Impulse control disorders in Parkinson's disease: a national Swedish registry study on high-risk treatments and vulnerable patient groups.

BACKGROUND: Impulse control disorders (ICDs) are known psychiatric conditions in Parkinson's disease (PD), especially as a side effect of antiparkinsonian therapy. Screening for vulnerable patients and avoiding high-risk treatments can be an effective approach to reduce the ICD burden in patients with PD. Thus, our goal was to identify risk factors for ICDs in PD in the Swedish total population. METHODS: Our longitudinal study was based on records of all patients with PD in the Swedish National Patient Registries and the Prescribed Drug Register (n=55 235). Patients with incident gambling disorder and other ICDs were compared with a control group on demographic factors, psychiatric comorbidity, antiparkinsonian dopaminergic treatment and therapies for advanced disease. Potential risk factors were analysed using logistic regressions and relative frequency comparisons (Fisher's exact test). RESULTS: Main predictors for incident gambling disorder were treatment with dopamine agonists (Frequency ratio 1.4, p=0.058), monoamine oxidase B (MAO-B) inhibitors (Frequency ratio 1.8, p=0.006) and a prescription for drugs used in addictive disorders (OR 5.85, 95% CI 2.00 to 17.10). Main predictors for other ICDs were dopamine agonist treatment (frequency ratio 1.6, p=0.003), anxiety disorders (OR 7.04, 95% CI 2.96 to 16.71) and substance use disorders other than alcohol (OR 5.66, 95% CI 1.75 to 18.23). CONCLUSIONS: Our results support possible risk factors for incident ICDs that had previously been identified, like dopamine agonist treatment and raise additional attention for risk factors like MAO-B inhibitor treatment and specific psychiatric comorbidities. These findings enable tailoring antiparkinsonian therapy to individual patient-specific risk profiles.

Prolonged Fatigue and Mental Health Challenges in Critical COVID-19 Survivors.

Background: The aim of this study was to investigate the development of fatigue and mental illness between 3 and 12 months after critical COVID-19 and explore risk factors for long-lasting symptoms. Study Design and Methods: A prospective, multicenter COVID-19 study in southern Sweden, including adult patients (≥18 years) with rtPCR-confirmed COVID-19 requiring intensive care. Survivors were invited to a follow-up at 3 and 12 months, where patient-reported symptoms were assessed using the Modified Fatigue Impact Scale (MFIS), the Hospital Anxiety and Depression Scale (HADS) and the Posttraumatic Stress Disorder Checklist version 5 (PCL-5). The development between 3 and 12 months was described by changes in relation to statistical significance and suggested values for a minimally important difference (MID). Potential risk factors for long-lasting symptoms were analyzed by multivariable logistic regression. Results: At the 3-month follow-up, 262 survivors (87%) participated, 215 (72%) returned at 12 months. Fatigue was reported by 50% versus 40%, with a significant improvement at 12 months (MFIS; median 38 vs. 33, P < .001, MID ≥4). There were no significant differences in symptoms of mental illness between 3 and 12 months, with anxiety present in 33% versus 28%, depression in 30% versus 22%, and posttraumatic stress disorder in 17% versus 13%. A worse functional outcome and less sleep compared to before COVID-19 were risk factors for fatigue and mental illness at 12 months. Conclusions: Fatigue improved between 3 and 12 months but was still common. Symptoms of mental illness remained unchanged with anxiety being the most reported. A worse functional outcome and less sleep compared to before COVID-19 were identified as risk factors for reporting long-lasting symptoms.

Rise in Gender Dysphoria Diagnoses and Legal Gender Changes in Sweden: 2005-2017.

Evidence suggests the incidence of gender dysphoria (GD), a condition characterized by psychological distress caused by a mismatch between an individual's gender identity and biological sex assigned as birth, has increased since the turn of the twenty-first century. We examined trends in the number of GD diagnoses and legal gender changes in Sweden using registry data from 5007 individuals diagnosed with GD between 2005 and 2017 (53.5% assigned female at birth). GD diagnoses increased substantially over time, especially in birth-assigned females and younger age groups. One-third of all subjects with GD legally changed their gender, with an increase of 1000% from 2005 to 2018. Generally, individuals who were assigned female at birth changed their gender earlier than birth-assigned males, and most did so within one year of GD diagnosis. Our findings highlight the need to analyze the causes and correlations of rapid changes in clinical presentation and to prepare healthcare systems for rising patient demand.

Gambling Habits and Attitudes among Athlete and Non-Athlete High School Students in Skåne Region, Sweden.

Previous literature has reported increased rates of gambling problems in athletes compared to non-athletes. More liberal gambling-related attitudes have been suggested as a reason, although this rarely has been researched. The present study aimed to examine gambling experience, gambling problems, and gambling-related attitudes and parental gambling experience in high school students, comparing student-athletes to students at conventional schools. This is a cross-sectional web survey study in high school students (N = 473, 53% at sports high schools, 57% male) at eleven schools in the Skåne region, Sweden, who answered a web survey addressed gambling experiences, parental gambling and gambling-related attitudes, and included validated screening instruments for gambling problems and psychological distress. A history of any gambling was common and increased with age. Problem gambling was detected in 10% (13% of males and 5% of females, p < .001), and was associated with paternal and maternal gambling but not with psychological distress. Sports high school students were not more likely (9%) than other students (10%) to endorse gambling problems and history of each gambling type. However, paternal (but not maternal) gambling was more commonly reported in athletes, who also had more positive attitudes to gambling's effects on society and gambling availability. In contrast to other studies, this study did not demonstrate higher prevalence of gambling or gambling problems among young athletes than among other students, but liberal attitudes towards gambling, and experience of parental gambling on the father's side, were more common among athletes than among non-athletes. Gambling attitudes in adolescents may need to be targeted in future preventive efforts in young athletes and others.

Symptoms of depression and anxiety among elite high school student-athletes in Sweden during the COVID-19 pandemic: A repeated cross-sectional study.

The COVID-19 pandemic precipitated numerous changes in daily life, including the cancellation and restriction of sports globally. Because sports participation contributes positively to the development of student-athletes, restricting these activities may have led to long-term mental health changes in this population. Using a repeated cross-sectional study design, we measured rates of depression using the Patient Health Questionnaire-2 and anxiety using the Generalized Anxiety Disorder-2 scale in student-athletes attending elite sport high schools in Sweden during the second wave of the pandemic (February 2021; n = 7021) and after all restrictions were lifted (February 2022; n = 6228). Depression among student-athletes decreased from 19.8% in 2021 to 17.8% in 2022 (p = .008, V = .026), while anxiety screening did not change significantly (17.4% to 18.4%, p > .05). Comparisons between classes across years revealed older students exhibited decreases in depressive symptoms, while younger cohorts experienced increases in symptoms of anxiety from 2021 to 2022. Logistic regressions revealed that being female, reporting poorer mental health due to COVID-19, and excessive worry over one's career in sports were significant predictors of both depression and anxiety screenings in 2022. Compared to times when sports participation was limited, the lifting of restrictions was associated with overall reduced levels of depression, but not anxiety.

HAMLET a human milk protein-lipid complex induces a pro-inflammatory phenotype of myeloid cells.

HAMLET is a protein-lipid complex with a specific and broad bactericidal and tumoricidal activity, that lacks cytotoxic activity against healthy cells. In this study, we show that HAMLET also has general immune-stimulatory effects on primary human monocyte-derived dendritic cells and macrophages (Mo-DC and Mo-M) and murine RAW264.7 macrophages. HAMLET, but not its components alpha-lactalbumin or oleic acid, induces mature CD14low/- CD83+ Mo-DC and M1-like CD14+ CD86++ Mo-M surface phenotypes. Concomitantly, inflammatory mediators, including IL-2, IL-6, IL-10, IL-12 and MIP-1α, were released in the supernatant of HAMLET-stimulated cells, indicating a mainly pro-inflammatory phenotype. The HAMLET-induced phenotype was mediated by calcium, NFκB and p38 MAPK signaling in Mo-DCs and calcium, NFκB and ERK signaling in Mo-M as inhibitors of these pathways almost completely blocked the induction of mature Mo-DCs and M1-like Mo-M. Compared to unstimulated Mo-DCs, HAMLET-stimulated Mo-DCs were more potent in inducing T cell proliferation and HAMLET-stimulated macrophages were more efficient in phagocytosis of Streptococcus pneumoniae in vitro. This indicates a functionally activated phenotype of HAMLET-stimulated DCs and macrophages. Combined, we propose that HAMLET has a two-fold anti-bacterial activity; one inducing direct cytotoxic activity, the other indirectly mediating elimination of bacteria by activation of immune cells of the myeloid lineage.

Prevalence and comorbidity in a Swedish adolescent community sample - gambling, gaming, substance use, and other psychiatric disorders.

BACKGROUND: This study investigates a broad spectrum of psychiatric disorders, substance use disorders, gambling, and internet gaming disorders in Swedish 18-year-old boys and girls with the aim of estimating the prevalence of disorders and comorbidity. METHODS: We used a two-phase design with screening to detect candidates for clinical interviews. Screening included 949 adolescents (55.6% girls), out of which 758 adolescents (57.0% girls) were selected for interview with at least one of four instruments: M.I.N.I., ADDIS, NODS and IGDS. Of these, 387 (61.2% girls) were interviewed. Gender separated prevalence was estimated on the assumption that those selected but not interviewed had the same distribution as those interviewed based on similar outcomes above screening cut-offs. Comorbidity between types of disorders was estimated on similar assumptions. In addition, comorbidity between dyads of the ten most common specified disorders was calculated based on recorded data without these assumptions. RESULTS: We estimated that 14.6% met the criteria of a substance use disorder (SUD), mostly concerning alcohol and more frequent in girls than in boys. Those meeting the criteria lifetime of at least one of 16 other psychiatric disorders were 26.7%, more than twice as frequent in girls compared to boys, and with depression being the most common disorder. Gambling and gaming disorders were found almost exclusively in boys, of which 5.8% met the criteria for gambling, and 2.3% for gaming disorders. Of girls with a SUD, 40% also had a psychiatric disorder, while on the other hand more than 28% of girls with a psychiatric disorder also had a SUD. In boys with a SUD, 22% had another psychiatric disorder, while 15% of those with a psychiatric disorder also had a SUD. CONCLUSIONS: Psychiatric comorbidity is common in SUDs in adolescents, which calls for screening and diagnostic efforts in young patients presenting with symptoms of SUDs. Girls with SUDs are at higher risk of also suffering from psychiatric conditions. Gambling and gaming disorders appear in a substantial minority of adolescents and warrant further study of their comorbidity. Since prevalences and comorbidity were estimated on the assumptions mentioned, some caution in interpreting the results is needed.

Healthcare utilization for somatic conditions among Swedish patients in opioid substitution treatment, with and without on-site primary healthcare.

BACKGROUND: Opioid substitution treatment (OST) populations are aging and have increased mortality and somatic morbidity compared to general populations internationally. While OST patients have poor self-rated physical health and unmet healthcare needs, documented healthcare utilization has been sparsely investigated. The aim of this study was to assess registered healthcare utilization for somatic conditions in a sample of Swedish OST patients, and compare healthcare utilization among OST patients with and without use of on-site primary healthcare (PHC). METHODS: Patients in OST in Malmö, Sweden, were recruited for a survey study conducted in 2017-2018. Survey data were compared with comprehensive patient records from specialized and primary care during one year prior to study inclusion (total n = 190). All patient records were examined for healthcare utilization, source of healthcare (PHC, emergency care and secondary care), and documented diagnoses and symptoms. Factors associated with healthcare utilization were analyzed by using logistic regression analysis. Patients with and without on-site PHC were compared by using descriptive statistics and Chi-2 test. RESULTS: A total of 88% of the sample had been in direct or indirect contact with somatic healthcare during one year (PHC 66%; emergency care 28%; secondary care 67%). The most prevalent somatic diagnoses were infectious diseases (39%) and symptom diagnoses (37%). Respiratory, dermatological and musculoskeletal diagnoses, and trauma/intoxication were documented in 21-26% of the sample, respectively. PHC utilization was associated with older age and being born in Sweden. Among patients with on-site PHC (n = 25), the number utilizing secondary care was 84%, and certain diagnostic codes were more frequent in this group. CONCLUSION: OST patients are seemingly underserved as regards their physical health. Since increased OST access decreases opioid overdose fatalities, the life expectancy among OST patients is likely to increase and thereby also increases the risk of age-related conditions. Thus, easily accessible physical healthcare is of great importance in this group. On-site PHC might be a way to establish healthcare contact with OST patients, especially for non-acute conditions, although further research is needed.

A Murine Model for Enhancement of Streptococcus pneumoniae Pathogenicity upon Viral Infection and Advanced Age.

Streptococcus pneumoniae (pneumococcus) resides asymptomatically in the nasopharynx (NP) but can progress from benign colonizer to lethal pulmonary or systemic pathogen. Both viral infection and aging are risk factors for serious pneumococcal infections. Previous work established a murine model that featured the movement of pneumococcus from the nasopharynx to the lung upon nasopharyngeal inoculation with influenza A virus (IAV) but did not fully recapitulate the severe disease associated with human coinfection. We built upon this model by first establishing pneumococcal nasopharyngeal colonization, then inoculating both the nasopharynx and lungs with IAV. In young (2-month-old) mice, coinfection triggered bacterial dispersal from the nasopharynx into the lungs, pulmonary inflammation, disease, and mortality in a fraction of mice. In aged mice (18 to 24 months), coinfection resulted in earlier and more severe disease. Aging was not associated with greater bacterial burdens but rather with more rapid pulmonary inflammation and damage. Both aging and IAV infection led to inefficient bacterial killing by neutrophils ex vivo. Conversely, aging and pneumococcal colonization also blunted alpha interferon (IFN-α) production and increased pulmonary IAV burden. Thus, in this multistep model, IAV promotes pneumococcal pathogenicity by modifying bacterial behavior in the nasopharynx, diminishing neutrophil function, and enhancing bacterial growth in the lung, while pneumococci increase IAV burden, likely by compromising a key antiviral response. Thus, this model provides a means to elucidate factors, such as age and coinfection, that promote the evolution of S. pneumoniae from asymptomatic colonizer to invasive pathogen, as well as to investigate consequences of this transition on antiviral defense.

The human milk protein-lipid complex HAMLET disrupts glycolysis and induces death in Streptococcus pneumoniae.

HAMLET is a complex of human α-lactalbumin (ALA) and oleic acid and kills several Gram-positive bacteria by a mechanism that bears resemblance to apoptosis in eukaryotic cells. To identify HAMLET's bacterial targets, here we used Streptococcus pneumoniae as a model organism and employed a proteomic approach that identified several potential candidates. Two of these targets were the glycolytic enzymes fructose bisphosphate aldolase (FBPA) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Treatment of pneumococci with HAMLET immediately inhibited their ATP and lactate production, suggesting that HAMLET inhibits glycolysis. This observation was supported by experiments with recombinant bacterial enzymes, along with biochemical and bacterial viability assays, indicating that HAMLET's activity is partially inhibited by high glucose-mediated stimulation of glycolysis but enhanced in the presence of the glycolysis inhibitor 2-deoxyglucose. Both HAMLET and ALA bound directly to each glycolytic enzyme in solution and solid-phase assays and effectively inhibited their enzymatic activities. In contrast, oleic acid alone had little to no inhibitory activity. However, ALA alone also exhibited no bactericidal activity and did not block glycolysis in whole cells, suggesting a role for the lipid moiety in the internalization of HAMLET into the bacterial cells to reach its target(s). This was verified by inhibition of enzyme activity in whole cells after HAMLET but not ALA exposure. The results of this study suggest that part of HAMLET's antibacterial activity relates to its ability to target and inhibit glycolytic enzymes, providing an example of a natural antimicrobial agent that specifically targets glycolysis.

A Role of Epithelial Cells and Virulence Factors in Biofilm Formation by Streptococcus pyogenes In Vitro.

Biofilm formation by Streptococcus pyogenes (group A streptococcus [GAS]) in model systems mimicking the respiratory tract is poorly documented. Most studies have been conducted on abiotic surfaces, which poorly represent human tissues. We have previously shown that GAS forms mature and antibiotic-resistant biofilms on physiologically relevant epithelial cells. However, the roles of the substratum, extracellular matrix (ECM) components, and GAS virulence factors in biofilm formation and structure are unclear. In this study, biofilm formation was measured on respiratory epithelial cells and keratinocytes by determining biomass and antibiotic resistance, and biofilm morphology was visualized using scanning electron microscopy. All GAS isolates tested formed biofilms that had similar, albeit not identical, biomass and antibiotic resistance for both cell types. Interestingly, functionally mature biofilms formed more rapidly on keratinocytes but were structurally denser and coated with more ECM on respiratory epithelial cells. The ECM was crucial for biofilm integrity, as protein- and DNA-degrading enzymes induced bacterial release from biofilms. Abiotic surfaces supported biofilm formation, but these biofilms were structurally less dense and organized. No major role for M protein, capsule, or streptolysin O was observed in biofilm formation on epithelial cells, although some morphological differences were detected. NAD-glycohydrolase was required for optimal biofilm formation, whereas streptolysin S and cysteine protease SpeB impaired this process. Finally, no correlation was found between cell adherence or autoaggregation and GAS biofilm formation. Combined, these results provide a better understanding of the role of biofilm formation in GAS pathogenesis and can potentially provide novel targets for future treatments against GAS infections.

Niche- and Gender-Dependent Immune Reactions in Relation to the Microbiota Profile in Pediatric Patients with Otitis Media with Effusion.

Otitis media with effusion (OME) is a common inflammatory disease that primarily affects children. OME is defined as a chronic low-grade inflammation of the middle ear (ME), without any signs of infection and with effusion persisting in the ME for more than 3 months. The precise pathogenesis is, however, not fully understood. Here, we comprehensively characterized and compared the host immune responses (inflammatory cells and mediators) and the overall microbial community composition (microbiota) present in matched middle ear effusion (MEE) samples, external ear canal (EEC) lavages, and nasopharynx (NPH) samples from children with OME. Female patients had significantly increased percentages of T lymphocytes and higher levels of a wide array of inflammatory mediators in their MEE compared to that of male patients, which were unrelated to microbiota composition. The relative abundances of identified microorganisms were strongly associated with their niche of origin. Furthermore, specific inflammatory mediators were highly correlated with certain bacterial species. Interestingly, some organisms displayed a niche-driven inflammation pattern in which presence of Haemophilus spp. and Corynebacterium propinquum in MEE was accompanied by proinflammatory mediators, whereas their presence in NPH was accompanied by anti-inflammatory mediators. For Turicella and Alloiococcus, we found exactly the opposite results, i.e., an anti-inflammatory profile when present in MEE, whereas their presence in the the NPH was accompanied by a proinflammatory profile. Together, our results indicate that immune responses in children with OME are highly niche- and microbiota-driven, but gender-based differences were also observed, providing novel insight into potential pathogenic mechanisms behind OME.

Protocol for a multi-site study of the effects of overdose prevention education with naloxone distribution program in Skåne County, Sweden.

BACKGROUND: Continuously high rates of overdose deaths in Sweden led to the decision by the Skåne County to initiate the first regional take-home naloxone program in Sweden. The project aims to study the effect of overdose prevention education and naloxone distribution on overdose mortality in Skåne County. Secondary outcome measures include non-fatal overdoses and overdose-related harm in the general population, as well as cohort-specific effects in study participants regarding overdoses, mortality and retention in naloxone program. METHODS: Implementation of a multi-site train-the-trainer cascade model was launched in June 2018. Twenty four facilities, including opioid substitution treatment units, needle exchange programs and in-patient addiction units were included for the first line of start-up, aspiring to reach a majority of individuals at-risk within the first 6 months. Serving as self-sufficient naloxone hubs, these units provide training, naloxone distribution and study recruitment. During 3 years, questionnaires are obtained from initial training, follow up, every sixth month, and upon refill. Estimated sample size is 2000 subjects. Naloxone distribution rates are reported, by each unit, every 6 months. Medical diagnoses, toxicological raw data and data on mortality and cause of death will be collected from national and regional registers, both for included naloxone recipients and for the general population. Data on vital status and treatment needs will be collected from registers of emergency and prehospital care. DISCUSSION: Despite a growing body of literature on naloxone distribution, studies on population effect on mortality are scarce. Most previous studies and reports have been uncontrolled, thus not being able to link naloxone distribution to survival, in relation to a comparison period. As Swedish registers present the opportunity to monitor individuals and entire populations over time, conditions for conducting systematic follow-ups in the Swedish population are good, serving the opportunity to study the impact of large scale overdose prevention education and naloxone distribution and thus fill the knowledge gap. TRIAL REGISTRATION: Naloxone Treatment in Skåne County - Effect on Drug-related Mortality and Overdose-related Complications, NCT03570099, registered on 26 June 2018.

Investigating opioid-related fatalities in southern Sweden: contact with care-providing authorities and comparison of substances.

BACKGROUND: Opioid-related deaths have increased in Western countries over recent decades. Despite numerous studies investigating opioid-related mortality, only a few have focused on the lives of the deceased individuals prior to their deaths, specifically regarding contact with care-providing authorities such as health, social and correctional services. Furthermore, a change has been noted in the last two decades as to which opioids cause most deaths, from heroin to prescription opioids. However, studies comparing fatalities caused by different substances are rare. The aim of this study was to investigate contact with care-providing authorities during the year prior to death among individuals who died as a result of opioid intoxication and to analyse differences relating to which opioids caused their deaths. METHODS: The study is based on retrospective register data and includes 180 individuals with a history of illicit drug use, who died from opioid intoxication in Skåne, Sweden, between 1 January 2012 to 31 December 2013 and 1 July 2014 to 30 June 2016. Intoxications caused by heroin, methadone, buprenorphine and fentanyl were included. Data were collected from the National Board of Forensic Medicine, regional health care services, municipal social services and the Prison and Probation Service. Statistical testing was performed using Pearson's chi-square test, Fisher's exact test and the Mann-Whitney U test to analyse group differences. RESULTS: A total of 89% of the deceased individuals had been in contact with one or more of the care-providing authorities during the year prior to death; 75% had been in contact with health care, 69% with the social services, 28% with the Prison and Probation Service, and 23% had been enrolled in opioid substitution treatment at some point during their final year of life. Few differences appeared between the substance groups with regard to which opioid contributed to the death. In addition to opioids, sedatives were present in more than 80% of the cases. Individuals whose deaths were buprenorphine-related had been in contact with the social services to a significantly lesser extent during the year prior to death. CONCLUSIONS: The studied population is characterised by extensive contact with care-providing authorities, thus providing numerous opportunities for authorities to reach this group with preventive and other interventions. Few differences emerged between groups with regard to which opioid had contributed to the death.

COVID Isolation Eating Scale (CIES): Analysis of the impact of confinement in eating disorders and obesity-A collaborative international study.

Confinement during the COVID-19 pandemic is expected to have a serious and complex impact on the mental health of patients with an eating disorder (ED) and of patients with obesity. The present manuscript has the following aims: (1) to analyse the psychometric properties of the COVID Isolation Eating Scale (CIES), (2) to explore changes that occurred due to confinement in eating symptomatology; and (3) to explore the general acceptation of the use of telemedicine during confinement. The sample comprised 121 participants (87 ED patients and 34 patients with obesity) recruited from six different centres. Confirmatory Factor Analyses (CFA) tested the rational-theoretical structure of the CIES. Adequate goodness-of-fit was obtained for the confirmatory factor analysis, and Cronbach alpha values ranged from good to excellent. Regarding the effects of confinement, positive and negative impacts of the confinement depends of the eating disorder subtype. Patients with anorexia nervosa (AN) and with obesity endorsed a positive response to treatment during confinement, no significant changes were found in bulimia nervosa (BN) patients, whereas Other Specified Feeding or Eating Disorder (OSFED) patients endorsed an increase in eating symptomatology and in psychopathology. Furthermore, AN patients expressed the greatest dissatisfaction and accommodation difficulty with remote therapy when compared with the previously provided face-to-face therapy. The present study provides empirical evidence on the psychometric robustness of the CIES tool and shows that a negative confinement impact was associated with ED subtype, whereas OSFED patients showed the highest impairment in eating symptomatology and in psychopathology.

HAMLET, a protein complex from human milk has bactericidal activity and enhances the activity of antibiotics against pathogenic Streptococci.

HAMLET is a protein-lipid complex derived from human milk that was first described for its tumoricidal activity. Later studies showed that HAMLET also has direct bactericidal activity against select species of bacteria, with highest activity against Streptococcus pneumoniae Additionally, HAMLET in combination with various antimicrobial agents can make a broader range of antibiotic-resistant bacterial species sensitive to antibiotics. Here, we show that HAMLET has direct antibacterial activity not only against pneumococci, but also against Streptococcus pyogenes (GAS) and Streptococcus agalactiae (GBS). Analogous to pneumococci, HAMLET-treatment of GAS and GBS resulted in depolarization of the bacterial membrane followed by membrane permeabilization and death that could be inhibited by calcium and sodium transport inhibitors. Treatment of clinical antibiotic-resistant isolates of S. pneumoniae, GAS, and GBS with sublethal concentrations of HAMLET in combination with antibiotics decreased the minimal inhibitory concentrations of the respective antibiotic into the sensitive range. This effect could also be blocked by ion transport inhibitors, suggesting that HAMLET's bactericidal and combination treatment effects used similar mechanisms. Finally, we show that HAMLET potentiated the effects of erythromycin against erythromycin-resistant bacteria more effectively than it potentiated killing by penicillin G of bacteria resistant to penicillin G. These results show for the first time that HAMLET effectively kills three different species of pathogenic Streptococci using similar mechanisms and also potentiate the activity of macrolides and lincosamides more effectively than combination treatment with beta-lactams. These findings suggest a potential therapeutic role for HAMLET in repurposing antibiotics currently causing treatment failures in patients.

A Protein Complex from Human Milk Enhances the Activity of Antibiotics and Drugs against Mycobacterium tuberculosis.

Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), has surpassed HIV/AIDS as the leading cause of death from a single infectious agent. The increasing occurrence of drug-resistant strains has become a major challenge for health care systems and, in some cases, has rendered TB untreatable. However, the development of new TB drugs has been plagued with high failure rates and costs. Alternative strategies to increase the efficacy of current TB treatment regimens include host-directed therapies or agents that make M. tuberculosis more susceptible to existing TB drugs. In this study, we show that HAMLET, an α-lactalbumin-oleic acid complex derived from human milk, has bactericidal activity against M. tuberculosis HAMLET consists of a micellar oleic acid core surrounded by a shell of partially denatured α-lactalbumin molecules and unloads oleic acid into cells upon contact with lipid membranes. At sublethal concentrations, HAMLET potentiated a remarkably broad array of TB drugs and antibiotics against M. tuberculosis For example, the minimal inhibitory concentrations of rifampin, bedaquiline, delamanid, and clarithromycin were decreased by 8- to 16-fold. HAMLET also killed M. tuberculosis and enhanced the efficacy of TB drugs inside macrophages, a natural habitat of M. tuberculosis Previous studies showed that HAMLET is stable after oral delivery in mice and nontoxic in humans and that it is possible to package hydrophobic compounds in the oleic acid core of HAMLET to increase their solubility and metabolic stability. The potential of HAMLET and other liprotides as drug delivery and sensitization agents in TB chemotherapy is discussed here.

Directed vaccination against pneumococcal disease.

Immunization strategies against commensal bacterial pathogens have long focused on eradicating asymptomatic carriage as well as disease, resulting in changes in the colonizing microflora with unknown future consequences. Additionally, current vaccines are not easily adaptable to sequence diversity and immune evasion. Here, we present a "smart" vaccine that leverages our current understanding of disease transition from bacterial carriage to infection with the pneumococcus serving as a model organism. Using conserved surface proteins highly expressed during virulent transition, the vaccine mounts an immune response specifically against disease-causing bacterial populations without affecting carriage. Aided by a delivery technology capable of multivalent surface display, which can be adapted easily to a changing clinical picture, results include complete protection against the development of pneumonia and sepsis during animal challenge experiments with multiple, highly variable, and clinically relevant pneumococcal isolates. The approach thus offers a unique and dynamic treatment option readily adaptable to other commensal pathogens.

Gambling Disorder in Male Violent Offenders in the Prison System: Psychiatric and Substance-Related Comorbidity.

Gambling disorder is an addiction that can cause major suffering, and some populations seem to be more vulnerable than others. Offender populations have a remarkably high prevalence of gambling problems and they are also over-represented in a number of diagnoses related to gambling disorder, like substance use disorders and antisocial personality disorder. Yet, there are few studies investigating gambling disorder prevalence and related psychiatric comorbidity in this group. This study aims to investigate the prevalence of, and association between, gambling disorder and other psychiatric diagnoses in a sample of young, male violent offenders. Two hundred and sixty-four male offenders, all serving sentences for violent crimes (recruited between 2010 and 2012) participated in this study and went through comprehensive psychiatric evaluation, including assessment for Diagnostic and Statistical Manual of Mental Disorders 4th Edition criteria. Sixteen percent of the participants met criteria for gambling disorder. Antisocial personality disorder, cannabis, cocaine and anabolic steroids abuse were significantly more common among participants with gambling disorder. The gambling disorder group also showed significantly lower educational attainment. Cocaine abuse and failure to graduate elementary and middle school in expected time were independently associated with gambling disorder in a regression analysis. This study confirms the previously described high prevalence of gambling disorder in offenders. The psychiatric comorbidity was high and the problems had started early, with lower educational attainment in the gambling disorder group. The findings stress the importance of increased awareness of gambling problems among convicted offenders and of gambling research on young people with delinquent behavior. There is a need of more research to investigate this further, in order to develop preventive strategies and treatment.

Acute Pancreatitis: Impact of Alcohol Consumption and Seasonal Factors.

AIMS: We aimed to evaluate the potential relation between the incidence of (alcoholic and non-alcoholic) acute pancreatitis (AP) and alcohol consumption in the general population, and whether the occurrence of AP shows any seasonal variation, particularly in relation to periods with expected increased alcohol consumption. METHODS: All patients with first-time AP between 2003 and 2012 in a well-defined area in Sweden were retrospectively identified. Data on AP aetiology (alcoholic and non-alcoholic) and severity were registered. Data on annual alcohol sales as well as on self-reported alcohol consumption were obtained. RESULTS: In total, 1457 AP patients were included (83% non-alcoholic AP, 17% alcoholic AP). The overall AP incidence showed increasing time trends for women and men (P < 0.05), but there were no significant changes in the incidence of alcoholic AP, in either sex (P > 0.05). Alcohol sales during the study period decreased (P = 0.002), mainly due to decreased sales of spirits (P = 0.001) and beer (P = 0.002), while self-reported alcohol consumption remained stable for women (P > 0.05) and decreased for men (P = 0.022). Neither alcohol sales nor consumption was related to the time trends of AP (P > 0.05 for all). No significant differences were found in the occurrence of AP among different seasons of the year or between holidays associated with higher alcohol consumption compared to periods before and after these holidays (P > 0.05 for all). CONCLUSIONS: Changes in alcohol consumption in the general population do not appear to be related to changes in the incidence of AP and there are no significant seasonal differences in the occurrence of AP in Sweden. SHORT SUMMARY: The incidence of acute pancreatitis (AP) is increasing, and alcohol is still recognized as one of the most common causes. In this study, however, we could not ascertain any clear relations between the sales and consumption of alcohol in the general population and the incidence of alcoholic or non-alcoholic AP.