Pneumocystis jirovecii pneumonia in paediatric acute lymphoblastic leukaemia: A report from the multi-international clinical trial AIEOP-BFM ALL 2009.

Pneumocystis jirovecii can cause life-threatening pneumonia (PjP), and patients with haematological malignancies are at high risk of this infection. Prophylactic measures have significantly decreased morbidity and mortality, but there is a paucity of contemporary data on the incidence and clinical course of PjP in well-defined and homogenous patient populations, such as children suffering from acute lymphoblastic leukaemia (ALL). In the multi-international trial AIEOP-BFM ALL2009, PjP was diagnosed in six children (incidence 1/1000) and was associated with insufficient prophylaxis in five of them. Although none of the patients died of PjP, the long-term impact of the infection is unclear.

Treatment recommendations for glycogen storage disease type IB- associated neutropenia and neutrophil dysfunction with empagliflozin: Consensus from an international workshop.

Glycogen storage disease type Ib (GSD Ib, biallelic variants in SLC37A4) is a rare disorder of glycogen metabolism complicated by neutropenia/neutrophil dysfunction. Since 2019, the SGLT2-inhibitor empagliflozin has provided a mechanism-based treatment option for the symptoms caused by neutropenia/neutrophil dysfunction (e.g. mucosal lesions, inflammatory bowel disease). Because of the rarity of GSD Ib, the published evidence on safety and efficacy of empagliflozin is still limited and does not allow to develop evidence-based guidelines. Here, an international group of experts provides 14 best practice consensus treatment recommendations based on expert practice and review of the published evidence. We recommend to start empagliflozin in all GSD Ib individuals with clinical or laboratory signs related to neutropenia/neutrophil dysfunction with a dose of 0.3-0.4 mg/kg/d given as a single dose in the morning. Treatment can be started in an outpatient setting. The dose should be adapted to the weight and in case of inadequate clinical treatment response or side effects. We strongly recommend to pause empagliflozin immediately in case of threatening dehydration and before planned longer surgeries. Discontinuation of G-CSF therapy should be attempted in all individuals. If available, 1,5-AG should be monitored. Individuals who have previously not tolerated starches should be encouraged to make a new attempt to introduce starch in their diet after initiation of empagliflozin treatment. We advise to monitor certain safety and efficacy parameters and recommend continuous, alternatively frequent glucose measurements during the introduction of empagliflozin. We provide specific recommendations for special circumstances like pregnancy and liver transplantation.

Pathways to adolescent social anxiety: Testing interactions between neural social reward function and perceived social threat in daily life.

Recent theories suggest that for youth highly sensitive to incentives, perceiving more social threat may contribute to social anxiety (SA) symptoms. In 129 girls (ages 11-13) oversampled for shy/fearful temperament, we thus examined how interactions between neural responses to social reward (vs. neutral) cues (measured during anticipation of peer feedback) and perceived social threat in daily peer interactions (measured using ecological momentary assessment) predict SA symptoms two years later. No significant interactions emerged when neural reward function was modeled as a latent factor. Secondary analyses showed that higher perceived social threat was associated with more severe SA symptoms two years later only for girls with higher basolateral amygdala (BLA) activation to social reward cues at baseline. Interaction effects were specific to BLA activation to social reward (not threat) cues, though a main effect of BLA activation to social threat (vs. neutral) cues on SA emerged. Unexpectedly, interactions between social threat and BLA activation to social reward cues also predicted generalized anxiety and depression symptoms two years later, suggesting possible transdiagnostic risk pathways. Perceiving high social threat may be particularly detrimental for youth highly sensitive to reward incentives, potentially due to mediating reward learning processes, though this remains to be tested.

Postoperative Immobilization Period for Pediatric Supracondylar Fractures: The Shorter the Better?

BACKGROUND: There are now recognized standards of care published by the British and American Orthopaedic Associations which detail key areas of evidence-based recommendations for the treatment of children with displaced supracondylar humerus fractures. Although many aspects of treatment are covered in these recommendations, both the American and British Orthopaedic Associations do not recommend the exact duration of immobilization postoperatively. METHODS: This study retrospectively compared outcomes of operatively managed supracondylar fractures immobilized postoperatively for short immobilization (SI) defined as 28 days or less, with long immobilization (LI) defined as more than 28 days. The outcomes measured were clinical (deformity, range of motion, and pin site infection) and radiologic (loss of position after the removal of K-wires, Baumann's angle, anterior humeral line, refracture, and signs of osteomyelitis). Demographic data were recorded to evaluate and ensure satisfactory matching of the 2 groups for analysis. RESULTS: The study included 193 pediatric supracondylar fractures over a 4-year period which were treated with manipulation under anesthetic and K-wire fixation. The difference in average time in plaster between the 2 groups was statistically significant (SI: n=27.5 d, SD 1.23; LI: n=43.9 d, SD 15.29, P =0.0001). Data for operative techniques-closed or open reduction (SI: n=66, LI: n=78, P =0.59), and crossed wires (SI: n=37, LI: n=50, P =0.57) between the two groups showed no statistical significance. There was no statistical difference between the groups for the average number of days postoperatively at which wires were taken out (SI: n=28.9 d, SD 5.95, LI: n=30.1 d, SD 5.57, P =0.15), number of pin site infections requiring antibiotic treatment (SI: n=3, LI: n=5, P =0.70), or children from each group who were recorded to have regained full range of motion symmetrical to their contralateral arm (SI: n=79, LI: n=99, P =0.74). CONCLUSIONS: Our study therefore suggests that shorter immobilization of these patients (SI group) does not yield a higher rate of complications including refracture and malunion.

Pyrophilic Plants Respond to Postfire Soil Conditions in a Frequently Burned Longleaf Pine Savanna.

AbstractFire-plant feedbacks engineer recurrent fires in pyrophilic ecosystems like savannas. The mechanisms sustaining these feedbacks may be related to plant adaptations that trigger rapid responses to fire's effects on soil. Plants adapted for high fire frequencies should quickly regrow, flower, and produce seeds that mature rapidly and disperse postfire. We hypothesized that the offspring of such plants would germinate and grow rapidly, responding to fire-generated changes in soil nutrients and biota. We conducted an experiment using longleaf pine savanna plants that were paired on the basis of differences in reproduction and survival under annual ("more" pyrophilic) versus less frequent ("less" pyrophilic) fire regimes. Seeds were planted in different soil inoculations from experimental fires of varying severity. The more pyrophilic species displayed high germination rates followed by species-specific rapid growth responses to soil location and fire severity effects on soils. In contrast, the less pyrophilic species had lower germination rates that were not responsive to soil treatments. This suggests that rapid germination and growth constitute adaptations to frequent fires and that plants respond differently to fire severity effects on soil abiotic factors and microbes. Furthermore, variable plant responses to postfire soils may influence plant community diversity and fire-fuel feedbacks in pyrophilic ecosystems.

Neural activity during negative self-evaluation is associated with negative self-concept and depressive symptoms in adolescent girls.

Self-concept becomes reliant on social comparison, potentially leading to excessive self-focused attention, persistently negative self-concept and increased risk for depression during early adolescence. Studies have implicated neural activation in cortical midline brain structures in self-related information processing, yet it remains unclear how this activation may underlie subjective self-concept and links to depression in adolescence. We examined these associations by assessing neural activity during negative vs. positive self-referential processing in 39 11-to-13-year-old girls. During a functional neuroimaging task, girls reported on their perceptions of self-concept by rating how true they believed positive and negative personality traits were about them. Girls reported on depressive symptoms at the scan and 6 months later. Activation in the dorsomedial and ventrolateral prefrontal cortexes (dMPFC; VLPFC), and visual association area was significantly associated with subjective self-concept and/or depressive symptoms at the scan or 6 months later. Exploratory models showed higher activation in the dMPFC to Self-negative > Self-positive was indirectly associated with concurrent depressive symptoms through more negative self-concept. Higher activation in the visual association area to Self-positive > Self-negative was associated with lower depressive symptoms at follow-up through more positive self-concept. Findings highlight how differential neural processing of negative versus positive self-relevant information maps onto perceptions of self-concept and adolescent depression.

Subgenual Anterior Cingulate Cortex Reactivity to Rejection Vs. Acceptance Predicts Depressive Symptoms among Adolescents with an Anxiety History.

OBJECTIVE: The goal of this study was to examine whether neural sensitivity to negative peer evaluation conveys risk for depression among youth with a history of anxiety. We hypothesized that brain activation in regions that process affective salience in response to rejection, relative to acceptance, from virtual peers would predict depressive symptoms 1 year later and would be associated with ecological momentary assessment (EMA) reports of peer connectedness. METHOD: Participants were 38 adolescents ages 11-16 (50% female) with a history of anxiety, recruited from a previous clinical trial. The study was a prospective naturalistic follow-up of depressive symptoms assessed 2 years (Wave 2) and 3 years (Wave 3) following treatment. At Wave 2, participants completed the Chatroom Interact Task during neuroimaging and 16 days of EMA. RESULTS: Controlling for depressive and anxiety symptoms at Wave 2, subgenual anterior cingulate (sgACC; ß = .39, p = .010) activation to peer rejection (vs. acceptance) predicted depressive symptoms at Wave 3. SgACC activation to rejection (vs. acceptance) was highly negatively correlated with EMA reports of connectedness with peers in daily life (r = - .71, p < .001). CONCLUSION: Findings suggest that elevated sgACC activation to negative, relative to positive, peer evaluation may serve as a risk factor for depressive symptoms among youth with a history of anxiety, perhaps by promoting vigilance or reactivity to social evaluative threats. SgACC activation to simulated peer evaluation appears to have implications for understanding how adolescents experience their daily social environments in ways that could contribute to depressive symptoms.

Tendon Transfer for Correction of the Radial Deviation Deformity of the Wrist and Centralization in Posterior Interosseous Nerve Palsy.

There are very few descriptions of tendon transfers designed specifically to address the reconstruction of posterior interosseous nerve palsy (PINP). Unlike a radial nerve palsy (RNP), a patient with a PINP is able to extend their wrist but in radial deviation, because of the preserved innervation of the extensor carpi radialis longus (ECRL). Tendon transfers to restore finger and thumb extension in PINP have been extrapolated from tendon transfers to restore these functions in RNP, specifically using flexor carpi radialis, not flexor carpi ulnaris, so as not to further exacerbate the distinctive radial deviation deformity of the wrist. However, the standard pronator teres to extensor carpi radialis brevis transfer for a RNP fails to address or correct the radial deviation deformity in PINP. We present a simple tendon transfer specifically to address this radial deviation deformity in a PINP, by performing a side-to-side tenorrhaphy of the ECRL tendon to the extensor carpi radialis brevis tendon, followed by transection of the ECRL insertion onto the base of the index finger metacarpal distal to the tenorrhaphy. This technique converts a functioning ECRL from a radially deforming force, transferring its vector of pull onto the base of the middle finger metacarpal and so producing centralization of wrist extension in axial alignment with the forearm.

At What Time Interval After a Sharp Nerve Laceration Is Primary Nerve Repair No Longer Possible?

PURPOSE: The timeframe after a sharp nerve injury when nerve grafting becomes required remains unclear. A retrospective analysis was performed to determine the timeframe when primary repair of a sharp nerve laceration can no longer be performed and grafting becomes necessary. METHODS: All sharp nerve injuries in three regions of the hands and upper extremity-major nerves, common digital nerves, and proper digital nerves-treated between 2016 and 2021 were reviewed. Time from injury to repair, need for nerve grafting, length of graft, age, and associated injuries were collected and analyzed. RESULTS: A total of 313 nerve lacerations were included. Predictors of the need for grafting included time from injury to repair and level of injury. The odds ratio of time from injury in predicting the need for grafting was 1.04 for proper digital nerves, 1.05 for common digital nerves, and 1.18 for major nerves. Age and other injuries were not associated with increased rates of grafting. Only level of injury was associated with length of graft needed. CONCLUSIONS: Patients with sharp major nerve injuries required grafting more frequently after several days from injury, whereas primary repair of common and proper digital nerves could be achieved up to two weeks or greater after injury. This suggests that the window for primary neurorrhaphy may be as short as two days after injury for major nerve injuries, much shorter than for common and proper digital nerve injuries. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Outcomes of Distal Radius Fractures in Solid Organ Transplant Recipients.

PURPOSE: Distal radius fractures (DRFs) are one of the most common conditions that musculoskeletal providers treat. As the frequency of solid organ transplants (SOT) increases, these providers are often called upon to manage DRFs in these patients. These patients are at increased risk for osteopenia and osteoporosis, given the altered bone metabolism after SOT and frequent use of glucocorticoid and immunosuppressive medications. This study aimed to examine both surgical and nonsurgical treatment outcomes of DRFs in the SOT population and the prevalence of decreased bone mineral density. METHODS: A retrospective review of patients treated at a single institution who had previously undergone SOT and subsequently sustained DRF between 2013 and 2022 was completed. Patients were excluded for incomplete documentation and treatment initiation at an outside institution. Demographic variables, clinical outcomes, organ transplant, steroid use, and second metacarpal cortical percentage were collected for both groups. A telephone survey with the QuickDASH questionnaire was conducted for all available patients. RESULTS: A total of 34 DRFs in 33 patients were included in the analysis. Of these, 15 fractures in 14 patients underwent surgical intervention, and 19 fractures in 19 patients were managed nonsurgically. The following three adverse events were observed in the patients managed operatively: hardware failure, postoperative carpal tunnel syndrome, and tendon irritation. No reported treatment complications were recorded in the patients managed nonsurgically. Of the 33 included patients, 32 had radiographic evidence of decreased bone mineral density and five were receiving treatment for osteoporosis. CONCLUSIONS: Management of DRFs in SOT patients is challenging, given their increased medical complexity. Decreased bone mineral density was nearly universal and undertreated in this patient population. Most of these patients in both groups had good or excellent functional outcomes with both surgical and nonsurgical management. Additionally, surgery was well tolerated with no reported anesthesia complications, wound-healing issues, or infections. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Incidence and Risk Factors of Venous Thromboembolism in Childhood Acute Lymphoblastic Leukaemia - a Population-Based Analysis of the Austrian Berlin-Frankfurt-Münster (BFM) Study Group.

Venous thromboembolism (VTE) is a well-known complication of the treatment of pediatric acute lymphoblastic leukemia (ALL). We analyzed 1026 ALL patients 1-18-years-old, who were enrolled into the AIEOP-BFM ALL 2000 or 2009 studies in Austria, with regard to the incidence and risk factors of VTE. The 2.5-year cumulative incidence (CI) of VTE ≥ grade 2 was 4%±1% (n = 36/1026). Twenty VTE (56%) were found in the central nervous system (19 cerebral venous sinus and 1 cortical vein thrombosis), and 16 (44%) at other sites (7 deep vein thromboses (DVT) of the lower extremity, 4 DVT of the upper extremity, 4 central venous line-thromboses, 1 pulmonary embolism). Most VTE occurred during induction and early consolidation therapy (81%) and were associated with L-asparaginase within 4 and corticosteroids withing 1 week(s) preceding the event (89 and 86%, respectively). In multivariable analysis, two independent risk factors were found. Patients 10-18-years-old had an increased (hazard-ratio: 2.156, p = 0.0389), whereas treatments in trial AIEOP-BFM ALL 2009 had a lower risk for VTE (hazard-ratio: 0.349, p = 0.0270). In conclusion, the 2.5-year CI of VTE among our pediatric patient cohort was <5% and adolescent age was the main patient-related risk factor. This older age group might benefit from primary prophylactic measures.

A Simplified Modification of the Henderson Extensor Carpi Ulnaris Opposition Transfer.

PURPOSE: There are several potential donor muscle-tendon units for a thumb opposition transfer. The extensor carpi ulnaris (ECU) is useful when the more usual donor units are not available. The technique and results of a simplified ECU opposition transfer elongated with a free tendon graft are described. METHODS: Ten ECU opposition transfers were performed using this modification of Henderson technique in 5 adults after complex trauma, 3 adults with median and ulnar nerve palsies, and 2 children with congenital hand differences. RESULTS: Seven patients achieved a Kapandji opposition score of 6 to the distal phalanx of the small finger, and 3 patients achieved a Kapandji score of 5 to the distal phalanx of the ring finger. None of the patients required a secondary tenolysis or developed a radial deviation imbalance of their wrist. CONCLUSIONS: This modification of the Henderson technique using ECU elongated with a free tendon graft and inserted directly and only into the abductor pollicis brevis tendon is an effective method of restoring opposition to the thumb, especially when other conventional donor muscle-tendon units are not available. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Dermatology and Skin Conditions for Hand Surgeons.

The hand surgeon must be familiar with all aspects of hand pathology, and while faced with dermatological pathology in daily practice, a comprehensive understanding of skin pathology is often lacking. Dermatological pathology may have an impact on the hand surgeon in multiple ways-before surgery (requiring optimization), after surgery, or by mimicking surgical pathology (whereby surgical management may be contraindicated). Adequate knowledge of the basics of dermatology allows for optimal patient care. This review article highlights the common (and the not so common) skin conditions that hand surgeons may encounter in their practice.

Tick-Borne Encephalitis Virus RNA Found in Frozen Goat's Milk in a Family Outbreak.

Tick-borne encephalitis (TBE) is one of the commonest arthropod-borne viral diseases in Middle-East Europe and North Asia. The main reservoir of the virus is comprised of small rodents and domestic mammals with the common tick (Ixodes) being the usual vector. The clinical spectrum of TBE ranges from mild meningitis to severe meningoencephalomyelitis. This disease can lead to severe sequelae and has a mortality up to 2% in Europe. Even though the majority of cases are transmitted through bites of infected ticks, infections through ingestion of contaminated milk and dairy products from farms in endemic areas have been reported. We report a family outbreak of a febrile disease, initially suggestive of human-to-human infection, during the early summertime in Austria. Tick-borne encephalitis was diagnosed following consumption of unpasteurised goat's milk and the virus was subsequently detected in frozen milk samples. Although this is a rare manifestation of TBE, this case series shows that TBE should be included in the differential diagnosis of an outbreak of febrile disease, and a careful clinical history with reference to unpasteurized dairy products is crucial in order to prevent further disease spread. The best preventive measure is active immunisation of people living in, or travelling to, endemic areas.

Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity.

BACKGROUND: Interferon (IFN) signalling pathways, a key element of the innate immune response, contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy, and are often deregulated in cancer. The deubiquitylating enzyme USP18 is a major negative regulator of the IFN signalling cascade and is the predominant human protease that cleaves ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo. METHODS: In this study, using advanced proteomic techniques, we have significantly expanded the USP18-dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line. USP18-dependent effects were explored further in CML and colorectal carcinoma cellular models. RESULTS: Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation. CONCLUSIONS: Our results provide strong evidence for USP18 in regulating antigenicity and radiosensitivity, highlighting its potential as a cancer target.

Emotional Interference in Early Adolescence: Positive Reinforcement Modulates the Behavioral and Neural Effects of Negative Emotional Distracters.

Limited research has examined functioning within fronto-limbic systems subserving the resistance to emotional interference in adolescence despite evidence indicating that alterations in these systems are implicated in the developmental trajectories of affective disorders. This study examined the functioning of fronto-limbic systems subserving emotional interference in early adolescence and whether positive reinforcement could modulate these systems to promote resistance to emotional distraction. Fifty healthy early adolescents (10-13 years old) completed an emotional delayed working memory (WM) paradigm in which no distractors (fixation crosshair) and emotional distracters (neutral and negative images) were presented with and without positive reinforcement for correct responses. WM accuracy decreased with negative distracters relative to neutral distracters and no distracters, and activation increased in amygdala and prefrontal cortical (PFC) regions (ventrolateral, dorsomedial, ventromedial, and subgenual anterior cingulate) with negative distracters compared with those with no distracters. Reinforcement improved performance and reduced activation in the amygdala, dorsomedial PFC, and ventrolateral PFC. Decreases in amygdala activation to negative distracters due to reinforcement mediated observed decreases in reaction times. These findings demonstrate that healthy adolescents recruit similar fronto-limbic systems subserving emotional interference as adults and that positive reinforcement can modulate fronto-limbic systems to promote resistance to emotional distraction.

Neural Responses to Social Reward Predict Depressive Symptoms in Adolescent Girls During the COVID-19 Pandemic.

OBJECTIVE: Adolescent depression is increasing during the COVID-19 pandemic, possibly related to dramatic social changes. Individual-level factors that contribute to social functioning, such as temperament and neural reactivity to social feedback, may confer risk for or resilience against depressive symptoms during the pandemic. METHODS: Ninety-three girls (12-17 years) oversampled for high shy/fearful temperament were recruited from a longitudinal study for a follow-up COVID-19 study. During the parent study (2016-2018), participants completed a functional magnetic resonance imaging task eliciting neural activity to performance-related social feedback. Depressive symptoms were assessed during the parent study and COVID-19 follow-up (April-May 2020). In 65 participants with complete data, we examined how interactions between temperament and neural activation to social reward or punishment in a socio-affective brain network predict depressive symptoms during COVID-19. RESULTS: Depressive symptoms increased during COVID-19. Significant interactions between temperament and caudate, putamen, and insula activation to social reward were found. Girls high in shy/fearful temperament showed negative associations between neural activation to social reward and COVID-19 depressive symptoms, whereas girls lower in shy/fearful temperament showed positive associations. CONCLUSIONS: Girls high in shy/fearful temperament with reduced neural activation to social reward may be less likely to engage socially, which could be detrimental during the pandemic when social interactions are limited. In contrast, girls lower in shy/fearful temperament with heightened neural reactivity to social reward may be highly motivated to engage socially, which could also be detrimental with limited social opportunities. In both cases, improving social connection during the pandemic may attenuate or prevent depressive symptoms.

Peer Connectedness and Pre-Existing Social Reward Processing Predicts U.S. Adolescent Girls' Suicidal Ideation During COVID-19.

There is major concern about the impact of the COVID-19 pandemic on adolescent suicidal ideation (SI) and peer relationships. We investigated (1) rates of SI and (2) the extent to which peer connectedness and pre-existing neural activation to social reward predicted SI during the initial stay-at-home orders of the pandemic (April-May 2020) in a longitudinal sample of adolescent girls (N = 93; Mage  = 15.06; 69% White non-Hispanic). Daily diary and fMRI methods were used to assess peer connectedness and neural activation to social reward, respectively. Nearly 40% of girls endorsed SI during the initial stay-at-home orders. Greater peer connectedness and neural responsivity to anticipated social reward were associated with a reduced odds of SI during the pandemic among girls.

The Role of International Traveling Fellowships in Training the Contemporary US Hand Surgeon.

Hand trauma has always been a common etiology treated by the hand surgeon. However, the amount of severe hand trauma in the United States has decreased as the safety of working environments have improved and the amount of heavy industry jobs has decreased. Largely because of this, the typical hand surgery trainee is now exposed relatively infrequently to pathologies such as brachial plexus injuries, replantation surgery, and upper-extremity reconstructive microsurgery. Our hand surgery colleagues in countries such as India and China have a different experience, though. This difference provides an opportunity for educational exchange through the form of well-structured international fellowships. The American Society for Surgery of the Hand International Traveling Fellowship is specifically designed to supplement the training of young US hand surgeons in brachial plexus surgery, replantation surgery, and reconstructive microsurgery by spending short but intensive periods at some of the premier institutions in China and India.

Distinct molecular response patterns of activating STAT3 mutations associate with penetrance of lymphoproliferation and autoimmunity.

Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.