Combining treatment for chronic hepatitis C with opioid agonist therapy is an effective microelimination strategy for people who inject drugs with high risk of non-adherence to direct-acting antiviral therapy.

Background & aims: Despite effective direct-acting antivirals (DAAs), hepatitis C virus (HCV) prevalence is high among people who inject drugs (PWIDs) and non-adherence to therapy remains a major obstacle towards HCV elimination in this subpopulation. To overcome this issue, we have combined ongoing opioid agonist therapy (OAT) with DAAs in a directly-observed therapy (DOT) setting. Method: From September 2014 until January 2021 PWIDs at high risk of non-adherence to DAA therapy, who were also on OAT, were included into this microelimination project. Individuals received their OAT and DAAs under supervision of healthcare workers as DOT in a pharmacy or low-threshold facility. Results: In total, 504 HCV RNA-positive PWIDs on OAT (387 men, 76.8%; median age: 38 years [IQR 33-45], HIV: 4.6%; hepatitis B: 1.4%) were included into this study. Two thirds reported ongoing intravenous drug use (IDU) and half of them had no permanent housing. Only 41 (8.1%) were lost to follow-up and two (0.4%) died of reasons unrelated to DAA toxicity. Overall, 90.7% of PWIDs achieved sustained virological response 12 weeks after treatment (SVR12) (95% CI: 88.1-93.2%). By excluding those lost to follow-up and hose who had died of causes unrelated to DAAs, the SVR12 rate was 99.1% (95% CI: 98.3-100.0%; modified intention-to-treat analysis). Four PWIDs (0.9%) experienced treatment failure. Over a median follow-up of 24 weeks (IQR 12-39), 27 reinfections (5.9%) were observed in individuals with the highest IDU rates (81.2%). Importantly, even though some were lost to follow-up, all completed their DAA treatment. By using DOT, adherence to DAAs was excellent with only a total of 86 missed doses (0.3% of 25,224 doses). Conclusions: In this difficult-to-treat population of PWIDs with high rates of IDU , coupling DAA treatment to OAT in a DOT setting resulted in high SVR12 rates equivalent to conventional treatment settings in non-PWID populations.

Hybrid social learning in human-algorithm cultural transmission.

Humans are impressive social learners. Researchers of cultural evolution have studied the many biases shaping cultural transmission by selecting who we copy from and what we copy. One hypothesis is that with the advent of superhuman algorithms a hybrid type of cultural transmission, namely from algorithms to humans, may have long-lasting effects on human culture. We suggest that algorithms might show (either by learning or by design) different behaviours, biases and problem-solving abilities than their human counterparts. In turn, algorithmic-human hybrid problem solving could foster better decisions in environments where diversity in problem-solving strategies is beneficial. This study asks whether algorithms with complementary biases to humans can boost performance in a carefully controlled planning task, and whether humans further transmit algorithmic behaviours to other humans. We conducted a large behavioural study and an agent-based simulation to test the performance of transmission chains with human and algorithmic players. We show that the algorithm boosts the performance of immediately following participants but this gain is quickly lost for participants further down the chain. Our findings suggest that algorithms can improve performance, but human bias may hinder algorithmic solutions from being preserved. This article is part of the theme issue 'Emergent phenomena in complex physical and socio-technical systems: from cells to societies'.

Adaptation capacity of Boer goats to saline drinking water.

Due to global climatic changes, water and soil salinization is an increasing worldwide phenomenon, thus creating new threats for farm animal production. The present study was designed to investigate the adaptation capacity of goats towards sodium chloride (NaCl) in drinking water. Twelve non-pregnant Boer goats with an average body weight of 50.5 ± 9.0 kg were kept in individual pens. The study was conducted in four phases applying a two-choice preference test. In the control phase (phase 1) only fresh water was supplied in two containers. In phase 2, water with different salt concentrations (0.25%, 0.5%, 0.75%, 1.0%, 1.25% and 1.5%) was offered in one container and tap water in the other (sensitivity test). During the third phase (adaptation), goats were stepwise habituated to saline water by offering only saline water with different increasing concentrations (between 0% and 1.5% NaCl) in both containers. Subsequently, in phase 4 (sensitivity re-test) the same treatment as in phase 2 was repeated. Goats had ad libitum access to hay, water and a mineral licking block. Individual water and feed intake were recorded daily, while body weight and body condition score were measured every 2nd week. Body weight was not affected by saline water intake, whereas dry matter intake and body condition scores decreased significantly during the experiment. Water intake was significantly (P<0.001) higher in phase 2 (sensitivity test) and phase 3 (adaptation), compared to phase 1 (control) and phase 4 (sensitivity re-test). Total sodium intake followed the same pattern. In phase 2, when goats had the choice between fresh and saline water for the first time they preferred higher salt concentrations and consumed significantly (P<0.001) higher amounts of saline water (75.4 ± 53.2 g/kg BW0.82 per day) than in the re-test (40.4 ± 34.0 g/kg BW0.82 per day) after the habituation period. Thus, salt discrimination rejection thresholds were lowered to 1.25% in phase 4 compared to 1.5% in phase 2. The results suggest that a stepwise adaptation to saline drinking water in goats is an effective method to habituate the animals to saline water intake when concentrations were below 1.5%. Goats reacted more sensitively to the salinity of drinking water after prolonged exposure to saline water indicating flexible regulation mechanisms depending on the total sodium balance of the animal.

Reactions to saline drinking water in Boer goats in a free-choice system.

Salinization of groundwater and soil is a prevalent global issue with serious consequences on animal health and production. The present study was conducted to investigate the capacity of Boer goats to adjust their salt intake from saline drinking water in a free-choice system. In total, 12 non-pregnant Boer goats aged between 1 and 8 years with an average BW of 46.4±8.3 kg were kept in individual pens for 4 weeks. In the control phase (1 week), only fresh water was supplied in five identical buckets for each pen. During the subsequent treatment phase (3 weeks), fresh water and four different concentrations (0.75, 1.0, 1.25 and 1.5% NaCl) of saline water were offered simultaneously in a free-choice system. The positions of the concentrations were changed daily at random. Cut hay and water were provided ad libitum, and a mineral supplement was allocated. Feed and water intake, mineral supplement intake, ambient temperature and relative humidity were recorded daily, whereas BW and body condition score were measured weekly. Dry matter intake, total water intake and total sodium intake were significantly (P<0.001) higher during the treatment phase. Body weight and body condition were not affected by saline water intake. Across the treatment phase, saline water consumption was significantly (P<0.001) lower in young (19.6±27.1 g/kg BW0.82 per day) than in adult goats (27.9±31.5 g/kg BW0.82 per day), indicating that young goats were more sensitive towards the saline water. All goats had a significant preference for fresh water (0% salt) over saline water. At the first offering of the simultaneous choice situation (week 2), animals did not differentiate between the salt concentration of 0.75% and 1.0%. However, with successive treatment (weeks 3 and 4), animals distinguished between saline water concentrations and preferred the 0.75% salt concentration. Salt concentrations of 1% to 1.5% were avoided. The total sodium intake of the goats ranged between 0.37 and 0.55 g /kg BW0.75 per day during the treatment phase, being 8- to 11-fold higher than the daily requirements of sodium for body maintenance. The results suggest that goats are able to differentiate between saline water concentrations and to adjust their sodium intake by quick adjustments in self-selection in a free-choice system. Compared with two-choice preference tests, the present free-choice situation allows evaluating changes in saline water acceptance with prolonged exposure.

Neural correlates of trauma-related single word processing in posttraumatic stress disorder.

Interpersonal violence (IPV) is one of the most frequent causes for the development of posttraumatic stress disorder (PTSD) in women. One key component in PTSD is altered processing of trauma-related cues, leading to emotional symptoms. In the everyday environment, words with trauma-associated semantic content represent typical, albeit abstract, trauma-related stimuli for patients suffering from PTSD. However, the functional neuroanatomy associated with processing single trauma-related words in IPV-PTSD is not understood. The present event-related functional magnetic resonance imaging study investigated the neural basis of trauma-related word processing in women with IPV-PTSD relative to healthy controls (HC) during a non-emotional vigilance task in which the emotional content of the words was task-irrelevant. On the behavioral level, trauma-related relative to neutral word stimuli evoked more unpleasant feelings, higher arousal as well as anxiety in IPV-PTSD patients as compared to HC. Functional imaging data showed hyperactivation to trauma-related versus neutral words in the basolateral amygdala (BLA) and cortical language-processing regions (inferior frontal gyrus, posterior cingulate cortex, angular/supramarginal gyrus) in IPV-PTSD compared to HC. These results propose a role of the BLA in hypervigilant responding to verbal trauma associated cues in IPV-PTSD. Furthermore, the particular involvement of cortical language-processing regions indicates enhanced processing of trauma-related words in brain regions associated with analysis and memory of verbal material. Taken together, our findings suggest that both subcortical and cortical mechanisms contribute to automatic responsivity to verbal trauma cues in PTSD.

Specific amygdala response to masked fearful faces in post-traumatic stress relative to other anxiety disorders.

BACKGROUND: Altered amygdala activation to fear-related stimuli has been proposed to be a potential neural correlate of heightened threat sensitivity in anxiety- and stress-related disorders. However, the role of stimulus awareness and disorder specificity remains widely unclear. Here we investigated amygdala responses to conscious and unconscious fearful faces in patients suffering from panic disorder (PD), generalized anxiety disorder (GAD), or post-traumatic stress disorder (PTSD) and in a large sample of healthy controls (HC). METHODS: During event-related functional magnetic resonance imaging participants (n = 120; 20 PD, 20 GAD, 20 PTSD, 60 HC) were confronted with briefly presented fearful faces, neutral faces, and non-faces in a backward masking paradigm. The design allowed for the analysis of trial-by-trial face detection performance and amygdala responses to fearful v. neutral faces. RESULTS: All participants exhibited increased amygdala activation to fearful v. neutral faces during conscious trials. Specifically during unconscious face processing, the PTSD, compared with all other groups, showed higher right basolateral (BLA) amygdala activity to fearful v. neutral faces. CONCLUSIONS: The present study shows that BLA amygdala hyperactivity during unconscious, but not conscious, processing of fearful faces differentiates PTSD from the investigated disorders. This finding suggests an automatic and specific neural hyper-responsivity to general fear cues in PTSD and supports the idea of categorical differences between PTSD and other anxiety-related disorders.

Long-term adaptation capacity of ponies: effect of season and feed restriction on blood and physiological parameters.

Domesticated horses are increasingly kept under semi-natural housing conditions, whereas their adaptation capacity is not fully investigated. In all, 10 Shetland pony mares were held under semi-extensive conditions for 1 year. In winter animals were allocated into two feeding groups (60% and 100% of maintenance energy requirement, respectively). Triiodothyronine, thyroxine, non-esterified fatty acids (NEFA), total bilirubin, total protein, triglyceride, glucose, insulin and hair length were measured at monthly intervals, whereas BW, body condition score, cresty neck score and resting heart rate were recorded every 2 weeks. From summer to winter all Ponies showed a reduction in resting heart rate (P0.05). Refeeding of restrictively fed ponies resulted in a rapid increase in resting heart rate and BW and a return of blood parameters to reference values. Adequately supplied animals adapted without difficulty to varying environmental conditions, whereas feed restriction in ponies during winter resulted in reduced resting heart rates suggesting a reduced basal metabolic rate. The energy restriction was compensated by mobilizing body fat reserves which led to changes in blood parameters. Refeeding in feed restricted animals revealed a remarkably quick recovery of physiological and blood parameters to reference values. We therefore suggest that year round-outdoor housing can be a suitable housing system for robust horse breeds provided that an adequate food supply is available.

Directed threat imagery in generalized anxiety disorder.

BACKGROUND: Worrying has been suggested to prevent emotional and elaborative processing of fears. In cognitive-behavioral therapy (CBT), generalized anxiety disorder (GAD) patients are exposed to their fears during the method of directed threat imagery by inducing emotional reactivity. However, studies investigating neural correlates of directed threat imagery and emotional reactivity in GAD patients are lacking. The present functional magnetic resonance imaging (fMRI) study aimed at delineating neural correlates of directed threat imagery in GAD patients. METHOD: Nineteen GAD patients and 19 healthy controls (HC) were exposed to narrative scripts of either disorder-related or neutral content and were encouraged to imagine it as vividly as possible. RESULTS: Rating results showed that GAD patients experienced disorder-related scripts as more anxiety inducing and arousing than HC. These results were also reflected in fMRI data: Disorder-related v. neutral scripts elicited elevated activity in the amygdala, dorsomedial prefrontal cortex, ventrolateral prefrontal cortex and the thalamus as well as reduced activity in the ventromedial prefrontal cortex/subgenual anterior cingulate cortex in GAD patients relative to HC. CONCLUSION: The present study presents the first behavioral and neural evidence for emotional reactivity during directed threat imagery in GAD. The brain activity pattern suggests an involvement of a fear processing network as a neural correlate of initial exposure during directed imagery in CBT in GAD.

Distinct phasic and sustained brain responses and connectivity of amygdala and bed nucleus of the stria terminalis during threat anticipation in panic disorder.

BACKGROUND: Panic disorder (PD) patients are constantly concerned about future panic attacks and exhibit general hypersensitivity to unpredictable threat. We aimed to reveal phasic and sustained brain responses and functional connectivity of the amygdala and the bed nucleus of the stria terminalis (BNST) during threat anticipation in PD. METHODS: Using functional magnetic resonance imaging (fMRI), we investigated 17 PD patients and 19 healthy controls (HC) during anticipation of temporally unpredictable aversive and neutral sounds. We used a phasic and sustained analysis model to disentangle temporally dissociable brain activations. RESULTS: PD patients compared with HC showed phasic amygdala and sustained BNST responses during anticipation of aversive v. neutral stimuli. Furthermore, increased phasic activation was observed in anterior cingulate cortex (ACC), insula and prefrontal cortex (PFC). Insula and PFC also showed sustained activation. Functional connectivity analyses revealed partly distinct phasic and sustained networks. CONCLUSIONS: We demonstrate a role for the BNST during unpredictable threat anticipation in PD and provide first evidence for dissociation between phasic amygdala and sustained BNST activation and their functional connectivity. In line with a hypersensitivity to uncertainty in PD, our results suggest time-dependent involvement of brain regions related to fear and anxiety.

Seasonal changes of total body water and water intake in Shetland ponies measured by an isotope dilution technique.

Water is an essential nutrient necessary to support life, and adequate water supply is crucial for animal survival and productivity. The present study was designed to determine seasonal changes in the water metabolism of horses under outdoor conditions. Total body water (TBW) and total water intake (TWI) of 10 adult Shetland pony mares were estimated at monthly intervals for 14 mo by using the deuterium dilution technique. During the last 4 mo, 5 ponies were fed restrictively to simulate natural feed shortage in winter, and 5 ponies served as controls. The TBW (kg) was closely related to body mass [TBW (kg) = -2.86 + 0.67 × body mass (kg); P < 0.001; n = 105] explaining 86% of the variation. In contrast to TBW (kg), TBW (%) remained relatively stable across all measurements (57.8 to 71.2%). The TWI showed an increase in summer and a decrease in winter [TWI (mL·kg(-1)·d(-1)) = 15.07 + 23.69 × month - 1.45 × month(2) (R(2) = 0.64, P < 0.01)]. However, TWI measured at ambient temperatures (Ta) < 0°C did not follow the same trend as TWI at Ta > 0°C. Therefore, removing TWI values measured at Ta < 0°C from the analysis resulted in high correlations with locomotor activity (r = 0.87), Ta (r = 0.86), and resting heart rate (r = 0.88). The multiple regression among TWI, Ta, and heart rate explained 84% of the variation in TWI [TWI (mL·kg(-1)·d(-1)) = -13.38 + 1.77 × heart rate (beats/min) + 2.11 × Ta (°C); P < 0.001]. Feed restriction had no effect on TWI and TBW. The TBW content was unaffected by season and physical activity. The established regression equation for TBW and body mass can be used to predict TBW from body mass in ponies under field conditions. The comparison of TWI with published data on drinking water intake revealed that ponies had 1.7 to 5.1 times greater total water intakes when other sources of water such as feed and metabolic water were included. The TWI was highly influenced by environmental conditions and metabolic rate. Contrary to expectation, water supply during the cold seasons might be more critical than under summer conditions when water content of grass is high to allow for the compensation of limited availability of drinking water.

[Minilaparoscopic surgery : alternative or supplement to single-port surgery?]. / Minilaparoskopie : Alternative oder Ergänzung zur Single-Port-Chirurgie?

In recent years scarless surgery (axillo-bilateral-breast aproach [ABBA], natural orifice transluminal endoscopic surgery [NOTES], single-port surgery) has gained importance in order to improve postoperative outcome in laparoscopic surgery. As part of this effort minilaparoscopic surgery might be a suitable alternative concerning cosmetic outcome without implementing a completely new technique. Due to the definition minilaparoscopic surgery is based on instruments which reduce the total length of trocar incisions to less than 2.5 cm. Nevertheless the total number of incisions is similar to conventional laparoscopic techniques. Most recent indications for minilaparoscopic surgery are cholecystectomy, appendectomy, hernia and colorectal surgery. This article describes the technical aspects and feasibility of minilaparoscopic cholecystectomy and transabdominal preperitoneal hernia repair (TAPP).While the trocar positions remain in the original setting the laparoscopic surgeon benefits from experience gained in conventional laparoscopic surgery. Although the cosmetic outcome is not comparable to single-port surgery, in the author's opinion minilaparoscopic surgery is a useful alternative in scarless surgery due to the fact that it is easy to adapt without establishing a completely new technique.

Experiences with an interoperable data acquisition platform for multi-centric research networks based on HL7 CDA.

A remote data entry (RDE) module was successfully integrated within a Web-based telemedicine system in a German multi-centric research network for a rare disease called Epidermolysis Bullosa. The use of standards like XML and HL7 CDA (Clinical Document Architecture) for structured data storage, guarantees long-term accessibility and high level interoperability.

Early experiences of robotic surgery in children.

BACKGROUND: Laparoscopic surgery using a robotic system (Da Vinci) was recently introduced into surgical practice for adult patients. To investigate the feasibility of this system in pediatric surgery, laparoscopic fundoplication (Thal and Nissen), cholecystectomy, and bilateral salpingo-oophorectomy were performed. METHODS: Eleven children with a mean age of 12 years (range, 7-16 years) underwent either laparoscopic anterior partial fundoplication (Thal, n = 8) or Nissen fundoplication (n = 3) for correction of gastroesophageal reflux disease in the presence of uncontrolled symptoms of regurgitation and pulmonary infection. Two children underwent laparoscopic cholecystectomy due to symptomatic cholecystolithiasis. One child underwent bilateral salpingo-oophorectomy due to a gonadoblastoma. RESULTS: Mean operating time for fundoplication was 146 min (range, 105-180 min), the operating times for cholecystectomy were 150 and 105 min, and that for salpingo-oophorectomy was 95 min. No complications were registered during either the robotic procedures or the postoperative courses. CONCLUSIONS: Compared to conventional laparoscopy, the three-dimensional high-quality vision, advanced instrument movement, and improved ergonomic position of the surgeon appear to enhance surgical precision. Robotic surgery in children using the Da Vinci system seems to be feasible and safe. However, the technique is limited due to the fact that instruments adapted to the size of small children are not available. Furthermore, the high costs and prolonged system setup are disadvantages.

Impact of dopamine and endothelin-1 antagonism on portal venous blood flow during laparoscopic surgery.

BACKGROUND: Recent data indicate that pneumoperitoneal carbondioxide (CO2) insufflation impairs hepatic macro- and microcirculation. Whether dopamine and endothelin-1 (ET-1) antagonists might restore liver blood during laparoscopic surgery has not yet been investigated. METHODS: For this study, 30 male WAG/Rij rats were randomized into two groups to obtain pneumoperitoneum with CO2 (n=15) or helium (n = 15). All the animals were implanted with a polyethylene-50 cannula into the right vena jugularis and a Doppler ultrasound flow probe around the portal vein. In each group, the rats were administered dopamine (n = 5); JKC-10, JKC-301, which is a selective endothelin-1 (ET-1) antagonist (n = 5), or sodium chloride as a control (n = 5). Portal blood flow was measured during intraabdominal pressures 2 to 12 mmHg. Data were analyzed using the Kruskal-Wallis h-test. RESULTS: The application of dopamine and ET-1 antagonists significantly improved portal blood flow over that of the control animals (p <0.05). No significant differences were found between CO2 and helium insufflation (P > 0.05). CONCLUSIONS: Dopamine and ET-1 antagonism restore portal blood flow during laparoscopic surgery independently of the insufflation gas. Whether improved hepatic perfusion might have beneficial effects on liver function needs further investigation.

Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus.

Antiretroviral therapy (ART) is frequently associated with metabolic alterations, including insulin resistance and diabetes mellitus. In this pilot study, we evaluated the effect of the PPARgamma activator troglitazone on ART-associated insulin resistance in HIV-infected patients with ART-associated diabetes mellitus. Six patients with protease inhibitor (PI)-associated diabetes mellitus, lipodystrophy and dyslipidemia were treated with troglitazone 400 mg q.d. for 3 months. Previous oral antidiabetics were discontinued prior to the study. At baseline and after 3 months, insulin sensitivity (intravenous insulin tolerance test), body composition (multifrequence bioelectrical impedance analysis) and fat distribution (CT scan quantification) were assessed. Glycaemic control (fasting and postprandial blood glucose, fructosamine, glycosylated haemoglobin) and serum lipid status were determined monthly. In four of the six patients, there was a clear improvement in insulin sensitivity, resulting in a reversal of insulin resistance in two of these patients. Overall, there was an increase in lean body mass and a decrease in total body fat. The volume of visceral adipose tissue decreased whilst the volume of subcutaneous adipose tissue increased. Total cholesterol, LDL and HDL cholesterol increased, and total triglycerides and VLDL-cholesterol decreased. No adverse effects such as hepatotoxicity were observed. Treatment with troglitazone 400 mg q.d. can ameliorate and in some cases even reverse ART-associated insulin resistance. Therefore, further studies including non-diabetic patients with ART-associated insulin resistance may be helpful in evaluating the long-term effects of thiazolidinediones on ART-associated insulin resistance and other metabolic complications, such as adipose maldistribution and dyslipidaemia.