Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel-Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study.

PURPOSE: PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. METHODS: Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. RESULTS: Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean -4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). CONCLUSION: Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

Control of landing under conditions of height-induced threat.

PURPOSE: Landing involves a tuned anticipatory control to allow for soft and safe contact with the ground. Fearful situations are known to affect postural control strategies during standing, but it is still unclear how fear interferes with the control of a voluntary dynamic task requiring coordination between posture and movement. METHODS: Ground reaction forces, limb movements, physiological arousal, and perceived levels of confidence and fear of falling were recorded when hopping off a box to a platform situated 0.8 m above ground and 3.2 m above ground. RESULTS: Height induced a perceived threat as arousal was augmented by the elevated surface for all subjects. Threat induced by height modifies the way participants land, leading to a stiffer landing, as evidenced by an increased loading rate at touchdown during high threat conditions. Greater psychological and physiological changes are associated with greater changes in the control of landing: individuals that are less confident/more fearful appear to compensate for this stiffer landing, by slowing down their landing. CONCLUSION: Threatening conditions induces a harder contact to the ground, but the strategy is dependent of the level of confidence/fear. Less confident/more fearful participants are more focused on coping strategy and adopt a more cautious behaviour.

Quantitative lymph node burden as a 'very-high-risk' factor identifying head and neck cancer patients benefiting from postoperative chemoradiation.

Background: Adjuvant chemoradiation (CRT) is standard for head and neck squamous cell carcinoma (HNSCC) patients with positive margins or extranodal extension (ENE) following surgery. However, emerging evidence suggests the number of positive lymph nodes (LNs) is the dominant determinant of survival in non-oropharyngeal HNSCC and thus may better identify those benefiting from treatment intensification. Patients and methods: Patients from the National Cancer Database diagnosed with non-oropharyngeal HNSCC (oral cavity, larynx, hypopharynx) between 2004 and 2014 and undergoing surgical resection, neck dissection, and postoperative radiotherapy (RT) were included. Multivariable regression with first-order interaction terms was used to model the interaction between postoperative CRT and continuous number of positive LNs with respect to overall survival. Results: In total, 7144 patients met inclusion criteria. In multivariable analysis, increasing number of positive LNs was associated with both increasing mortality (P < 0.001) and increasing benefit from postoperative CRT versus RT alone (interaction P < 0.001). While there was no benefit from postoperative CRT in patients with 0-2 LN+ [hazard ratio (HR) 0.96, 95% confidence interval (CI) 0.86-1.07, P = 0.47], increased benefit was seen in those with 3-5 LN+ (HR 0.84, 95% CI 0.70-1.00, P = 0.05) and those with ≥6 LN+ (HR 0.65, 95% CI 0.51-0.82, P < 0.001) in multivariable models. By contrast, margin status and ENE did not reliably identify patients benefitting from postoperative CRT based on statistical tests of interaction. Even in patients with ENE, positive margins, or both, only those with ≥6 LN+ had improved survival with postoperative CRT. Conclusion: Increasing metastatic nodal burden was associated with increased benefit from CRT compared with RT alone, surpassing conventional high-risk factors in identifying patients benefiting from CRT. Stratification by metastatic LN number may characterize a very-high-risk patient cohort best suited for treatment intensification.

Utilizing Physiological Principles of Motor Unit Recruitment to Reduce Fatigability of Electrically-Evoked Contractions: A Narrative Review.

Neuromuscular electrical stimulation (NMES) is used to produce contractions to restore movement and reduce secondary complications for individuals experiencing motor impairment. NMES is conventionally delivered through a single pair of electrodes over a muscle belly or nerve trunk using short pulse durations and frequencies between 20 and 40Hz (conventional NMES). Unfortunately, the benefits and widespread use of conventional NMES are limited by contraction fatigability, which is in large part because of the nonphysiological way that contractions are generated. This review provides a summary of approaches designed to reduce fatigability during NMES, by using physiological principles that help minimize fatigability of voluntary contractions. First, relevant principles of the recruitment and discharge of motor units (MUs) inherent to voluntary contractions and conventional NMES are introduced, and the main mechanisms of fatigability for each contraction type are briefly discussed. A variety of NMES approaches are then described that were designed to reduce fatigability by generating contractions that more closely mimic voluntary contractions. These approaches include altering stimulation parameters, to recruit MUs in their physiological order, and stimulating through multiple electrodes, to reduce MU discharge rates. Although each approach has unique advantages and disadvantages, approaches that minimize MU discharge rates hold the most promise for imminent translation into rehabilitation practice. The way that NMES is currently delivered limits its utility as a rehabilitative tool. Reducing fatigability by delivering NMES in ways that better mimic voluntary contractions holds promise for optimizing the benefits and widespread use of NMES-based programs.

Report From the American Society of Transplantation Conference on Donor Heart Selection in Adult Cardiac Transplantation in the United States.

Cardiac transplantation remains the only definitive treatment for end-stage heart failure. Transplantation rates are limited by a shortage of donor hearts. This shortage is magnified because many hearts are discarded because of strict selection criteria and concern for regulatory reprimand for less-than-optimal posttransplant outcomes. There is no standardized approach to donor selection despite proposals to liberalize acceptance criteria. A donor heart selection conference was organized to facilitate discussion and generate ideas for future research. The event was attended by 66 participants from 41 centers with considerable experience in cardiac donor selection. There were state-of-the-art presentations on donor selection, with subsequent breakout sessions on standardizing the process and increasing utilization of donor hearts. Participants debated misconceptions and established agreement on donor and recipient risk factors for donor selection and identified the components necessary for a future donor risk score. Ideas for future initiatives include modification of regulatory practices to consider extended criteria donors when evaluating outcomes and prospective studies aimed at identifying the factors leading to nonacceptance of available donor hearts. With agreement on the most important donor and recipient risk factors, it is anticipated that a consistent approach to donor selection will improve rates of heart transplantation.

Report from a forum on US heart allocation policy.

Since the latest revision in US heart allocation policy (2006), the landscape and volume of transplant waitlists have changed considerably. Advances in mechanical circulatory support (MCS) prolong survival, but Status 1A mortality remains high. Several patient subgroups may be disadvantaged by current listing criteria and geographical disparity remains in waitlist time. This forum on US heart allocation policy was organized to discuss these issues and highlight concepts for consideration in the policy development process. A 25-question survey on heart allocation policy was conducted. Among attendees/respondents were 84 participants with clinical/published experience in heart transplant representing 51 US transplant centers, and OPTN/UNOS and SRTR representatives. The survey results and forum discussions demonstrated very strong interest in change to a further-tiered system, accounting for disadvantaged subgroups and lowering use of exceptions. However, a heart allocation score is not yet viable due to the long-term viability of variables (used in the score) in an ever-developing field. There is strong interest in more refined prioritization of patients with MCS complications, highly sensitized patients and those with severe arrhythmias or restrictive physiology. There is also strong interest in distribution by geographic boundaries modified according to population. Differences of opinion exist between small and large centers.

Substance use and mental health factors associated with self-reported higher risk cannabis use among people with HIV screened in primary care.

Background: While cannabis use is prevalent among people with HIV (PWH), factors associated with higher-risk use require further study. We examined factors associated with indicators risk for cannabis use disorder (CUD) among PWH who used cannabis. Methods: Participants included adult (≥18 years old) PWH from 3 HIV primary care clinics in Kaiser Permanente Northern California who reported past three-month cannabis use through the computerized Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS) screening. Primary outcome was TAPS cannabis score (range 1-3), categorized as any use (1) and higher risk for CUD (≥2). Measures included sociodemographics (age, sex, race, neighborhood deprivation index [NDI]), Charlson Comorbidity Index (CCI), HIV RNA, CD4 cell counts, higher risk tobacco use (TAPS tobacco score≥2), depression, and anxiety symptoms. Unadjusted and multivariable logistic regression examined factors associated with higher risk for CUD. Results: Of the complete sample (N=978; 94.1% Male; 58.3% White; Age Mode=51-60), 35.8% reported higher risk for CUD. Unadjusted models indicated younger age, Black race, higher CCI, depression, anxiety, and higher risk tobacco use were associated with higher risk, while only Black race (OR=1.84, 95% CI[1.29, 2.63]), anxiety (OR=1.91, 95% CI[1.22, 2.98]), and higher risk tobacco use (OR=2.27, 95% CI[1.47, 3.51]) remained significant in the multivariable model. Conclusions: Black race, anxiety and tobacco use, but not HIV clinical markers, were associated with higher risk for CUD among PWH. Clinical efforts to screen and provide interventions for preventing CUD alongside anxiety and tobacco use among PWH should be evaluated.

Phase-diverse Fresnel coherent diffractive imaging of malaria parasite-infected red blood cells in the water window.

Phase-diverse Fresnel coherent diffractive imaging has been shown to reveal the structure and composition of biological specimens with high sensitivity at nanoscale resolution. However, the method has yet to be applied using X-ray illumination with energy in the so-called 'water-window' that lies between the carbon and oxygen K edges. In this range, differences in the strength of the X-ray interaction for protein based biological materials and water is increased. Here we demonstrate a proof-of-principle application of FCDI at an X-ray energy within the water-window to a dehydrated cellular sample composed of red blood cells infected with the trophozoite stage of the malaria parasite, Plasmodium falciparum. Comparison of the results to both optical and electron microscopy shows that the correlative imaging methods that include water-window FCDI will find utility in studying cellular architecture.

Haemangioma: clinical course, complications and management.

Despite their high incidence, most infantile haemangiomas (IH) do not require treatment as they regress spontaneously and most do not leave significant sequelae. For the subset of haemangiomas that require treatment, indications for intervention can be divided into three main categories: ulceration, disfigurement and impairment of function or vital structures. In addition, certain IH have a risk of associated structural anomalies. Given the wide heterogeneity of haemangiomas, deciding which haemangiomas need intervention and when to intervene requires a detailed knowledge of natural history and clinical indicators of increased risk.

The evolving role of biologics in the treatment of pediatric psoriasis.

The exact role of biologics in the treatment of pediatric psoriasis remains undefined but is evolving. Biologics are an attractive option for use in children in part because they offer more convenient dosing regimens and less frequent laboratory monitoring than traditional systemic agents. Further, because their action is targeted, they theoretically lack many of the potential end-organ toxicities of traditional agents. However, compared to adult psoriasis populations, there is a relative lack of long-term safety data specific to the pediatric psoriasis population. Thus, the clear advantages of using biologic agents must be balanced with a measure of caution. This article will provide a summary of the cumulative pediatric safety and efficacy data for the anti-tumor necrosis factor-alpha (TNF-α) agents and interleukin (IL)-12 and IL-23 (IL12/23) pathway inhibitor and suggestions for a rational clinical approach to their use in children with psoriasis.

Prevalence and characteristics of gastroesophageal reflux disease in pregnant women.

INTRODUCTION AND AIMS: The prevalence of gastroesophageal reflux disease (GERD) has been reported to be increasing in recent years. However, there have been few reports on the prevalence of GERD during pregnancy in the Asian population. The aim of our study was to evaluate the prevalence and characteristics of GERD in Vietnamese pregnant women. MATERIALS AND METHODS: This cross-sectional study was conducted at the antenatal clinic of the Nhan Dan Gia Dinh Hospital, Ho Chi Minh, Vietnam. Four hundred females, at various stages of pregnancy, were enrolled. GERD was diagnosed if there was troublesome heartburn and/or acid regurgitation, at least once a week, during the current pregnancy. RESULTS: The overall prevalence of GERD in pregnancy was 38.5% (154/400). The prevalence of GERD in the third trimester was significantly higher than that in the second trimester (46.8% vs. 30.7%, P=0.008) and tended to be higher than its prevalence in the first trimester (46.8% vs. 35.4%, P=0.051). In the pregnant women with GERD, the frequency of regurgitation was significantly higher than that of heartburn (92.9% vs. 30.5%, P<0.001). Those typical symptoms were more prevalent in the daytime, compared with nighttime. CONCLUSION: Our study showed that GERD was prevalent during pregnancy in Vietnam. In the pregnant women with GERD, regurgitation was much more common than heartburn, and those typical reflux symptoms occurred more frequently in the daytime, compared with nighttime.

Higher severity grade of erlotinib-induced rash is associated with lower skin phototype.

BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) are associated with a characteristic papulopustular rash, an adverse event considered to be a class effect of these agents. Erlotinib, a small-molecule EGFRI, causes a papulopustular rash in 68-75% of patients. The limited reported data suggest that deleterious effects of ultraviolet radiation (UVR) may enhance the development of EGFRI-induced rash. Because the level of the biological pigment melanin correlates with increased protection against UVR, we hypothesized that lighter levels of skin pigmentation are associated with greater severity of rash. AIM: To characterize the relationship between skin phototype (SPT) and rash severity. METHODS: A retrospective chart review was conducted of 40 patients on erlotinib. Skin sensitivity to UVR was categorized using the Fitzpatrick SPT classification scheme. Grading of rash was performed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3. RESULTS: There was an inverse relationship between SPT and rash severity. Grade 0 was seen in the majority of patients with SPT V/VI, grade 1/2 in the majority of patients with SPT III/IV, and grade 3/4 rash in the majority of patients with SPT I/II (grade 0: 7% SPT I/II, 32% SPT III/IV and 50% SPT IV/V; grade 1/2: 33%, 63% and 50%, respectively; grade 3/4: 60%, 5% and 0%, respectively) (P < 0.01, Fisher exact test). CONCLUSIONS: Prevention and management of cutaneous side-effects from EGFR inhibitors is important to achieve maximum patient compliance and therapeutic benefit. The results of this study suggest that SPT may be an independent predictive factor for EGFRI-induced papulopustular rash, thus pre-therapy counselling and early intervention are important.

Glycation induction and antiglycation activity of skin care ingredients on living human skin explants.

Glycation is an ageing reaction of naturally occurring sugars with dermal proteins, whose clinical signs may appear in vivo around age 30, and increases steadily/regularly with age. The suppleness of the dermis is affected by the formation of bridges between proteins and sugars (Maillard's reaction). The residues formed (Amadori products, Advanced Glycation End products) as well as the proteins they alter, can be visualized by specific immunostainings. Induced in a few days on living skin explants by methylglyoxal, glycation can be prevented by the application of aminoguanidine HCl, the reference anti-glycation molecule. This model enabled to highlight the anti-glycation activity of substances of vegetal origin such as puerarin and chlorogenic acid.

Decreased excitability of motor axons contributes substantially to contraction fatigability during neuromuscular electrical stimulation.

The present study was designed to (i) determine the time course of changes in motor axon excitability during and after neuromuscular electrical stimulation (NMES); and (ii) characterize the relationship between contraction fatigability, NMES frequency, and changes at the axon, neuromuscular junction, and muscle. Eight neurologically intact participants attended 3 sessions. NMES was delivered over the common peroneal nerve at 20, 40, or 60 Hz for 8 min (0.3 s "on", 0.7 s "off"). Threshold tracking was used to measure changes in axonal excitability. Supramaximal stimuli were used to assess neuromuscular transmission and force-generating capacity of the tibialis anterior muscle. Torque decreased by 49% and 62% during 8 min of 40 and 60 Hz NMES, respectively. Maximal twitch torque decreased only during 60 Hz NMES. Motor axon excitability decreased by 14%, 27%, and 35% during 20, 40, and 60 Hz NMES, respectively. Excitability recovered to baseline immediately (20 Hz) and at 2 min (40 Hz) and 4 min (60 Hz) following NMES. Overall, decreases in axonal excitability best predicted how torque declined over 8 min of NMES. During NMES, motor axons become less excitable and motor units "drop out" of the contraction, contributing substantially to contraction fatigability and its dependence on NMES frequency. Novelty: The excitability of motor axons decreased during NMES in a frequency-dependent manner. As excitability decreased, axons failed to reach threshold and motor units dropped out of the contraction. Overall, decreased excitability best predicted how torque declined and thus is a key contributor to fatigability during NMES.

Mathematical models to describe the growth curves of Vietnamese Ri chicken.

Ri chicken is the most popular backyard chicken breed in Vietnam, but little is known about the growth curve of this breed. This study compared the performances of models with three parameters (Gompertz, Brody, and Logistic) and models containing four parameters (Richards, Bridges, and Janoschek) for describing the growth of Ri chicken. The bodyweight of Ri chicken was recorded weekly from week 1 to week 19. Growth models were fitted using minpack.lm package in R software and Akaike's information criterion (AIC), Bayesian information criterion (BIC), and root mean square error (RMSE) were used for model comparison. Based on these criteria, the models having four parameters showed better performance than the ones with three parameters, and the Richards model was the best one for males and females. The lowest and highest value of asymmetric weights (α) were obtained by Bridges and Brody models for each of sexes, respectively. Age and weight estimated by the Richard model were 8.46 and 7.51 weeks and 696.88 and 487.58 g for males and for females, respectively. Differences in the growth curves were observed between males and female chicken. Overall, the results suggested using the Richards model for describing the growth curve of Ri chickens. Further studies on the genetics and genomics of the obtained growth parameters are required before using them for the genetic improvement of Ri chickens.

The influence of postural threat on strategy selection in a stepping-down paradigm.

To walk safely in their environment, people need to select adequate movement strategies during gait. In situations that are perceived as more threatening, older adults adopt more cautious strategies. For individuals with excessive fear, selecting adequate strategies might be troubling. We investigated how a postural threat affects the selection of strategies within and between older adults by using a stepping-down paradigm. In twenty-four older adults we determined the height at which they switched in stepping-down strategies from a less demanding but more balance threatening heel landing to a more demanding yet safer toe landing. We expected that this switching height would be lower in the high (0.78 m elevation) compared to low threat (floor level) condition. Furthermore, we investigated if older adults, for which the postural threat evoked an increase in the perceived fear, presented a different stepping down strategy due to the postural threat. Our results indicated that the postural threat changed older adults' strategies selection towards a more conservative toe landing. Hence, despite the additional effort, older adults prefer more cautious strategies during a postural threat. No effects of perceived fear on strategy selection between individuals were observed, potentially due to relatively small differences in fear among participants.