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Purpose Ipilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis. Methods A retrospective cohort study was performed for all patients ( n  = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis. Results and conclusions Ipilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance ( P  = 0.053). A significant fall in FT4 ( P  < 0.001), TSH index ( P  < 0.001) and standardised TSH index ( P  < 0.001) prior to cycles 3 and 4 in hypophysitis cohort was observed. TSH is not useful in predicting development of IH. FT4, TSH index and standardised TSH index may be valuable but a high index of clinical suspicion remains paramount in early detection of hypophysitis.

Abstract Dumbbell schwannoma of the cervical spine is a known entity,1-5 and should be radically resected with the preservation or improvement of neurological function. However, to our knowledge, an operative video of a C1-C2 cervical dumbbell schwannoma with ventral extension and dorsal spinal cord compression has not been reported previously. This tumor resection video performed by the senior author (KIA) includes details of dural opening, and techniques for microsurgical resection and for postoperative closure to avoid cerebrospinal fluid (CSF) leak and pseudomeningocele formation. Fat grafting was performed through a small paraumbilical incision. The patient was prone in MAYFIELD 3-point pin fixation (Integra LifeSciences, Plainsboro Township, New Jersey). Intraoperative neurophysiological electrodes were placed for somatosensory evoked potential (SSEP) and motor evoked potential (MEP) monitoring. Stealth neuronavigation was used to aid in tumor localization. A small suboccipital craniectomy and C1 laminectomy were performed before opening the dura. Using a microsurgical technique, the dura was opened in the form of the letter “Y.” The right-sided dentate ligament was cut to aid in the mobilization of the tumor away from the spinal cord. After dividing the tumor at the dumbbell isthmus, the ventral tumor component was removed, with attention paid to the division of a perforator coming from the vertebral artery. Intraforaminal tumor debulking was performed with a cavitron ultrasonic surgical aspirator (CUSA) and resected. High cervical dumbbell schwannoma should be radically resected while preserving and improving preoperative neurological function. Avoidance of CSF leak and formation of pseudomeningocele should be planned at the beginning, utilizing fascia and fat graft to avoid this feared complication. The patient provided written consent and permission to publish her image.

Objectives: To evaluate the impact in terms of use of health services, clinical outcomes, functional status, and patient’s satisfaction of an integrated care program, the CareWell program, for complex patients with multimorbidity, supported by information and communication technology platforms in six European regions. Data Sources: Primary data were used and the follow-up period ranged between 8 and 12 months. Study design: A quasi-experimental study, targeting chronic patients aged 65 or older, with 2 or more conditions – one of them necessarily being diabetes, congestive heart failure or congestive obstructive pulmonary disease. The intervention group received the integrated care program and the control group received usual care. Generalized mixed regression models were used. Data collection: Data were obtained from individual interviews and electronic clinical records. Principal Findings: Overall, 856 patients were recruited (475 intervention and 381 control). In the intervention group, the number of visits to emergency rooms was significantly lower, and the number of visits to the general practitioners and primary care nurses was higher than in the control group. Conclusion: The CareWell program resulted in improvements in the use of health services, strengthening the role of PC as the cornerstone of care provision for complex patients with multimorbidity.

Introduction: The nasals and hand carriage of Staphylococcus aureus in food handlers (FHs) represent a significant source of Staphylococcal food contamination and food poisoning. Antimicrobial resistance (AMR) is a microorganism’s ability to resist the action of one or more antimicrobial agents. S. aureus has demonstrated the ability to rapidly respond to each new antimicrobial with the development of a resistance mechanism. The aim of the study was to assess the prevalence of nasal carriage rate and AMR pattern of isolated strains S. aureus among FHs in Canton Sarajevo, Bosnia and Herzegovina. Methods: The retrospective study included laboratory results of 11.139 tested subjects between January 2014 and December 2018. The study was conducted in the laboratory of the Institute of Public Health of the Federation of Bosnia and Herzegovina in Sarajevo. Samples of nasal swabs were collected from FHs, employees in companies located in Canton Sarajevo, during sanitary surveillance prescribed by applicable legal standards. S. aureus isolates were identified according to conventional microbiological methods and antimicrobial susceptibility testing was performed by the agar disk diffusion method according to the European Committee on Antimicrobial Susceptibility Testing; 2013 standard. Results: Among the 11.138 subjects, 792 (7.1%) were carriers of S. aureus. Isolated strains were tested on eight different antibiotics, and the resistance to penicillin, ampicillin, and amoxicillin was 788 (99.5%), 776 (97.9%), and 752 (94.9%), retrospectively. In total, 86.36% of isolated strains were multidrug-resistant. Conclusions: The low percentage of S. aureus carriers indicates that preventive measures of carrier control are being actively implemented within the legally prescribed measures. The emergence of numerous isolated strains with multidrug-resistance characteristics is a significant public health problem and consequently limits the range of antibiotics available for therapeutic purposes. The results of this research indicate that AMR has increased in Sarajevo Canton and it is following the trend of global growth.

Rhabdomyolysis is a common cause of acute kidney injury, featuring muscle pain, weakness and dark urine and concurrent laboratory evidence of elevated muscle enzymes and myoglobinuria. Rhabdomyolysis is often seen in elderly and frail patients following prolonged immobilization, for example after a fall, but a variety of other causes are also well-described. What is unknown to most physicians dealing with such patients is the fascinating history of rhabdomyolysis. Cases of probable rhabdomyolysis have been reported since biblical times and during antiquity, often in the context of poisoning. Equally interesting is the link between rhabdomyolysis and armed conflict during the 20th century. Salient discoveries regarding the pathophysiology, diagnosis and treatment were made during the two world wars and in their aftermath. 'Haff disease', a form of rhabdomyolysis first described in 1920, has fascinated scientists and physicians alike, but the marine toxin causing it remains enigmatic even today. As a specialty, we have also learned a lot about the disease from 20th-century earthquakes, and networks of international help and cooperation have emerged. Finally, rhabdomyolysis has been described as a sequel to torture and similar forms of violence. Clinicians should be aware that rhabdomyolysis and the development of renal medicine are deeply intertwined with human history.

Sleep and wakefulness are not simple homogenous all-or-none states, but instead are characterized by rich dynamics of brain activity across many temporal and spatial scales. Rapid global state transitions between waking and sleeping are believed to be controlled by hypothalamic circuits, but the contribution of the hypothalamus to within-state changes of sleep and wake “intensity” remains largely unexplored. Here we show that stimulation of inhibitory neurons in the preoptic hypothalamus does not merely trigger awakening from sleep, but the resulting awake state is also characterized by increased cortical activity. This activation is associated with a faster build-up of sleep pressure, proportional to the arousal level. These findings show that hypothalamic systems thought to exclusively control global state switching, also regulate within-state “intensity”, which we propose as a key intrinsic variable in shaping the architecture of sleep/wake states across the 24h day.

We have recently proposed that research in anorexia nervosa (AN) requires greater focus on the biopsychosocial model of the illness as a whole, and that biologically inspired treatments for the condition are lacking (Phillipou et al., 2019). Russell (2019) disagrees with this proposal and suggests that we have an ‘effective biological treatment’ for AN – refeeding and nutritional rehabilitation. The author goes on to propose that ‘this can bring about complete resolution of physical, endocrine and psychological symptoms’ and that food is a ‘miracle cure’ for AN. Refeeding is not a treatment for AN itself – it is a treatment for restoring the resultant weight loss driven by the psychological symptoms of AN. Restoring one’s physical state is indeed a critical component of AN treatment, but it does not address the underlying mental illness that has led to weight loss in the first place. It is not responsible to suggest that the primary purpose of refeeding is much more than restoring a patient’s physical state. The effects of starvation can, and are likely to, exacerbate psychological symptoms including depression and anxiety (Kezelman et al., 2015), but these symptoms do not completely resolve with weight restoration (Phillipou et al., 2018). Psychological symptoms of AN are present before weight loss, may be exacerbated in the acute state, and frequently continue at high rates into weight restoration and recovery. We are not suggesting that refeeding and nutritional rehabilitation are not critical components to AN treatment. They are essential for medical stabilisation of patients to restore physical health and to improve some aspects of mental health affected by starvation. Refeeding is an important component of treatment but is not a biological treatment for AN in itself. AN is a psychiatric illness that requires psychiatric treatment through psychosocial and/or biological interventions. There is no evidence-based biological treatment currently available to treat AN specifically. Psychiatric medications and neurostimulation are routinely available for other mental illnesses, and there is strong evidence that these interventions remediate important psychiatric symptoms in these conditions. Although these biologically based treatments are not available for AN specifically, some medications can be used with some success to reduce co-morbid symptoms in AN such as increased arousal during the early stages of refeeding. There are no ‘cures’ for mental illnesses. Our treatments do not improve all symptoms associated with an illness. Antipsychotics, for example, have significant success in reducing positive symptoms in individuals with psychosis, but do not improve cognition or other aspects of functioning. However, antipsychotics are an effective evidence-based treatment for reducing some of the most distressing symptoms of psychosis itself. Simply, we do not have a treatment of similar efficacy to reduce some of the most distressing symptoms of AN. In fact, refeeding itself is considered a very distressing experience by many AN patients (Levinson et al., 2019). Food may be a ‘miracle cure’ for starvation; it is most certainly not a cure for AN. Our psychosocial interventions show limited efficacy and biological treatments simply do not exist for AN itself. Clinicians are doing the best they can with the treatments we have available. However, as a community of researchers and clinicians, we need to acknowledge that there is significant room for improvement in AN treatment. We need to give hope to our patients who have not responded to treatment, that we are trying to do better. Recognising that we need to improve our therapeutic interventions for AN is the first step. Gaining a better understanding of the illness so we can develop treatments that are more effective is the next step. Only by gaining a clear picture of the wide-ranging biological, psychological and sociocultural mechanisms involved in AN will we be able to progress our Commentaries 924474 ANP ANZJP CorrespondenceANZJP Correspondence

Water consumption in a settlement is an extremely variable size that changes constantly over time. Changes in water consumption occur on an annual, monthly, weekly, daily and hourly basis, and depend on many factors such as: climate, season, temperatures, hours of work, consumer habits, etc.Extreme value of consumption, ie. the peak hour flow is defined as the product of the average daily consumption and the hourly non-uniformity coefficient. Non-uniformity coefficient is defined as the ratio of maximum flow to mean flow over a day, and given that actual flows fluctuate constantly over time, then it is easy to conclude that the non-uniformity coefficient is a variable that varies over time. In this case, the non-uniformity coefficient can be represented as a function C=f(t), which has local extremes at certain points, while at all other time intervals it has a smaller value.With the known function of uneven consumption, using computer technology, it is possible to program different simulations of consumption and flow in the water supply system. In this way it is possible to optimize the system itself in terms of water consumption, dimensions and capacities of facilities in the system, as well as energy consumption for water transport.

Introduction: The most common mental disorders in the elderly are depression and dementia. Objective: Examine the impact of sociodemographic characteristics on the appearance of depression and dementia in elder patients treated in Primary Health Center (PHC), Banja Luka. Method: The study included 208 patients over 65 years of age, selected by random selection method, registered in 6 family medicine teams at the PHC Banja Luka in the period from March to May 2016. Respondents completed the Sociodemographic Questionnaire, Beck’s Depression Inventory, and Folstein Mini-Mental State Examination (MMSE) for dementia assessment. Different statistical procedures were used in the data processing: descriptive analysis in the form of frequencies and percentages, Chi-square test, T-test. The results of the research were statistically analyzed by SPSS 11.5 program. Results: The study included 208 patients older than 65, of whom 38.9% were male. Impaired cognition was found in 7.2% and moderate depression in 24.5% of patients. Dementia was statistically significantly (p = 0.000) more present in the eldest respondents ≥ 81 years, while depression was mostly present in patients aged 76-80. Physically active individuals were significantly less affected by depression (p = 0.001) and dementia (p = 0.000). Dementia and depression occurred more frequently in people living alone and people with a low level of education. Conclusion: A family physician plays an important role in the early detection of depression and dementia in the elderly, the identification of risk factors, prevention, and treatment of these patients.