The impact and opportunities of large language models like ChatGPT in oral and maxillofacial surgery: a narrative review.

Since its release at the end of 2022, the social response to ChatGPT, a large language model (LLM), has been huge, as it has revolutionized the way we communicate with computers. This review was performed to describe the technical background of LLMs and to provide a review of the current literature on LLMs in the field of oral and maxillofacial surgery (OMS). The PubMed, Scopus, and Web of Science databases were searched for LLMs and OMS. Adjacent surgical disciplines were included to cover the entire literature, and records from Google Scholar and medRxiv were added. Out of the 57 records identified, 37 were included; 31 (84%) were related to GPT-3.5, four (11%) to GPT-4, and two (5%) to both. Current research on LLMs is mainly limited to research and scientific writing, patient information/communication, and medical education. Classic OMS diseases are underrepresented. The current literature related to LLMs in OMS has a limited evidence level. There is a need to investigate the use of LLMs scientifically and systematically in the core areas of OMS. Although LLMs are likely to add value outside the operating room, the use of LLMs raises ethical and medical regulatory issues that must first be addressed.

A resonant sextuplet of sub-Neptunes transiting the bright star HD 110067.

Planets with radii between that of the Earth and Neptune (hereafter referred to as 'sub-Neptunes') are found in close-in orbits around more than half of all Sun-like stars1,2. However, their composition, formation and evolution remain poorly understood3. The study of multiplanetary systems offers an opportunity to investigate the outcomes of planet formation and evolution while controlling for initial conditions and environment. Those in resonance (with their orbital periods related by a ratio of small integers) are particularly valuable because they imply a system architecture practically unchanged since its birth. Here we present the observations of six transiting planets around the bright nearby star HD 110067. We find that the planets follow a chain of resonant orbits. A dynamical study of the innermost planet triplet allowed the prediction and later confirmation of the orbits of the rest of the planets in the system. The six planets are found to be sub-Neptunes with radii ranging from 1.94R⊕ to 2.85R⊕. Three of the planets have measured masses, yielding low bulk densities that suggest the presence of large hydrogen-dominated atmospheres.

Perceived Criticism in Relation to the Dialectical Behaviour Therapy Network Training in a Residential Program: A Pre-Post Study

Perceived Criticism is a transdiagnostic construct that captures the patients’ perception of criticism. PC seems to be a reliable predictor of negative clinical outcomes concerning recurrence of symptoms or relapse in a broad range of stress-related psychiatric disorders and is thought to be related to underlying stress-related psychobiological vulnerabilities. Dialectical Behavior Therapy (DBT) is a treatment targeting these stress-related psychobiological vulnerabilities. In this pilot study we focus on the possible change in Perceived Criticism due to a (residential) DBT network training. This study follows a pre-post design where PC is recorded in 33 patients (mean age 25 years) and 61 relatives during 8 group sessions of a DBT network training, as part of a residential DBT program. The degree of perceived criticism is systematically assessed using the Perceived Criticism Measure, a two item self-report questionnaire that assesses mutual (perceived) criticism from patients and network members. Overall scores of the perceived criticism measure decrease significantly for both patients and relatives after following the DBT network training. More specific, item scores of both patients and relatives concerning how critical they are towards the other and how critical they thought the other was of them also decreased significantly after following the DBT network training. Findings suggest that a DBT network training as part of a residential DBT program may be instrumental in decreasing levels of perceived criticism. We recommend further exploration of Perceived Criticism as a possible moderator in effect size studies in randomized controlled clinical trials on DBT and in more fundamental research on the putative mechanisms of behavioural change such as improved perspective taking, and the evaluation of social cues (AU)

Deciphering radiological stable disease to immune checkpoint inhibitors.

BACKGROUND: 'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research. PATIENTS AND METHODS: A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts. RESULTS: Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated. CONCLUSIONS: RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research.

[Evaluation of cancelled emergency physician missions and patient handovers in the area of Innsbruck : Retrospective assessment of physician-staffed emergency medical service cancellations and handovers from the emergency physician to the emergency medical service in 2017 and 2018]. / Evaluierung der NEF-Fehl- und Übergabeeinsätze im Raum Innsbruck : Retrospektive Auswertung der NEF-Stornierungen und Übergabeeinsätze vom Notarzt an den Rettungsdienst in den Jahren 2017 und 2018.

BACKGROUND: Human and vehicle resource management indicates a good emergency medical system (EMS). Frequently, an emergency medical technician (EMT) is the first responder to the emergency, which negates the necessity for an emergency physician (EP) and is just as sensible as handing over a stable patient to the EMT for transport to the hospital. The Austrian EMS is utilized by EMTs, in cases of potential life-threatening emergencies the dispatch center dispatches an additional team with an on-board EP. During the years 2017-2018 nearly every fifth EP mission in Innsbruck (including surrounding areas) ended in a cancellation. The numbers of patient handovers from EP to EMT are slightly lower with mission cancellations resulting in every fourth patient. Therefore, due to the high number of cancellations and handovers evaluated in this study, the findings suggest that there is a potential need to re-evaluate procedures. The re-evaluation of these procedures could determine whether these cancellations/handovers were justified or if an over hasty decision making was at fault. All cases considered in this study were from the Innsbruck and Telfs EP bases between 1 January 2017 and 13 December 2018. METHODS: Out of a total of 96,908 emergency dispatches, there were 2470 cancellation/handover occurrences. These occurrences consisted of 1190 cancellations and 1280 patient handovers from the EP to the EMT. Patients who were transferred to the University Hospital Innsbruck were included in these figures. The protocols of the emergency dispatches have been filtered from the so-called CarPC. They have subsequently been grouped into cancellation and handover categories. The clinical diagnoses of the patients with inpatient treatment were evaluated from the hospital information system (KIS) of the University Hospital Innsbruck. This was done with the help of the so-called emergency physician indications catalogue of the German Medical Council. The diagnosis was documented in the hospital information system. The emergency protocols from the EMTs were also evaluated retrospectively. The Innsbruck based EP patients are hospitalized in the Innsbruck Hospital due their geographical position. When there is no need for a specific intervention the patients of the EPs based in Telfs are transferred to a local hospital. When a specific intervention is necessary, patient care must be provided by the University Hospital Innsbruck. Due to the privacy practices of the Innsbruck Medical University "vote of ethics" only the data of patients transferred to the Innsbruck Clinic can be evaluated. The information provided from the EPs based in Innsbruck was exclusively from the University Hospital Innsbruck's anesthesiologists. The physicians from the Telfs EP base are of mixed medical specialities. All of them, however, have an emergency medical physician diploma, in addition to the ius practicandi. Lastly, there are no EPs in Innsbruck or Telfs, who have any special obligations during their duty. RESULTS: The results show that in 210 cases (8.5%) the indications for the EP, based on the emergency physician indications catalogue of the German Medical Council were given. Also, 8.7% of all cancellations and 8.4% of patient handovers were not justified. Patients with emergency indications had a longer hospitalization. The EP base EMS Innsbruck had more cancellations than the EP base EMS Telfs. The EMS Innsbruck also had more cancellations than patient handovers. Conversely, the EMS Telfs had more patient handovers than cancellations. On the weekends between 6:00 pm and 6:00 am there were less cancellations and handovers from both EP bases. The documentation from the EMT protocols was incomplete in 284 cancellations (23.9% of the cancellations) and 339 handovers (26.5% of the handovers), 35 patients after cancellations (2.9%), 35 patients after handovers (2.7%) needed intensive care treatment, 20 patients after cancellations (1.7% of all cancellations), and 24 patients after handovers (1.9% of all handovers) who needed intensive care treatment had a critical diagnosis. In 40 cases of patient handovers, the EP was alerted to another emergency follow-up within 10 min. CONCLUSION: In Austria, the introduction of a standardized emergency indication checklist might help dispatch centers to provide a more accurate dispatch as well as all EMS team members. Furthermore, a better traceability system (according to EP cancellations and patient handovers from the EP to the EMT) could be achieved. The documentation requirements should be more precise by all members of the EMT staff, not only for the legal aspects but also for improving the overall management quality. Intense education and training as well as diagnosis feedbacks could help to reduce the number of risky cancellations/patient handovers.

COVID-19 in patients with lung cancer.

BACKGROUND: Patients with lung cancers may have disproportionately severe coronavirus disease 2019 (COVID-19) outcomes. Understanding the patient-specific and cancer-specific features that impact the severity of COVID-19 may inform optimal cancer care during this pandemic. PATIENTS AND METHODS: We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n = 102) at a single center from 12 March 2020 to 6 May 2020. Thresholds of severity were defined a priori as hospitalization, intensive care unit/intubation/do not intubate ([ICU/intubation/DNI] a composite metric of severe disease), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. Human leukocyte antigen (HLA) alleles were inferred from MSK-IMPACT (n = 46) and compared with controls with lung cancer and no known non-COVID-19 (n = 5166). RESULTS: COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease [odds ratio for severe COVID-19 2.9, 95% confidence interval 1.07-9.44 comparing the median (23.5 pack-years) to never-smoker and 3.87, 95% confidence interval 1.35-9.68, respectively]. Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. Human leukocyte antigen supertypes were generally similar in mild or severe cases of COVID-19 compared with non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes. CONCLUSION: COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.

Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression is the only FDA-approved biomarker for immune checkpoint inhibitors (ICIs) in patients with lung adenocarcinoma, but sensitivity is modest. Understanding the impact of molecular phenotype, clinical characteristics, and tumor features on PD-L1 expression is largely unknown and may improve prediction of response to ICI. PATIENTS AND METHODS: We evaluated patients with lung adenocarcinoma for whom PD-L1 testing and targeted next-generation sequencing (using MSK-IMPACT) was performed on the same tissue sample. Clinical and molecular features were compared across PD-L1 subgroups to examine how molecular phenotype associated with tumor PD-L1 expression. In patients treated with anti-PD-(L)1 blockade, we assessed how these interactions impacted efficacy. RESULTS: A total of 1586 patients with lung adenocarcinoma had paired PD-L1 testing and targeted next-generation sequencing. PD-L1 negativity was more common in primary compared to metastatic samples (P < 0.001). The distribution of PD-L1 expression (lymph nodes enriched for PD-L1 high; bones predominantly PD-L1 negative) and predictiveness of PD-L1 expression on ICI response varied by organ. Mutations in KRAS, TP53, and MET significantly associated with PD-L1 high expression (each P < 0.001, Q < 0.001) and EGFR and STK11 mutations associated with PD-L1 negativity (P < 0.001, Q = 0.01; P = 0.001, Q < 0.001, respectively). WNT pathway alterations also associated with PD-L1 negativity (P = 0.005). EGFR and STK11 mutants abrogated the predictive value of PD-L1 expression on ICI response. CONCLUSION: PD-L1 expression and association with ICI response vary across tissue sample sites. Specific molecular features are associated with differential expression of PD-L1 and may impact the predictive capacity of PD-L1 for response to ICIs.

Exploring the cognitive phenotype of Kabuki (Niikawa-Kuroki) syndrome.

BACKGROUND: Kabuki syndrome (KS) is a Mendelian disorder, characterised by short stature, facial dysmorphisms and developmental delay and/or intellectual disability. Clarification of the neurocognitive profile in KS may provide directions for education and treatment interventions for KS. Previous studies on cognitive functioning in KS are scarce and have mainly focused on the general level of intelligence. The few more extensive studies suggested weaknesses in language skills, visuoconstruction, perceptual reasoning and speed of information processing. Other relevant domains such as memory, executive functioning and social cognition have not been studied yet. METHOD: This is the first study in which cognitive functioning within multiple domains is systematically explored in 29 participants with KS (age range: 5-48 years) and compared to both norm groups (healthy population) and an appropriate control group of 15 individuals with other genetic syndromes (age range: 6-28 years). RESULTS: Compared to the norm groups of the cognitive test manuals, as expected, participants with KS show a weaker performance on all cognitive tests. Comparison with the more appropriate genetic control group indicates weaknesses in visuoconstruction and visual memory and no weaknesses in planning, cognitive flexibility or social cognition. Verbal memory seems to be a relative strength. CONCLUSIONS: Individuals with KS suffer from specific weaknesses in visuoconstruction, in addition to their intellectual disability/developmental delay. These impairments in visuoconstruction plausibly result from problems in visual perceptual processing, which highlight the importance of the use of auditory cues instead of visual cues in targeted educational support and psychosocial interventions.

Executive Dysfunction in Patients With Korsakoff's Syndrome: A Theory-Driven Approach.

AIMS: In addition to amnesia, executive deficits are prominent in Korsakoff's syndrome (KS), yet poorly studied. This study investigates the degree of executive dysfunction in patients with KS for the three main executive subcomponents shifting, updating and inhibition using novel, theory-driven paradigms. SHORT SUMMARY: Compared to healthy controls, patients with KS show impairments on the executive subcomponents shifting and updating, but not on inhibition. METHODS: Executive functions were measured with six carefully designed tasks in 36 abstinent patients with KS (mean age 62.3; 28% woman) and compared with 30 healthy non-alcoholic controls (mean age 61.8; 40% woman). ANOVAs were conducted to examine group differences and effect sizes were calculated. RESULTS: Compared to healthy controls, patients with KS were impaired on the executive subcomponents shifting and updating. No statistically significant group difference was found on the factor inhibition. CONCLUSIONS: Executive dysfunction in long-abstinent patients with alcoholic KS shows a profile in which shifting and updating ability are affected most. It also highlights that executive dysfunction is an important feature of KS and requires more attention in scientific and clinical practice, as these deficits may also affect daily functioning.

Inhibition, shifting and updating in relation to psychometric intelligence across ability groups in the psychiatric population.

BACKGROUND: Assessment of intelligence and executive function (EF) is common in complex neuropsychiatric practice. Although previous studies have shown that EF and intelligence are related, it is unknown whether these constructs relate to one another in a similar manner across different ability groups (mild intellectual disability, borderline intellectual disability and normal/high intelligence). This study therefore examines the relation between three EFs (inhibition, shifting and updating) and intelligence in a heterogeneous psychiatric sample. It is hypothesised that the strength of the relation between intelligence and the three EFs decreases when the level of intelligence increases, in accordance with Spearman's Law of Diminishing Returns. METHODS: In a cross-sectional, between and within subject design, one of the three intelligence tests (Kaufman Adolescent and Adult Intelligence Test and Wechsler Adult Intelligence Scale - third and fourth editions) and several EF tests (Stroop Colour-Word Test, Trail Making Test and Spatial Working Memory task) were administered to 250 neuropsychiatric inpatients and outpatients (Mage  = 39.8, standard deviation = 14.3, 52.8% male). Based upon their full-scale IQ score, patients were divided into three ability groups (mild intellectual disability, borderline intellectual disability or normal/high intelligence). The relation between EF and intelligence was assessed through analyses of the correlation pattern; groups were compared using analysis of covariance. RESULTS: Analyses showed significant correlations between the constructs of EF and intelligence. A significant interaction effect was found for shifting, with highest correlations in the normal to high intelligence group, but not for inhibition and updating. CONCLUSIONS: Results support a specific role for shifting in this EF-intelligence relation. The correlational pattern of updating and intelligence, as well as the differential relation of shifting and intelligence across ability groups, suggests that EF tasks may not measure distinct EFs in lower intellectual ability but rely on cognitive primitives such as processing speed. EF tasks can be considered less valid indicators of EF ability. Implications in terms of the need for development of specific tasks to measure cognition in low intellectual ability are discussed.

Experimental search for the violation of Pauli exclusion principle: VIP-2 Collaboration.

The VIolation of Pauli exclusion principle -2 experiment, or VIP-2 experiment, at the Laboratori Nazionali del Gran Sasso searches for X-rays from copper atomic transitions that are prohibited by the Pauli exclusion principle. Candidate direct violation events come from the transition of a 2p electron to the ground state that is already occupied by two electrons. From the first data taking campaign in 2016 of VIP-2 experiment, we determined a best upper limit of [Formula: see text] for the probability that such a violation exists. Significant improvement in the control of the experimental systematics was also achieved, although not explicitly reflected in the improved upper limit. By introducing a simultaneous spectral fit of the signal and background data in the analysis, we succeeded in taking into account systematic errors that could not be evaluated previously in this type of measurements.

Validation of spirometry prediction equations in western Kenya.

SETTING: Community of Eldoret, Kenya. OBJECTIVE: To test the performance of three commonly used spirometry prediction equations in a healthy Kenyan population. DESIGN: Cross-sectional assessment of healthy adults in Eldoret. RESULTS: Of the 331 subjects enrolled in the study, 282 subjects aged 18-85 years (45% males, 55% females) produced high-quality spirograms. Lung function predictions were made using the Global Lung Initiative 2012 (GLI 2012) prediction equations for African Americans, the National Health and Nutrition Examination Survey III (NHANES III) prediction equations for African Americans, and the Crapo prediction equation. Bland-Altman analyses were performed to measure the agreement between observed and predicted spirometry parameters. Overall, the GLI 2012 and NHANES equations for African Americans performed similarly for forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), significantly overestimating FVC while accurately predicting observed FEV1 values. CONCLUSION: The study brings into question the utility of three major spirometry prediction equations in a Kenyan population. The significant overestimation of FVC by the best-performing equations despite accurate prediction of FEV1 suggests poor performance of these equations in our population.

[Simple is not always easy: genetics in general psychiatry]. / Drie patiënten met langdurig onopgehelderde psychiatrische klachten waarbij genetische diagnostiek uitkomst bracht.

Many of the patients who attend the outpatient mental health clinics already have a long history of psychiatric problems. Their symptoms seem easy to classify, but the misdiagnosis of the patients' underlying problems can lead to a long series of costly referrals as inpatients or to an ineffective treatment outcome. In this article we focus on three patients whose history and background circumstances had been analysed in detail and who had also been subjected to a genetic analysis. The analyses pointed to an etiology-based diagnosis which had important implications for their future treatment and its outcome.

Improvement in advanced pancreatic cancer survival with novel chemotherapeutic strategies - experience of a community based hospital.

Background: New chemotherapeutic strategies for locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) have been shown to improve survival in randomized clinical trials. Little is known about the use of such chemotherapies and their benefit in community-based hospitals. This retrospective study analyzes the overall survival of these patients under "real life conditions" before and after the introduction of FOLFIRINOX in 2011. Methods: We retrospectively identified consecutive patients with PDAC who were treated at our hospital from 2011 to June 2014 (2011+ cohort) and 2004 to 2010 (historical cohort). Patients were included if PDAC was diagnosed in a locally advanced or metastatic state and at least 1 cycle of chemotherapy was given. Survival was assessed until April 2016. Patients with FOLFIRINOX were further analyzed regarding drug administration and side effects. Results: 128 patients met the inclusion criteria. Of the 74 patients in the historical cohort, 62 patients received Gemcitabine. Of the 54 patients diagnosed between 2011 and June 2014, 28 patients received FOLFIRINOX and 22 Gemcitabine as the first-line chemotherapy. Only 34 % of the patients in the historical cohort received a second-line chemotherapy in comparison to 69 % in the 2011+ cohort. Median overall survival (OS) showed a survival of 13.1 months (95 % CI; 11.6 - 14.5) for the 2011+ cohort compared to 9.6 months (95 % CI; 6.1 - 13.1) in the historical group. Conclusion: This study shows a marked improvement in survival of patients diagnosed with locally advanced or metastatic PDAC in a community-based hospital during the past 4 years. The most likely reasons are the use of new polychemotherapies like FOLFIRINOX and the use of second-line chemotherapy.

[Alcohol-related cognitive impairment and the DSM-5]. / Alcoholgerelateerde cognitieve stoornissen in de DSM-5.

BACKGROUND: It is evident from the dsm-iv-tr that alcohol-related impairment is extremely difficult to classify accurately. As a result, cognitive deficits can easily be overlooked. The dsm-5, however, incorporates a new category, namely 'neurocognitive disorders', which may lead to significant improvements in clinical practice. AIM: To compare the classification of alcohol-related cognitive dysfunction in dsm-iv-tr and dsm-5 and to discuss the clinical relevance of the revised classification in the dsm-5. METHOD: We compare the chapters of the dsm-iv-tr and the dsm-5 concerning alcohol-related cognitive impairment and describe the changes that have been made. RESULTS: The dsm-5 puts greater emphasis on alcohol-related neurocognitive impairment. Not only does dsm-5 distinguish between the degree of severity (major or minor neurocognitive disorder), it also distinguishes between the type of impairment (non-amnestic-type versus confabulating-amnestic type). It also makes a distinction between the durations of impairment (behavioural and/or persistent disorders). CONCLUSION: The dsm-5 gives a clearer description of alcohol-related neurocognitive dysfunction than does dsm-iv-tr and it stresses the essential role of neuropsychological assessment in the classification, diagnosis, and treatment of neurocognitive disorders.

[Could you please reduce your seclusion rates? To structure patient care by the methodical work approach]. / 'Kunnen de separatiecijfers omlaag?' Structuur geven aan behandelbeleid met methodisch werken.

BACKGROUND: Creating a safe treatment environment with a minimum use of seclusion at a ward for intensive psychiatric care is a complex process involving many actors. Although s/he is accountable for the use of seclusion, the psychiatrist's influence on actual seclusion practices is limited. The methodical work approach (MWA) to patient care is designed to improve multidisciplinary care delivery. AIM: To investigate ways in which the psychiatrist can structure the treatment and reduce seclusion rates by introducing the MWA. METHOD: We performed a quantitative analysis of the effects that the implementation of the MWA on an intervention ward had on the use of seclusion, comparing the intervention ward to control wards. We also conducted a qualitative analysis of the changes that occurred in the work process and in the roles of the various professionals involved. RESULTS: The use of seclusion had reduced significantly more at the intervention ward than it had at the control wards. The reduced seclusion rates were associated with an increase in interdisciplinary collaboration and professionalisation. CONCLUSION: By helping to limit the use of seclusion, possibly due to enhanced interdisciplinary collaboration and professionalisation, the MWA offers new horizons for mental health care professionals and their patients.

Neuropsychological phenotype and psychopathology in seven adult patients with Phelan-McDermid syndrome: implications for treatment strategy.

Phelan-McDermid syndrome (PMS) or 22q13.3 deletion syndrome is characterized by a variable degree of intellectual disability, impaired speech and language as well as social communicative skills and mild dysmorphic features. The SHANK3 gene is thought to be a major contributor to the phenotype. Apart from the syndrome-associated autistic features, symptoms from the bipolar spectrum can be discerned, in particular behavior instability and fluctuating mood culminating in a (hypo)manic state. In case of coincident major somatic events, a deteriorating course may occur. This study comprises seven adult patients (four females and three males; aged 21-44 years) with genetically proven PMS. Data from medical records were collected and extensive assessment of neuropsychological variables was performed to identify cognitive characteristics and their relation with psychopathology and treatment. All patients showed profound communication deficits and their developmental functioning ranged from 1.0 to 6.3 years. In addition, they had slow speed of information processing, impairment of attentional and executive functions and cognitive alexithymia. As to psychopathology, features from the affective and anxiety domains were prominent findings in these seven patients suggesting the presence of a bipolar spectrum disorder that could be effectively moderated with mood-stabilizing agents. Results are discussed in terms of the putative involvement of structural brain abnormalities, in particular cerebellar vermis hypoplasia and corpus callosum thinning and their cognitive and emotional sequelae. It is concluded that the treatment of 22q13.3-associated psychopathology should include prescription of mood-stabilizing agents in combination with individually tailored contextual neuropsychological measures.

A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma.

BACKGROUND: This randomized, double-blind, placebo-controlled, phase II study evaluated the efficacy and safety of mapatumumab (a human agonistic monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 1) in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with advanced HCC (stratified by Barcelona Clinic Liver Cancer stage and Eastern Cooperative Oncology Group performance status) were randomized 1:1 to receive sorafenib (400 mg, twice daily per 21-day cycle) and either placebo (placebo-sorafenib arm) or mapatumumab (30 mg/kg on day 1 per 21-day cycle; mapatumumab-sorafenib arm). The primary end point was time to (radiologic) progression (TTP), assessed by blinded independent central review. Key secondary end points included progression-free survival, overall survival, and objective response. RESULTS: In total, 101 patients were randomized (placebo-sorafenib arm: N = 51; mapatumumab-sorafenib arm: N = 50). There was no significant difference in median TTP between both arms [5.6 versus 4.1 months, respectively; adjusted hazard ratio (one-sided 90% confidence interval) 1.192 (0-1.737)]. No mapatumumab-related benefit was identified when TTP was evaluated in the stratified subgroups. The addition of mapatumumab to sorafenib did not demonstrate improvement in the secondary efficacy end points. The reported frequency of adverse events (AEs) and serious AEs was comparable in both treatment arms. CONCLUSIONS: The addition of mapatumumab to sorafenib did not improve TTP or other efficacy end points, nor did it substantially change the toxicity profile of sorafenib in patients with advanced HCC. Based on these results, further development of the combination of mapatumumab and sorafenib in HCC is not planned.

22q11.2 deletion syndrome: atypical antipsychotics and relapsing psychoses.

In their letter to the editor, Boot and colleagues comment on the results of treatment with atypical antipsychotics in patients with 22q11.2 deletion syndrome and relapsing psychoses. They identify 3 issues (i. e., description of study rationale and assessments, the importance of endocrine dysfunctions and possible effects of sample bias) and conclude that "until strong evidence to the contrary [is available], standard pharmacological management of psychotic illness in 22q11DS remains recommended." In our reply, we will illustrate the erroneous nature of their conjectures.