versus standard care on clinical and social outcomes (Aim 1) and explored intervention fidelity (Aim 2). METHODS: A hybrid type II effectiveness-implementation, cluster-randomized trial was conducted in five SEE countries: Bosnia and Herzegovina, Kosovo*, Montenegro, North Macedonia, and Serbia. The intervention was offered to patients six times across 12 months instead of routine care. The outcomes were subjective quality of life (primary), clinical symptoms, satisfaction with services, and economic costs. Intervention fidelity was operationalized as adherence to the protocol in terms of frequency, duration, content, and coverage. Data were analyzed using multilevel regression. RESULTS: A total of 81 clinicians and 468 patients with psychosis were randomized to DIALOG+ or standard care. The intervention was delivered with high fidelity. The average number of delivered sessions was 5.5 (SD = 2.3) across 12 months. Patients in the intervention arm had better quality of life (MANSA) at 6 months (p = 0.03). No difference was found for other outcomes at 6 months. Due to disruptions caused by the COVID-19 pandemic, 12-month data were not interpretable. CONCLUSIONS: DIALOG+ improved subjective quality of life of individuals with psychosis at 6 months (after four sessions), albeit with small effect size. The intervention has the potential to contribute to holistic care of patients with psychosis.

Vector-apodizing phase plate coronagraph: design, current performance, and future development [Invited].

Over the last decade, the vector-apodizing phase plate (vAPP) coronagraph has been developed from concept to on-sky application in many high-contrast imaging systems on 8 m class telescopes. The vAPP is a geometric-phase patterned coronagraph that is inherently broadband, and its manufacturing is enabled only by direct-write technology for liquid-crystal patterns. The vAPP generates two coronagraphic point spread functions (PSFs) that cancel starlight on opposite sides of the PSF and have opposite circular polarization states. The efficiency, that is, the amount of light in these PSFs, depends on the retardance offset from a half-wave of the liquid-crystal retarder. Using different liquid-crystal recipes to tune the retardance, different vAPPs operate with high efficiencies (${\gt}96\%$) in the visible and thermal infrared (0.55 µm to 5 µm). Since 2015, seven vAPPs have been installed in a total of six different instruments, including Magellan/MagAO, Magellan/MagAO-X, Subaru/SCExAO, and LBT/LMIRcam. Using two integral field spectrographs installed on the latter two instruments, these vAPPs can provide low-resolution spectra (${\rm{R}} \sim 30$) between 1 µm and 5 µm. We review the design process, development, commissioning, on-sky performance, and first scientific results of all commissioned vAPPs. We report on the lessons learned and conclude with perspectives for future developments and applications.

Eye injury and demographic parameters associated with poor visual outcome.

BACKGROUND: Eye injuries can result in long-term disability, and healthcare providers need better tools to predict outcomes. Few prognostic models for poor visual acuity have been examined using variables usually present in very severe injuries, which creates a gap in prognosis. Therefore, a model associated with severe and less severe injuries is examined. METHODS: Eye injuries hospitalized in Bosnia and Herzegovina from 2006 through 2014 were included. A total of 258 eye injuries met the inclusion criteria of being an acute mechanical, chemical or physical eye injury. Prognostic variables were grouped by patient characteristics, eye injury characteristics and eye injury diagnosis. Poor final visual acuity was the main outcome measure (vision less than 20/200). Multivariable regression analysis used stepwise selection to identify the strongest set of predictive variables. RESULTS: Lens subluxation (95 % CI: 2.09-14.83), vitreous prolapse (95 % CI: 2.76-26.87), vitreous hemorrhage (95 % CI: 1.71-10.03), posterior segment intraocular foreign body (95 % CI: 1.19-39.09), and vitritis (95 % CI: 0.97-11.12) were significantly associated with poor final visual acuity. The predictive model identified the combination of age over 36, lens subluxation, vitreous prolapse and hemorrhage, vitritis, and macular hemorrhage as the combination most likely to have poor visual acuity. The final model resulted in a strong fit as measured by AIC, log likelihood, goodness-of-fit, and the c-statistic. CONCLUSIONS: This model can be used in clinical practice to evaluate the severity and predict final visual acuity in both severe and less severe eye injuries. The model accounts for characteristics of the injury as well as the patient. Additional studies with larger samples could further verify this model.

Functional and pharmacological analysis of agmatine administration in different cerebral ischemia animal models.

Agmatine (AgM, 100 mg/kg i.p.) effect was tested in parallel at two animal models of cerebral ischemia - rat MCAO model (60'/24 h, 60'/48 h, 90'/24 h, 90'/48 h) and gerbil global ischemia (10') model, administrated 5 min after reperfusion. Aim was to evaluate AgM effect on functional outcome 24 and 48 h after MCAO on neurological and sensor-motor function, and coordination in rats. AgM administration significantly reduced infarct volume, improved neurological score and improved post-ischemic oxidative status. Results of behavioral tests (cylinder test, beam walking test, and adhesive removal test) have shown very effective functional recovery after AgM administration. Efficiency of AgM administration in gerbils was observed in forebrain cortex, striatum, hippocampus, and cerebellum at the level of each examined oxidative stress parameter (nitric oxide level, superoxide production, superoxide dismutase activity, and index of lipid peroxidation) measured in four different time points starting at 3 h up to 48 h after reperfusion. The highest levels were obtained 6 h after the insult. The most sensitive oxidative stress parameter to AgM was nitric oxide. Additionally, we performed pharmacological analysis of AgM on rat isolated common carotid arteries. The findings imply that mixed population of potassium channels located on the smooth muscle cells was involved in common carotid artery response to AgM, with predominance of inward rectifying K+ channels. In our comparative experimental approach, judged by behavioral, biochemical, as well as pharmacological data, the AgM administration showed an effective reduction of ischemic neurological damage and oxidative stress, hence indicating a direction towards improving post-stroke recovery.

Modal noise in an integrated photonic lantern fed diffraction-limited spectrograph.

In an attempt to develop a streamlined astrophotonic instrument, we demonstrate the realization of an all-photonic device capable of both multimode to single mode conversion and spectral dispersion on an 8-m class telescope with efficient coupling. The device was a monolithic photonic spectrograph which combined an integrated photonic lantern and an efficient arrayed waveguide grating device. During on-sky testing, we discovered a previously unreported type of noise that made spectral extraction and calibration extremely difficult. The source of the noise was traced to a wavelength-dependent loss mechanism between the feed fiber's multimode near-field pattern and the modal acceptance profile of the integrated photonic lantern. Extensive modeling of the photonic components replicates the wavelength-dependent loss, and demonstrates an identical effect on the final spectral output. We outline that this could be mitigated by directly injecting into the integrated photonic lantern.

Demonstration of an efficient, photonic-based astronomical spectrograph on an 8-m telescope.

We demonstrate for the first time an efficient, photonic-based astronomical spectrograph on the 8-m Subaru Telescope. An extreme adaptive optics system is combined with pupil apodiziation optics to efficiently inject light directly into a single-mode fiber, which feeds a compact cross-dispersed spectrograph based on array waveguide grating technology. The instrument currently offers a throughput of 5% from sky-to-detector which we outline could easily be upgraded to ∼ 13% (assuming a coupling efficiency of 50%). The isolated spectrograph throughput from the single-mode fiber to detector was 42% at 1550 nm. The coupling efficiency into the single-mode fiber was limited by the achievable Strehl ratio on a given night. A coupling efficiency of 47% has been achieved with ∼ 60% Strehl ratio on-sky to date. Improvements to the adaptive optics system will enable 90% Strehl ratio and a coupling of up to 67% eventually. This work demonstrates that the unique combination of advanced technologies enables the realization of a compact and highly efficient spectrograph, setting a precedent for future instrument design on very-large and extremely-large telescopes.

Burnout syndrome among psychiatric trainees in 22 countries: Risk increased by long working hours, lack of supervision, and psychiatry not being first career choice.

BACKGROUND: Postgraduate medical trainees experience high rates of burnout, but evidence regarding psychiatric trainees is missing. We aim to determine burnout rates among psychiatric trainees, and identify individual, educational and work-related factors associated with severe burnout. METHODS: In an online survey psychiatric trainees from 22 countries were asked to complete the Maslach Burnout Inventory (MBI-GS) and provide information on individual, educational and work-related parameters. Linear mixed models were used to predict the MBI-GS scores, and a generalized linear mixed model to predict severe burnout. RESULTS: This is the largest study on burnout and training conditions among psychiatric trainees to date. Complete data were obtained from 1980 out of 7625 approached trainees (26%; range 17.8-65.6%). Participants were 31.9 (SD 5.3) years old with 2.8 (SD 1.9) years of training. Severe burnout was found in 726 (36.7%) trainees. The risk was higher for trainees who were younger (P<0.001), without children (P=0.010), and had not opted for psychiatry as a first career choice (P=0.043). After adjustment for socio-demographic characteristics, years in training and country differences in burnout, severe burnout remained associated with long working hours (P<0.001), lack of supervision (P<0.001), and not having regular time to rest (P=0.001). Main findings were replicated in a sensitivity analysis with countries with response rate above 50%. CONCLUSIONS: Besides previously described risk factors such as working hours and younger age, this is the first evidence of negative influence of lack of supervision and not opting for psychiatry as a first career choice on trainees' burnout.

Pharmaceutical industry interactions of psychiatric trainees from 20 European countries.

BACKGROUND: Interactions between the pharmaceutical industry (PI) and psychiatrists have been under scrutiny recently, though there is little empirical evidence on the nature of the relationship and its intensity at psychiatry trainee level. We therefore studied the level of PI interactions and the underlying beliefs and attitudes in a large sample of European psychiatric trainees. METHODS: One thousand four hundred and forty-four psychiatric trainees in 20 European countries were assessed cross-sectionally, with a 62-item questionnaire. RESULTS: The total number of PI interactions in the preceding two months varied between countries, with least interactions in The Netherlands (M (Mean)=0.92, SD=1.44, range=0-12) and most in Portugal (M=19.06, SD=17.44, range=0-100). Trainees were more likely to believe that PI interactions have no impact on their own prescribing behaviour than that of other physicians (M=3.30, SD=1.26 vs. M=2.39, SD=1.06 on a 5-point Likert scale: 1 "completely disagree" to 5 "completely agree"). Assigning an educational role to the pharmaceutical industry was associated with more interactions and higher gift value (IRR (incidence rate ratio)=1.21, 95%CI=1.12-1.30 and OR=1.18, 95%CI=1.02-1.37). CONCLUSIONS: There are frequent interactions between European psychiatric trainees and the PI, with significant variation between countries. We identified several factors affecting this interaction, including attribution of an educational role to the PI. Creating alternative educational opportunities and specific training dedicated to PI interactions may therefore help to reduce the impact of the PI on psychiatric training.

Suicide ideators and attempters with schizophrenia--the role of 5-HTTLPR, rs25531, and 5-HTT VNTR Intron 2 variants.

AIM: To examine the role of 5-HTTLPR, rs25531 and 5-HTT VNTR Intron 2 variants in subjects with psychotic disorders manifesting suicide ideation and behaviour. METHODS: The study included 519 subsequently hospitalized subjects who were genotyped for 5-HTTLPR, rs25531 and 5-HTT VNTR In2 variants. Clinical assessments included structured psychiatric interview, sociodemographic characteristics, suicide ideation and behaviour (SIBQ), severity of psychopathology (PANSS) and depression (CDSS). RESULTS: Three subgroups were identified: suicide attempters (N = 161), suicide ideators (N = 174) and subjects who never reported suicide ideation or behaviour (comparative group, N = 184). MAJOR FINDINGS: 1) Suicide attempters scored highest on the CDSS, while no differences between the three clinical subgroups were detected in the PANSS scores; 2) Suicide attempters were more frequently the carriers of L(A) allele, while subjects in the comparative group were more frequently the carriers of low expression 5-HTTLPR/5-HTT rs25531 haplotype SL(G); 3) No difference was found between the three clinical groups in the 5-HTT VNTR In2 variants; 4) Subjects with 5-HTTLPR/5-HTT rs25531 intermediate expression haplotype (L(A)L(G,)SL(A)) scored higher on the PANSS general psychopathology subscale; 5) There was no association between suicide attempt or ideation and 5-HTTLPR/In2 or 5-HTTLPR/rs25531/In2 haplotype distribution. CONCLUSION: The suicide ideators, attempters and controls did not differ significantly in 5-HTTLPR or 5-HTT VNTR In 2 variants, but 5-HTTLPR/5-HTT rs25531 haplotype might be a useful genetic marker in distinguishing these three clinical groups.

Glucocorticoid-resistant Evans' syndrome successfully controlled with low-dose cyclosporine.

OBJECTIVE: To present a patient suffering from Evans' syndrome (ES), whose bouts of severe cytopenia were prevented by low-dose cyclosporine maintenance therapy. CASE SUMMARY: A boy suffering from frequent mild respiratory infections, first time evaluated in a tertiary care pediatric center at age 4, was found to have lymphadenopathy and mild splenomegaly. The thrombocytopenia was first noted at age 6. He was diagnosed to have ES at the age of 8, during another bout of thrombocytopenia, this time associated with Coombs-positive hemolytic anemia. Immunoglobulin concentration in the plasma was measured repeatedly, and was in the normal range, or even increased. Lymphocyte subpopulation numbers were in the normal range, with decreased CD4+/ CD8+ ratio (0.6). Autoimmune lymphoproliferative syndrome was excluded by the absence of CD4-CD8- T lymphocytes. Since the patient failed to respond to standard therapy with prednisolon 2 mg/kg, high dose intravenous methylprednisolone (10 mg/ kg/d for 3 days) and high dose intravenous immunoglobulin (1 g/kg/d for 2 days), cyclosporine treatment was initiated (6 mg/ kg/d) and resulted in normalization of platelet count and resolution of hemolysis. Two attempts to withdraw cyclosporine therapy resulted in life-threatening hemolytic crisis with severe thrombocytopenia, requiring the re-institution of cyclosporine. The dose of cyclosporine was eventually tapered to the present 0.5 mg/kg, corresponding to drug serum levels of 5 - 8 mg/ml. The patient is now free of manifestations of Evans' syndrome but, after 20 years of cyclosporine treatment, has slightly impaired kidney function. CONCLUSION: Low-dose cyclosporine therapy given to our patient appears to have subdued the autoimmune process thought to underlie the manifestations of ES, albeit at the cost of some toxicity to the kidneys.

Association study of MDR1 and 5-HT2C genetic polymorphisms and antipsychotic-induced metabolic disturbances in female patients with schizophrenia.

The objective of this study was to determine the association of 5-HT2C (serotonin 2C receptor) and MDR1 (multidrug resistant protein) genetic polymorphisms and antipsychotic-induced metabolic abnormalities among female patients with DSM IV schizophrenia spectrum disorders. We have previously reported the associations of -759CT 5-HT2C and G2677T and C3435T MDR1 genetic polymorphisms and olanzapine/risperidone-induced weight gain in a similar sample of patients. Here, we included a total of 101 previously non-medicated female patients treated with olanzapine/risperidone over a 3-month period. The variables analyzed included fasting glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglyceride levels in blood, blood pressure and waist circumferences. We observed significant association of -759T 5-HT2C genetic variant and greater increase in waist circumference (P=0.03), fasting glucose level (P=0.046) and triglyceride level (P=0.045) in blood after a 3-month period. The 2677T and 3435T MDR1 genetic variants were significantly associated with the greater increase in fasting glucose level in blood when patients were using olanzapine (P<0.001 and P=0.028, respectively). Our data indicate a possible influence of -759CT 5-HT2C and MDR1 G2677T and C3435T MDR1 genetic polymorphisms on the development of metabolic abnormalities among female patients treated with olanzapine/risperidone.

Impact of metabolic syndrome and malnutrition on mortality in chronic hemodialysis patients.

OBJECTIVE: Metabolic abnormalities contribute to increases in the mortality rate of patients on hemodialysis. Here, we estimate the importance and influence of metabolic syndrome and malnutrition on mortality rate. DESIGN: This was a follow-up study. METHODS: We examined the demographic characteristics of time on dialysis, body mass index, indications for hospitalization, treatment outcomes, and biochemical parameters over a 4-year period. RESULTS: Whereas 31.7% of patients had metabolic syndrome, 26.7% showed evidence of malnutrition. More than two thirds of the malnourished patients died. Many patients (46%) with malnutrition were hospitalized because of problems with vascular access, whereas hospitalization of half of the examined patients with metabolic syndrome was attributable to cardiovascular disorders. Differences between groups in the parameters of anemia, total proteins, albumin, and low-density lipoprotein cholesterol also occurred, with the lowest values in malnourished patients. Glycemia, total cholesterol, and fibrinogen were significantly higher in patients with metabolic syndrome, whereas those with malnutrition had a markedly higher concentration of C-reactive protein. The mean survival was 24 months with metabolic syndrome and 17.5 months with malnutrition, which was significantly shorter. CONCLUSIONS: More than half of the examined patients had metabolic abnormalities. Patients with malnutrition had a lower rate of survival compared with those who had metabolic syndrome. Two thirds of our malnourished patients died, and the total rate of mortality in the examined sample was 38%.

Metabolic syndrome in female patients with schizophrenia treated with second generation antipsychotics: a 3-month follow-up.

The objective of this study was to determine the occurrence of metabolic abnormalities among previously unmedicated female patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition schizophrenia spectrum disorders and their associations with olanzapine and risperidone treatment. We analysed 94 female patients who were treated with olanzapine or risperidone in the period of 3 months. Analysed variables included fasting glucose, total cholesterol, low-density lipoprotein (LDL), high-density lipoproteins and triglycerides in blood, blood pressure (BP), waist and hip circumferences and body mass index (BMI). At baseline, 14 patients (15%) fulfilled criteria for metabolic syndrome. After 3 months of treatment, 25 patients (27%) fulfilled criteria for metabolic syndrome, and their baseline BMI was the only predictor for its development. Treatment with both antipsychotics was associated with significant increase in waist circumference. Positive family history of diabetes mellitus contributed to a significant greater increase in abdominal obesity, significant higher baseline levels and a borderline significant increase in fasting glucose among olanzapine-treated patients. Olanzapine admission was associated with a significant increase in LDL and risperidone with a significant increase in triglycerides. Metabolic abnormalities seem to be more prevalent in unmedicated female patients with schizophrenia spectrum disorders than expected based on results in general population (adjusted for age and sex). Olanzapine treatment might induce significant alterations in metabolic profiles, especially among patients with positive family history of diabetes, mostly by inducing abdominal obesity. The association of risperidone application and increase in triglyceride level still needs to be determined.

An experimental, non-uremic rabbit model of peritoneal dialysis.

Peritoneal dialysis (PD) is a well established method of depuration in uremic patients. Standard dialysis solutions currently in use are not biocompatible with the peritoneal membrane. Studying effects of dialysate on peritoneal membrane in humans is still a challenge. There is no consensus on the ideal experimental model so far. We, therefore, wanted to develop a new experimental non-uremic rabbit model of peritoneal dialysis, which would be practical, easy to conduct, not too costly, and convenient to investigate the long-term effect of dialysis fluids. The study was done on 17 healthy Chinchilla male and female rabbits, anesthetized with Thiopental in a dose of 0.5 mg/kg body mass. A catheter, specially made from Tro-soluset (Troge Medical GMBH, Hamburg, Germany) infusion system, was then surgically inserted and tunneled from animals' abdomen to their neck. The planned experimental procedure was 4 weeks of peritoneal dialysate instillation. The presented non-uremic rabbit model of peritoneal dialysis is relatively inexpensive, does not require sophisticated technology and was well tolerated by the animals. Complications such as peritonitis, dialysis fluid leakage, constipation and catheter obstruction were negligible. This model is reproducible and can be used to analyze the effects of different dialysis solutions on the rabbit peritoneal membrane.

[Functional reconstruction of the extremities in cases with definitive peripheral nerve lesions]. / Funkcionalna rekonstrukcija ekstremiteta u slucajevima definitivnih lezija perifernih nerava.

Deficit if the functional integrity of the limbs as a consequence of the definitive lesions of the peripheral nerves necessitates surgical treatment aimed at regaining of the optimal mobility and strength of the parts of the limbs or whole limbs. Our study was aimed at presenting our experience in functional reconstruction of the extremities, evaluation of significance of primary and delayed microsurgical reconstruction of the injured nerves with respect to further course of treatment and presenting innovative modifications of certain surgical techniques. The total of 101 surgical procedures were performed in 91 patients, out of which 76 were at the level of the shoulder, elbow and hand and 29 were on the feet. Depending on the local findings, the following techniques were applied: transposition of the muscles and tendons, transfer of the free microneurovascular muscle flaps and surgical fusion of the joints. Functional improvement was achieved in 98.7% of the cases. Increased range of movements and strength depended on the applied technique and preoperative findings. Primary and delayed microsurgical reconstruction of nerves increases the probability for choice of adequate surgical techniques. Muscle and tendon transfers are the methods of choice in most of the patients. Free microneurovascular muscle flaps are applied in the most complicated cases.

Hodgkin's lymphoma of the parotid gland: report of a case and literature review.

Hodgkin's lymphoma with its primary manifestation in the parotid gland is a very rare entity. In previously published reports the diagnosis was established by postoperative histopathological examination. The present report describes a case of primary Hodgkin's lymphoma of the parotid gland, diagnosed by fine needle aspiration (FNA) cytology, and includes a short review of the diagnostic approaches to the parotid gland tumors.

[Principles of lymph node surgery in differentiated thyroid carcinoma]. / Principi hirurgije limfnih nodusa kod diferentovanog tiroidnog karcinoma.

Surgery is the initial therapy in differentiated thyroid carcinoma (DTC). The surgery is performed on organ of tumor origin and regional lymphatic basins. The aim of surgery in DTC is to eradicate all tumor foci, cure the most number of patients, reduce recurrence and mortality rate, and provide good quality of life. There is no doubt between oncologists that the surgery for thyroid carcinoma has no alternative. The extent of surgery is matter of actual controversies. It should be performed by well trained surgeons. Dissection of central and biopsy of supraclavicular and lower third of jugulo-carotid chain of neck lymph nodes is the integral part of surgery in DTC, together with total thyroidectomy. If lymph node metastases are found in jugulo-carotid chain, modified radical neck dissection, unilateral or bilateral is indicated. Dissection of mediastinal lymph nodes should be performed too in cases of involvement. The extent of primary surgery should be dictated by stage of disease and prognostic factors. The quality of surgery and incidence of complications depends prognostic factors, as well as on surgeon's skill and experience. That is why the surgeon is factor of prognosis in treatment of patients with DTC.