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تناول الكتاب حيث يقول الكاتب أنني أعمل مع الناس على تحسين نغمة أصواتهم منذ 30 عامًا، وكمتخصصة علاج كلام ولغة، أستخدم التعليم والمهارات التي طورتها خلال عملي السريري، وأطبقها في التعامل مع الاحتياجات الأكثر حساسية في عالم الأعمال والحياة المهنية، وفيما يقدم آخرون تمارين للتحدث أمام جمهور، أو علاج الكلام، أو مهارات المسرح، أتبع طريقة شاملة تساعد الناس على التعامل مع أية مخاوف يمكن أن تكون لديهم إزاء الانطباع الذي يتركونه بطريقتهم في التواصل، سواء أكان هذا التواصل لفظيًّا أو غير لفظي، والسبب في نجاح هذه الطريقة هو أن الجسد والصوت والكلمات يجب أن تعبر جميعا بشكل عام عن الشيء نفسه في الوقت نفسه، حتى يبدو المتكلم مهنيًّا وذا مصداقية وجذابا، لقد وجدت أن في طريقة كلام كل إنسان تقريبا جانبًا يشعر إزاءه بعدم الثقة، أو يعلق عليه الآخرون، ويأتي الناس إلى مكتبي منفعلين، ويسألون دوما : \"هل يمكنني أن أغير صوتي؟\"، ويكون ردي، \"بالطبع تستطيع ؛ إذا اتبعت التعليمات والتمارين\"، وفي هذا الكتاب، عرضت كل الشكاوى الشائعة التي رأيتها في التواصل، إلى جانب بعض التمارين التي استخدمتها بنجاح مع آلاف من عملائي على مدار سنوات.

Objectives To describe the incidence and extent of lying on the floor for a long time after being unable to get up from a fall among people aged over 90; to explore their use of call alarm systems in these circumstances.Design 1 year follow-up of participants in a prospective cohort study of ageing, using fall calendars, phone calls, and visits.Setting Participants’ usual place of residence (own homes or care homes), mostly in Cambridge.Participants 90 women and 20 men aged over 90 (n=110), surviving participants of the Cambridge City over-75s Cohort, a population based sample.Main outcome measures Inability to get up without help, lying on floor for a long time after falling, associated factors; availability and use of call alarm systems; participants’ views on using call alarms to summon help if needed after falling.Results In one year’s intensive follow-up, 54% (144/265) of fall reports described the participant as being found on the floor and 82% (217/265) of falls occurred when the person was alone. Of the 60% who fell, 80% (53/66) were unable to get up after at least one fall and 30% (20/66) had lain on the floor for an hour or more. Difficulty in getting up was consistently associated with age, reported mobility, and severe cognitive impairment. Cognition was the only characteristic that predicted lying on the floor for a long time. Lying on the floor for a long time was strongly associated with serious injuries, admission to hospital, and subsequent moves into long term care. Call alarms were widely available but were not used in most cases of falls that led to lying on the floor for a long time. Comments from older people and carers showed the complexity of issues around the use of call alarms, including perceptions of irrelevance, concerns about independence, and practical difficulties.Conclusions Lying on the floor for a long time after falling is more common among the “oldest old” than previously thought and is associated with serious consequences. Factors indicating higher risk and comments from participants suggest practical implications. People need training in strategies to get up from the floor. Work is needed on access and activation issues for design of call alarms and information for their effective use. Care providers need better understanding of the perceptions of older people to provide acceptable support services.

Peripheral nerve injuries arising from trauma or disease can lead to sensory and motor deficits and neuropathic pain. Despite the purported ability of the peripheral nerve to self-repair, lifelong disability is common. New molecular and cellular insights have begun to reveal why the peripheral nerve has limited repair capacity. The peripheral nerve is primarily comprised of axons and Schwann cells, the supporting glial cells that produce myelin to facilitate the rapid conduction of electrical impulses. Schwann cells are required for successful nerve regeneration; they partially “de-differentiate” in response to injury, re-initiating the expression of developmental genes that support nerve repair. However, Schwann cell dysfunction, which occurs in chronic nerve injury, disease, and aging, limits their capacity to support endogenous repair, worsening patient outcomes. Cell replacement-based therapeutic approaches using exogenous Schwann cells could be curative, but not all Schwann cells have a “repair” phenotype, defined as the ability to promote axonal growth, maintain a proliferative phenotype, and remyelinate axons. Two cell replacement strategies are being championed for peripheral nerve repair: prospective isolation of “repair” Schwann cells for autologous cell transplants, which is hampered by supply challenges, and directed differentiation of pluripotent stem cells or lineage conversion of accessible somatic cells to induced Schwann cells, with the potential of “unlimited” supply. All approaches require a solid understanding of the molecular mechanisms guiding Schwann cell development and the repair phenotype, which we review herein. Together these studies provide essential context for current efforts to design glial cell-based therapies for peripheral nerve regeneration.

Background Early identification of autism spectrum disorder (ASD) provides an opportunity for early intervention and improved developmental outcomes. The use of electroencephalography (EEG) in infancy has shown promise in predicting later ASD diagnoses and in identifying neural mechanisms underlying the disorder. Given the high co-morbidity with language impairment, we and others have speculated that infants who are later diagnosed with ASD have altered language learning, including phoneme discrimination. Phoneme learning occurs rapidly in infancy, so altered neural substrates during the first year of life may serve as early, accurate indicators of later autism diagnosis. Methods Using EEG data collected at two different ages during a passive phoneme task in infants with high familial risk for ASD, we compared the predictive accuracy of a combination of feature selection and machine learning models at 6 months (during native phoneme learning) and 12 months (after native phoneme learning), and we identified a single model with strong predictive accuracy (100%) for both ages. Samples at both ages were matched in size and diagnoses ( n = 14 with later ASD; n = 40 without ASD). Features included a combination of power and nonlinear measures across the 10‑20 montage electrodes and 6 frequency bands. Predictive features at each age were compared both by feature characteristics and EEG scalp location. Additional prediction analyses were performed on all EEGs collected at 12 months; this larger sample included 67 HR infants (27 HR-ASD, 40 HR-noASD). Results Using a combination of Pearson correlation feature selection and support vector machine classifier, 100% predictive diagnostic accuracy was observed at both 6 and 12 months. Predictive features differed between the models trained on 6- versus 12-month data. At 6 months, predictive features were biased to measures from central electrodes, power measures, and frequencies in the alpha range. At 12 months, predictive features were more distributed between power and nonlinear measures, and biased toward frequencies in the beta range. However, diagnosis prediction accuracy substantially decreased in the larger, more behaviorally heterogeneous 12-month sample. Conclusions These results demonstrate that speech processing EEG measures can facilitate earlier identification of ASD but emphasize the need for age-specific predictive models with large sample sizes to develop clinically relevant classification algorithms.

Tics are a common feature of early-onset neurodevelopmental disorders, characterized by involuntary and repetitive movements or sounds. Despite affecting up to 2% of children and having a genetic contribution, the underlying causes remain poorly understood. In this study, we leverage dense phenotype information to identify features (i.e., symptoms and comorbid diagnoses) of tic disorders within the context of a clinical biobank. Using de-identified electronic health records (EHRs), we identified individuals with tic disorder diagnosis codes. We performed a phenome-wide association study (PheWAS) to identify the EHR features enriched in tic cases versus controls ( n  = 1406 and 7030; respectively) and found highly comorbid neuropsychiatric phenotypes, including: obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, and anxiety ( p  < 7.396 × 10 −5 ). These features (among others) were then used to generate a phenotype risk score (PheRS) for tic disorder, which was applied across an independent set of 90,051 individuals. A gold standard set of tic disorder cases identified by an EHR algorithm and confirmed by clinician chart review was then used to validate the tic disorder PheRS; the tic disorder PheRS was significantly higher among clinician-validated tic cases versus non-cases ( p  = 4.787 × 10 −151 ; β  = 1.68; SE = 0.06). Our findings provide support for the use of large-scale medical databases to better understand phenotypically complex and underdiagnosed conditions, such as tic disorders.

Increasing longevity means more people will be dying in very old age, but little is known about the preferences of the 'oldest old' regarding their care at the end of life. To understand very old people's preferences regarding care towards the end of life and attitudes towards dying, to inform policy and practice. Qualitative data collection for n = 42 population-based cohort study participants aged 95-101 (88% women, 42% in long-term-care): topic-guided interviews with n = 33 participants and n = 39 proxy informants, most with both (n = 30: 4 jointly + separate interviews for 26 dyads). Death was a part of life: these very old people mainly live day-to-day. Most were ready to die, reflecting their concerns regarding quality of life, being a nuisance, having nothing to live for and having lived long enough. Contrasting views were rare exceptions but voiced firmly. Most were not worried about death itself, but concerned more about the dying process and impacts on those left behind; a peaceful and pain-free death was a common ideal. Attitudes ranged from not wanting to think about death, through accepting its inevitable approach to longing for its release. Preferring to be made comfortable rather than have life-saving treatment if seriously ill, and wishing to avoid hospital, were commonly expressed views. There was little or no future planning, some consciously choosing not to. Uncertainty hampered end-of-life planning even when death was expected soon. Some stressed circumstances, such as severe dependency and others' likely decision-making roles, would influence choices. Carers found these issues harder to raise but felt they would know their older relatives' preferences, usually palliative care, although we found two discrepant views. This study's rare data show ≥95-year-olds are willing to discuss dying and end-of-life care but seldom do. Formal documentation of wishes is extremely rare and may not be welcome. Although being \"ready to die\" and preferring a palliative approach predominated, these preferences cannot be assumed.

The UK has had universal free health care and public health programmes for more than six decades. Several policy initiatives and structural reforms of the health system have been undertaken. Health expenditure has increased substantially since 1990, albeit from relatively low levels compared with other countries. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to examine the patterns of health loss in the UK, the leading preventable risks that explain some of these patterns, and how UK outcomes compare with a set of comparable countries in the European Union and elsewhere in 1990 and 2010. We used results of GBD 2010 for 1990 and 2010 for the UK and 18 other comparator nations (the original 15 members of the European Union, Australia, Canada, Norway, and the USA; henceforth EU15+). We present analyses of trends and relative performance for mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE). We present results for 259 diseases and injuries and for 67 risk factors or clusters of risk factors relevant to the UK. We assessed the UK's rank for age-standardised YLLs and DALYs for their leading causes compared with EU15+ in 1990 and 2010. We estimated 95% uncertainty intervals (UIs) for all measures. For both mortality and disability, overall health has improved substantially in absolute terms in the UK from 1990 to 2010. Life expectancy in the UK increased by 4·2 years (95% UI 4·2–4·3) from 1990 to 2010. However, the UK performed significantly worse than the EU15+ for age-standardised death rates, age-standardised YLL rates, and life expectancy in 1990, and its relative position had worsened by 2010. Although in most age groups, there have been reductions in age-specific mortality, for men aged 30–34 years, mortality rates have hardly changed (reduction of 3·7%, 95% UI 2·7–4·9). In terms of premature mortality, worsening ranks are most notable for men and women aged 20–54 years. For all age groups, the contributions of Alzheimer's disease (increase of 137%, 16–277), cirrhosis (65%, −15 to 107), and drug use disorders (577%, 71–942) to premature mortality rose from 1990 to 2010. In 2010, compared with EU15+, the UK had significantly lower rates of age-standardised YLLs for road injury, diabetes, liver cancer, and chronic kidney disease, but significantly greater rates for ischaemic heart disease, chronic obstructive pulmonary disease, lower respiratory infections, breast cancer, other cardiovascular and circulatory disorders, oesophageal cancer, preterm birth complications, congenital anomalies, and aortic aneurysm. Because YLDs per person by age and sex have not changed substantially from 1990 to 2010 but age-specific mortality has been falling, the importance of chronic disability is rising. The major causes of YLDs in 2010 were mental and behavioural disorders (including substance abuse; 21·5% [95 UI 17·2–26·3] of YLDs), and musculoskeletal disorders (30·5% [25·5–35·7]). The leading risk factor in the UK was tobacco (11·8% [10·5–13·3] of DALYs), followed by increased blood pressure (9·0 % [7·5–10·5]), and high body-mass index (8·6% [7·4–9·8]). Diet and physical inactivity accounted for 14·3% (95% UI 12·8–15·9) of UK DALYs in 2010. The performance of the UK in terms of premature mortality is persistently and significantly below the mean of EU15+ and requires additional concerted action. Further progress in premature mortality from several major causes, such as cardiovascular diseases and cancers, will probably require improved public health, prevention, early intervention, and treatment activities. The growing burden of disability, particularly from mental disorders, substance use, musculoskeletal disorders, and falls deserves an integrated and strategic response. Bill & Melinda Gates Foundation.

Background Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R. Methods Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c.2350G > A (p.V784M) CSF1R variant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL. Results The newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to cultured primary human microglia and with higher scavenging and inflammatory competence at ~ threefold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 ( P2RY12 ) expression, a heightened capacity to internalize myelin, as well as heightened inflammatory response to Pam 3 CSK 4 . Poor P2RY12 expression was confirmed to be a consequence of CSF1R haploinsufficiency, as this feature was also observed following CSF1R knockdown or inhibition in mature control iMGL, and in CSF1R WT/KO and CSF1R WT/E633K iMGL compared to their respective isogenic controls. Conclusions We optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenic CSF1R variant, with preliminary characterization pointing toward functional alterations in migratory, phagocytic and inflammatory activities. Graphical Abstract

Unsustainable increases in the prevalence and costs of chronic disease in the United States call for low-cost, high-impact interventions that can be readily incorporated into people's daily lives. Culinary medicine is one such intervention. As a practical discipline, culinary medicine integrates the art of preparing, cooking, and presenting food with the science of medicine to achieve desired health outcomes. This article describes how the underpinnings and components of culinary medicine enhance existing nutrition interventions. Evidence of improved well-being and reduced resource utilization as the result of culinary medicine interventions is compiled for easy reference by health care organizations, medical professionals, people living with or at risk for chronic disease, food industry specialists, and payers in both the public and private sectors. Suggestions for individual and organizational implementation of culinary medicine strategies are offered with a proposed lexicon for continued development of the field.

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein 1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals. Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.