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Therapeutic drug monitoring (TDM) is increasingly relevant for an individualized antibiotic therapy and subsequently a necessary tool to reduce multidrug-resistant pathogens, especially in light of diminishing antimicrobial capabilities. Critical illness is associated with profound pharmacokinetic and pharmacodynamic alterations, which challenge dose finding and the application of particularly hydrophilic drugs such as β-lactam antibiotics. Methods: Implementation strategy, potential benefit, and practicability of the developed standard operating procedures were retrospectively analyzed from January to December 2020. Furthermore, the efficacy of the proposed dosing target of piperacillin in critically ill patients was evaluated. Results: In total, 160 patients received piperacillin/tazobactam therapy and were subsequently included in the study. Of them, 114 patients received piperacillin/tazobactam by continuous infusion and had at least one measurement of piperacillin serum level according to the standard operating procedure. In total, 271 measurements were performed with an average level of 79.0 ± 46.0 mg/L. Seventy-one piperacillin levels exceeded 100 mg/L and six levels were lower than 22.5 mg/L. The high-level and the low-level group differed significantly in infection laboratory parameters (CRP (mg/dL) 20.18 ± 11.71 vs. 5.75 ± 5.33) and renal function [glomerular filtration rate (mL/min/1.75 m2) 40.85 ± 26.74 vs. 120.50 ± 70.48]. Conclusions: Piperacillin levels are unpredictable in critically ill patients. TDM during piperacillin/tazobactam therapy is highly recommended for all patients. Although our implementation strategy was effective, further strategies implemented into the daily clinical workflow might support the health care staff and increase the clinicians’ alertness.

Reduced Cl− conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca2+- and voltage-activated K+ channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia. Human and murine muscle specimens (wild-type and BK−/−) were exposed to anthracene-9-carboxylic acid (9-AC) to inhibit CLC-1 chloride channels and to induce myotonia in-vitro. Functional effects of BK-channel activation and blockade were investigated by exposing slow-twitch (soleus) and fast-twitch (extensor digitorum longus) murine muscle specimens or human musculus vastus lateralis to an activator (NS1608) and a blocker (Paxilline), respectively. Muscle-twitch force and relaxation times (T90/10) were monitored. Compared to wild type, fast-twitch muscle specimen of BK−/− mice resulted in a significantly decreased T90/10 in presence of 9-AC. Paxilline significantly shortened T90/10 of murine slow- and fast-twitch muscles as well as human vastus lateralis muscle. Moreover, twitch force was significantly reduced after application of Paxilline in myotonic muscle. NS1608 had opposite effects to Paxilline and aggravated the onset of myotonic activity by prolongation of T90/10. The currently used standard therapy for myotonia is, in some individuals, not very effective. This in vitro study demonstrated that a BK channel blocker lowers myotonic stiffness and thus highlights its potential therapeutic option in myotonia congenital (MC). [ABSTRACT FROM AUTHOR]

Manual palpation is a core skill in physical examination. Assessing elastic properties such as tissue stiffness has the potential for being an important diagnostics tool in the detection of cancer and other diseases. The study describes the newly developed Stiffness Comparison Test (SCT). The aim of our study was to test the SCT as a tool to detect interindividual differences in palpation skill related to gender, age and occupational experience. We used eight pairs of polyuterhane gel pads with the stiffness difference decreasing from the first to the last pair. Test subjects were asked to palpate each pair and determine stiffness differences. We recruited 25 osteopaths, 48 other manual therapists and 50 participants from other non-manual professions. As hypothesized there was no significant difference in SCT performance between the sexes (t (121) = 0.288, p =.774). To investigate if an age-related decline would have an effect on palpation skill, we carried out a linear regression. As hypothesized, the model did not predict any significant associations (F (1, 121) = 2.733, b = −0.149, p =.101, R2 = 0.022). To compare the effect of occupational groups on SCT performance a one-way ANOVA was conducted. There were no statistically significant differences between group means (F (2, 120) = 0.598, p =.552). The SCT can be used as simple and affordable tool for assessment, teaching and training in all disciplines of manual medicine. Further refinements of the tool are suggested to advance its discrimination power. [ABSTRACT FROM AUTHOR]

Aging is a one-way process associated with profound structural and functional changes in the organism. Indeed, the neuromuscular system undergoes a wide remodeling, which involves muscles, fascia, and the central and peripheral nervous systems. As a result, intrinsic features of tissues, as well as their functional and structural coupling, are affected and a decline in overall physical performance occurs. Evidence from the scientific literature demonstrates that senescence is associated with increased stiffness and reduced elasticity of fascia, as well as loss of skeletal muscle mass, strength, and regenerative potential. The interaction between muscular and fascial structures is also weakened. As for the nervous system, aging leads to motor cortex atrophy, reduced motor cortical excitability, and plasticity, thus leading to accumulation of denervated muscle fibers. As a result, the magnitude of force generated by the neuromuscular apparatus, its transmission along the myofascial chain, joint mobility, and movement coordination are impaired. In this review, we summarize the evidence about the deleterious effect of aging on skeletal muscle, fascial tissue, and the nervous system. In particular, we address the structural and functional changes occurring within and between these tissues and discuss the effect of inflammation in aging. From the clinical perspective, this article outlines promising approaches for analyzing the composition and the viscoelastic properties of skeletal muscle, such as ultrasonography and elastography, which could be applied for a better understanding of musculoskeletal modifications occurring with aging. Moreover, we describe the use of tissue manipulation techniques, such as massage, traction, mobilization as well as acupuncture, dry needling, and nerve block, to enhance fascial repair. [ABSTRACT FROM AUTHOR]

Key points: During myotonia congenita, reduced chloride (Cl−) conductance results in impaired muscle relaxation and increased muscle stiffness after forceful voluntary contraction.Repetitive contraction of myotonic muscle decreases or even abolishes myotonic muscle stiffness, a phenomenon called 'warm up'.Pharmacological inhibition of low Cl− channels by anthracene‐9‐carboxylic acid in muscle from mice and ADR ('arrested development of righting response') muscle from mice showed a relaxation deficit under physiological conditions compared to wild‐type muscle.At increased osmolarity up to 400 mosmol L–1, the relaxation deficit of myotonic muscle almost reached that of control muscle.These effects were mediated by the cation and anion cotransporter, NKCC1, and anti‐myotonic effects of hypertonicity were at least partly antagonized by the application of bumetanide. Low chloride‐conductance myotonia is caused by mutations in the skeletal muscle chloride (Cl−) channel gene type 1 (CLCN1). Reduced Cl− conductance of the mutated channels results in impaired muscle relaxation and increased muscle stiffness after forceful voluntary contraction. Exercise decreases muscle stiffness, a phenomena called 'warm up'. To gain further insight into the patho‐mechanism of impaired muscle stiffness and the warm‐up phenomenon, we characterized the effects of increased osmolarity on myotonic function. Functional force and membrane potential measurements were performed on muscle specimens of ADR ('arrested development of righting response') mice (an animal model for low gCl– conductance myotonia) and pharmacologically‐induced myotonia. Specimens were exposed to solutions of increasing osmolarity at the same time as force and membrane potentials were monitored. In the second set of experiments, ADR muscle and pharmacologically‐induced myotonic muscle were exposed to an antagonist of NKCC1. Upon osmotic stress, ADR muscle was depolarized to a lesser extent than control wild‐type muscle. High osmolarity diminished myotonia and facilitated the warm‐up phenomenon as depicted by a faster muscle relaxation time (T90/10). Osmotic stress primarily resulted in the activation of the NKCC1. The inhibition of NKCC1 with bumetanide prevented the depolarization and reversed the anti‐myotonic effect of high osmolarity. Increased osmolarity decreased signs of myotonia and facilitated the warm‐up phenomenon in different in vitro models of myotonia. Activation of NKCC1 activity promotes warm‐up and reduces the number of contractions required to achieve normal relaxation kinetics. Key points: During myotonia congenita, reduced chloride (Cl−) conductance results in impaired muscle relaxation and increased muscle stiffness after forceful voluntary contraction.Repetitive contraction of myotonic muscle decreases or even abolishes myotonic muscle stiffness, a phenomenon called 'warm up'.Pharmacological inhibition of low Cl− channels by anthracene‐9‐carboxylic acid in muscle from mice and ADR ('arrested development of righting response') muscle from mice showed a relaxation deficit under physiological conditions compared to wild‐type muscle.At increased osmolarity up to 400 mosmol L–1, the relaxation deficit of myotonic muscle almost reached that of control muscle.These effects were mediated by the cation and anion cotransporter, NKCC1, and anti‐myotonic effects of hypertonicity were at least partly antagonized by the application of bumetanide. [ABSTRACT FROM AUTHOR]