Pace of Aging in older adults matters for healthspan and lifespan.

As societies age, policy makers need tools to understand how demographic aging will affect population health and to develop programs to increase healthspan. The current metrics used for policy analysis do not distinguish differences caused by early-life factors, such as prenatal care and nutrition, from those caused by ongoing changes in people's bodies due to aging. Here we introduce an adapted Pace of Aging method designed to quantify differences between individuals and populations in the speed of aging-related health declines. The adapted Pace of Aging method, implemented in data from N=13,626 older adults in the US Health and Retirement Study, integrates longitudinal data on blood biomarkers, physical measurements, and functional tests. It reveals stark differences in rates of aging between population subgroups and demonstrates strong and consistent prospective associations with incident morbidity, disability, and mortality. Pace of Aging can advance the population science of healthy longevity.

Patients' experiences of a suppoRted self-manAGeMent pAThway In breast Cancer (PRAGMATIC): quality of life and service use results.

PURPOSE: To describe trends and explore factors associated with quality of life (QoL) and psychological morbidity and assess breast cancer (BC) health service use over a 12-month period for patients joining the supported self-management (SSM)/patient-initiated follow-up (PIFU) pathway. METHODS: Participants completed questionnaires at baseline, 3, 6, 9 and 12 months that measured QoL (FACT-B, EQ 5D-5L), self-efficacy (GSE), psychological morbidity (GHQ-12), roles and responsibilities (PRRS) and service use (cost diary). RESULTS: 99/110 patients completed all timepoints; 32% (35/110) had received chemotherapy. The chemotherapy group had poorer QoL; FACT-B total score mean differences were 8.53 (95% CI: 3.42 to 13.64), 5.38 (95% CI: 0.17 to 10.58) and 8.00 (95% CI: 2.76 to 13.24) at 6, 9 and 12 months, respectively. The odds of psychological morbidity (GHQ12 >4) were 5.5-fold greater for those treated with chemotherapy. Financial and caring burdens (PRRS) were worse for this group (mean difference in change at 9 months 3.25 (95% CI: 0.42 to 6.07)). GSE and GHQ-12 scores impacted FACT-B total scores, indicating QoL decline for those with high baseline psychological morbidity. Chemotherapy patients or those with high psychological morbidity or were unable to carry out normal activities had the highest service costs. Over the 12 months, 68.2% participants phoned/emailed breast care nurses, and 53.3% visited a hospital breast clinician. CONCLUSION: The data suggest that chemotherapy patients and/or those with heightened psychological morbidity might benefit from closer monitoring and/or supportive interventions whilst on the SSM/PIFU pathway. Reduced access due to COVID-19 could have affected service use.

Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial.

The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1-3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5-7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11-13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14-16 and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18-20.

Bite or brain: Implication of sensorimotor regulation and neuroplasticity in oral rehabilitation procedures.

Tooth loss, decreased mass and strength of the masticatory muscles leading to difficulty in chewing have been suggested as important determinants of eating and nutrition in the elderly. To compensate for the loss of teeth, in particular, a majority of the elderly rely on dental prosthesis for chewing. Chewing function is indeed an important aspect of oral health, and therefore, oral rehabilitation procedures should aim to restore or maintain adequate function. However, even if the possibilities to anatomically restore lost teeth and occlusion have never been better; conventional rehabilitation procedures may still fail to optimally restore oral functions. Perhaps this is due to the lack of focus on the importance of the brain in the rehabilitation procedures. Therefore, the aim of this narrative review was to discuss the importance of maintaining or restoring optimum chewing function in the superageing population and to summarise the emerging studies on oral motor task performance and measures of cortical neuroplasticity induced by systematic training paradigms in healthy participants. Further, brain imaging studies in patients undergoing or undergone oral rehabilitation procedures will be discussed. Overall, this information is believed to enhance the understanding and develop better rehabilitative strategies to exploit training-induced cortical neuroplasticity in individuals affected by impaired oral motor coordination and function. Training or relearning of oral motor tasks could be important to optimise masticatory performance in dental prosthesis users and may represent a much-needed paradigm shift in the approach to oral rehabilitation procedures.

Reliability of surface electromyography measurements from the suprahyoid muscle complex.

Assessment of swallowing musculature using motor evoked potentials (MEPs) can be used to evaluate neural pathways. However, recording of the swallowing musculature is often invasive, uncomfortable and unrealistic in normal clinical practice. To investigate the possibility of using the suprahyoid muscle complex (SMC) using surface electromyography (sEMG) to assess changes to neural pathways by determining the reliability of measurements in healthy participants over days. Seventeen healthy participants were recruited. Measurements were performed twice with one week between sessions. Single-pulse (at 120% and 140% of the resting motor threshold (rMT)) and paired-pulse (2 ms and 15 ms paired pulse) transcranial magnetic stimulation (TMS) were used to elicit MEPs in the SMC which were recorded using sEMG. ≈50% of participants (range: 42-58%; depending on stimulus type/intensity) had significantly different MEP values between day 1 and day 2 for single-pulse and paired-pulse TMS. A large stimulus artefact resulted in MEP responses that could not be assessed in four participants. The assessment of the SMC using sEMG following TMS was poorly reliable for ≈50% of participants. Although using sEMG to assess swallowing musculature function is easier to perform clinically and more comfortable to patients than invasive measures, as the measurement of muscle activity using TMS is unreliable, the use of sEMG for this muscle group is not recommended and requires further research and development.

Effect of transcranial direct current stimulation on neuroplasticity in corticomotor pathways of the tongue muscles.

The aim of this study is to investigate effects of transcranial direct current stimulation (tDCS) on neuroplasticity in corticomotor pathways related to tongue muscles evoked by a training task using the tongue drive system (TDS). Using a crossover design, 13 healthy participants completed two sessions of tDCS while performing 30 min of TDS training. Sessions were spaced at least 2 weeks apart and participants randomly received anodal and sham tDCS stimulation in the first session and the other condition in the second session. Single and paired pulse transcranial magnetic stimulation was used to elicit motor evoked potentials (MEPs) of the tongue at three time-points: before, immediately after and 30 min after training. Participant-based reports of fun, pain, fatigue and motivation, level of difficulty and effort were evaluated on numerical rating scales. There was no consistent significant effect of anodal and sham stimulation on single or paired pulse stimulation MEP amplitude immediately or 30 min after TDS training. Irrespective of tDCS type, training with TDS induced cortical plasticity in terms of increased MEP amplitudes for higher stimulus intensities after 30 min compared with before and immediately after training. Participant-based reports revealed no significant difference between tDCS conditions for level of fun, fatigue, motivation, difficulty and level of effort but a significant increase in pain in the anodal condition, although pain level was low for both conditions. In conclusion, tongue MEP amplitudes appear to be sensitive to training with the tongue using TDS; however, anodal tDCS does not have an impact on training-evoked neuroplasticity of tongue corticomotor pathways.

Bilateral sensory deprivation of trigeminal afferent fibres on corticomotor control of human tongue musculature: a preliminary study.

Transcranial magnetic stimulation (TMS) has demonstrated changes in motor evoked potentials (MEPs) in human limb muscles following modulation of sensory afferent inputs. The aim of this study was to determine whether bilateral local anaesthesia (LA) of the lingual nerve affects the excitability of the tongue motor cortex (MI) as measured by TMS. The effect on MEPs after bilateral LA of the lingual nerve was studied, while the first dorsal interosseous (FDI) muscle served as a control in ten healthy participants. MEPs were measured on the right side of the tongue dorsum in four different conditions: (i) immediately prior to anaesthesia (baseline), (ii) during bilateral LA block of the lingual nerve, (iii) after anaesthesia had subjectively subsided (recovery) and (iv) 3 h after bilateral lingual block injection. MEPs were assessed using stimulus-response curves in steps of 10% of motor threshold (T). Eight stimuli were given at each stimulus level. The amplitudes of the tongue MEPs were significantly influenced by the stimulus intensity (P < 0·001) but not by condition (P = 0·186). However, post hoc tests showed that MEPS were statistically significantly higher during bilateral LA block condition compared with baseline at T + 40%, T + 50% and T + 60% (P < 0·028) and also compared with recovery at T + 60% (P = 0·010) as well as at 3 h after injection at T + 50% and T + 60% (P < 0·029). Bilateral LA block of the lingual nerve seems to be associated with a facilitation of the corticomotor pathways related to the tongue musculature.

Training-induced cortical plasticity compared between three tongue-training paradigms.

The primary aim of this study was to investigate the effect of different training types and secondary to test gender differences on the training-related cortical plasticity induced by three different tongue-training paradigms: (1) therapeutic tongue exercises (TTE), (2) playing computer games with the tongue using the Tongue Drive System (TDS) and (3) tongue-protrusion task (TPT). Forty-eight participants were randomized into three groups with 1h of TTE, TDS, or TPT. Stimulus-response curves of motor evoked potentials (MEPs) and motor cortex mapping for tongue muscles and first dorsal interosseous (FDI) (control) were established using transcranial magnetic stimulation at three time-points: (1) before tongue-training, (2) immediately after training, (3) 1h after training. Subject-based reports of motivation, fun, pain and fatigue were evaluated on 0-10 numerical rating scales after training. The resting motor thresholds of tongue MEPs were lowered by training with TDS and TPT (P<0.011) but not by TTE (P=0.167). Tongue MEP amplitudes increased after training with TDS and TPT (P<0.030) but not with TTE (P=0.302). Men had higher MEPs than women in the TDS group (P<0.045) at all time-points. No significant effect of tongue-training on FDI MEPs was observed (P>0.335). The tongue cortical motor map areas were not significantly increased by training (P>0.142). Training with TDS was most motivating and fun (P<0.001) and TTE was rated the most painful (P<0.001). Fatigue level was not different between groups (P>0.071). These findings suggest a differential effect of tongue-training paradigms on training-induced cortical plasticity and subject-based scores of fun, motivation and pain in healthy participants.

Coronoidectomy, masticatory myotomy and buccal fat pad graft in management of advanced oral submucous fibrosis.

The purpose of this study is to evaluate coronoidectomy, masticatory myotomy and buccal fat pad graft in advanced (Stage III-IV) oral sub mucous fibrosis (OSF). 10 patients with clinically and histologically confirmed advanced OSF underwent surgery entailing bilateral coronoidectomy, masticatory muscle myotomy and closure with a pedicled buccal fat pad graft followed by vigorous mouth opening exercises. The result was evaluated using the interincisal distance at maximum mouth opening as the objective outcome measure over a follow up period of 12 months. Results showed a mean interincisal opening of 14.7 mm preoperatively and 32.5 mm at 12 months postoperatively. Relapse was encountered in one patient who did not cooperate with the postoperative exercise regime. Results suggest this regime is effective.

Scope and limitations of therapies: a neomillennial epistemological evaluation for helping medical practices.

Medical practice is in crisis - the sophistications are enormous and expensive, and the outcomes leave much to be desired. An epistemologic evaluation that weighs the scope and limitations of any -pathy or any procedure seems to be the need of the day. As an example, described herein is the logic of such an exercise; and a sample of the exercise itself, taking cancer as an example.

Maternal uniparental disomy of chromosome 4 in a patient with limb-girdle muscular dystrophy 2E confirmed by SNP array technology.

The limb-girdle muscular dystrophies (LGMDs) are a heterogenous group of diseases characterized by shoulder-girdle and pelvic muscle weakness and wasting. LGMD 2E is an autosomal recessively inherited form of the disease caused by mutations in the ß-sarcoglycan (SGCB) gene located at 4q12. In this report, we describe a patient who demonstrates non-Mendelian inheritance of a homozygous missense mutation in SGCB resulting in disease expression. A combination of single-nucleotide polymorphism (SNP) array technology and microsatellite analysis revealed the occurrence of maternal uniparental disomy (UPD) for chromosome 4 in the patient. As a consequence of segmental isodisomy at 4q12, the patient inherited two identical SGCB alleles carrying a missense mutation predicted to result in abnormal protein function. SNP array technology proved to be an elegant means to determine the most probable mechanism of UPD formation in this case, and enabled us to determine the location of recombination events along chromosome 4. In our patient, UPD likely arose from a trisomy rescue event due to maternal meiotic non-disjunction that we speculate may have been caused by abnormal recombination at the pericentromeric region. Maternal UPD 4 is a rare finding, and to our knowledge this is the first reported case of UPD in association with LGMD.

Sentinel lymph node biopsy after previous axillary surgery: A review.

BACKGROUND: The utility of axillary lymph node dissection (ALND) in the management of breast cancer is currently under close scrutiny. At primary diagnosis the use of sentinel lymph node biopsy (SLNB) has restricted ALND for proven nodal disease, however the management of the axilla at local (in-breast) relapse is less clearly defined with many undergoing routine ALND. This review examines the role of SLNB in the re-operative setting with the objective of developing an axillary management algorithm for use at in-breast local relapse, and restricting ALND to node-positive recurrent cancers. METHODS: We reviewed published reports of SLNB at local relapse in women who had previously undergone axillary surgery either as lymph node biopsy, SLNB, axillary sampling (AS) or axillary lymph node dissection (ALND). RESULTS: There have been no randomised trials. Six reports with 327 cases were identified; of which 61% (199/327) had previous SLNB or ALND with <9 nodes removed. There was an overall successful sentinel lymph node (SLN) localisation at re-operation of 69% (227/327), range of 51-100%. In patients who have previously had limited axillary surgery (<9 nodes removed), the rate of successful SLN localisation was 83% (165/199), range of 68-100% and 142/165 (86%, range 80-100%) were node negative. In these highly selected patients no axillary recurrences were noted in those who had a negative SLN at re-operation after 26-46 months follow up. CONCLUSION: SLNB at in-breast relapse is feasible and safe with successful localisation related to the extent of previous axillary surgery.

Influence of the ability to roll the tongue and tongue-training parameters on oral motor performance and learning.

OBJECTIVE: Training of tongue function is an important part of rehabilitation of patients with brain damage. A standardized tongue-training task has been shown to induce cortical plasticity. This study tested the possible influence of the natural ability to roll the tongue and modulations of tongue-training parameters on tongue-training performance. DESIGN: A total of 44 healthy adult subjects participated. 29 subjects (15 with and 14 without ability to roll their tongue) performed 1h standard tongue-training task. Another 15 subjects participated in 2 sessions: Standard and Modulation in randomized order. Standard session: 1h tongue-training with fixed training parameters; Modulation session: 1h tongue-training with modulation of training parameters every 20 min (3 different settings - A, B, C, with different timing of task). Perceived task difficulty was evaluated on a 0-10 numerical rating scale (NRS). RESULTS: All participants improved performance during training (P<0.001). The ability to roll the tongue did not influence tongue-training performance (P=0.617). Modulation of training parameters influenced baseline training performance (P<0.018) and improvement (P=0.039). The mean perceived difficulty on NRS was: Standard: 6 ± 2; Modulation: A: 6 ± 2; B: 7 ± 1;C: 4 ± 1. Perceived task difficulty (ρ=-0.740, P<0.001) and performance improvement (ρ=-0.610, P<0.001) were inversely correlated with baseline training performance. CONCLUSION: The natural ability to roll the tongue did not influence tongue-training performance. Modulation of tongue-training parameters by alteration of timing of the training task influenced tongue-training performance and perceived task difficulty.

New palpometer with implications for assessment of deep pain sensitivity.

The aims of this study were to compare test-retest variability and accuracy measures between (1) manual palpation and a novel palpometer and (2) different force levels. Sixteen clinicians were instructed to target 0.5, 1.0, and 2.0 kg on a force meter using manual palpation and the new palpometer (adjustable spring-coil with a small pin touching the examiner's hand when the correct pressure is reached). In all experiments, 10 consecutive measures of the force levels were recorded. The coefficient of variation (CV), actual force levels, and relative differences between target level and actual force level were compared between experiments and target levels. All outcome parameters had significantly lower values for the new palpometer than for manual palpation in a force-dependent manner (p<0.004). CVs and actual force levels were significantly different between all target levels (p<0.004). The new palpometer had low test-retest variability and provides a more accurate pressure stimulus than manual palpation.

Elevated B6 levels and peripheral neuropathies.

Polyneuropathy related to decreased levels of Vitamin B6 are well known. In contrast, the association between elevated levels of pyridoxine and neuropathy is not well described. This study is a retrospective review of patients in our neuromuscular clinic that were found to have elevated B6 levels. Twenty-six patients were found to have elevated serum B6 levels. The mean B6 level was 68.8 ng/ml. Twenty patients (76.9%) reported daily vitamin use. Twenty-one patients (80.8%) reported only sensory complaints. The most common symptoms reported were numbness (96%), burning pain (49.9%), tingling (57.7%), balance difficulties (30.7%), and weakness (7.8%). Nine (out of 26) had an abnormal EMG/NCS. Eight patients had an abnormal quantitative sensory study. We conclude that elevated pyridoxine levels should be considered in the differential diagnosis of any sensory or sensorimotor polyneuropathy.

Nitrous oxide induced sub-acute combined degeneration of spinal cord: a case report.

We report a patient who developed signs and symptoms of a myelopathy after exposure to nitrous oxide. Magnetic Resonance Imaging of the cervical spinal cord disclosed hyperintensities of the dorsal columns on T2 weighted images suggesting sub-acute combined degeneration.

False positive rate of thoracic outlet syndrome diagnostic maneuvers.

OBJECTIVE: In this study, we aim to determine the false-positive rate & specificity in normal subjects and carpal tunnel syndrome (CTS) patients of five provocative maneuvers used to diagnose thoracic outlet syndrome (TOS). DESIGN/METHODS: We prospectively evaluated subjects with clinical and electrophysiological evidence of CTS as well as normal subjects. All subjects underwent provocative testing by a blinded physician, which included the Adson A & B tests, Costoclavicular maneuver (CCM), Elevated arm stress test (Roos), and Supraclavicular pressure (SCP). RESULTS: In the CTS group, false positive tests were observed in 42% in the Adson A test, 45% in the Adson B test, 48% in the CCM, 77% in the Roos test, and 61% in the SCP 94% of the CTS patients had at least 1 positive TOS diagnostic maneuver. In the normal group, false positive tests were observed in 9% in the Adson A test, 20% in the Adson B test, 16% in the CCM, 47% in the Roos test, and 30% in the SCP 56% of the normal patients had at least 1 positive TOS diagnostic maneuver. CONCLUSIONS: We conclude that current provocative maneuvers used to diagnose TOS result in a high false-positive rate in normal subjects and an even higher false-positive rate in CTS patients.

Clinical and electrophysiological presentation of pronator syndrome.

Median neuropathy at the elbow (pronator syndrome [PS]) is rare compared to compression at the wrist. We sought to evaluate the clinical/electrophysiological parameters of this focal neuropathy. Between 1992 and 2002, we retrospectively reviewed records of eighty-three limbs in seventy-two patients with PS. Electrodiagnostic data as well as clinical symptoms, physical findings, demographic information and treatment modalities were examined. The main symptoms were forearm pain, numbness and weakness. One patient (two limbs) had nocturnal paresthesias. Twenty-five limbs (30%) showed decreased median forearm velocity. Fifty-four (65%) had abnormal median sensory studies of either abnormal conduction velocity or amplitude. Needle exam showed an abnormality of at least one median innervated muscle, abductor pollicis brevis, flexor carpi radialis, or pronator teres, in 70% (58/83). Sixteen limbs were identified as having undergone surgical decompression. In the surgical group, 10/16 (63%) were found to have constriction with a band which was released during surgery. Eight of the sixteen patients who underwent surgery were found to have documented improvement. Eleven patients (13%) had undergone previous surgery for Carpal Tunnel Syndrome (CTS) without benefit. The clinical and electrophysiological features of PS are quite different from patients with CTS. Proper localization is crucial to treatment options. Surgery can provide benefit in selected cases.