Chronic Pain Following Fracture-Related Surgery: Posttraumatic Rather Than Postsurgical Origin Promotes Chronification-A Prospective Observational Study With 1-Year Follow-up.

BACKGROUND: Chronic posttraumatic/postsurgical pain (CPSP) is common after traumatic or surgical damage. Exposure to both trauma and surgery, with the potential for repeated bone and nerve damage, may increase the risk of CPSP after fracture-related surgery. But the (long-term) incidences of CPSP and neuropathic CPSP and the ensuing burdens are unknown. Therefore, the patients were prospectively assessed within 1 year, and the patient-specific characteristics were explored. METHODS: Between 2017 and 2018, 127 patients (age: 52.9 ± 17.1 years, male: 55.1%) with traumatic fractures needing osteosynthesis (extremities: 91.3%) were assessed posttrauma (before surgery), postsurgery at days 1 to 5, 6 weeks, 3 and 12 months. The primary outcomes are as follows: incidence at 3 and 12 months of CPSP (defined as pain intensity on a numerical rating scale [NRS: 0-10] ≥3), secondary exploration: neuropathic CPSP (NRS ≥3 and Douleur Neuropathique 4 interview [DN4i] score ≥3 [Douleur Neuropathique interview: 0-7]); burden: quality of life (QoL, the EuroQOL five dimensions questionnaire [EQ-5D-3L] descriptive system); and inter alia, the number of analgesics (trial registration: DRKS00011601). RESULTS: The incidence of CPSP was 57.1% (52/91, n/N) at 3 and 42.7% (35/82) at 12 months postsurgery, including neuropathic CPSP 7.7% (4/52) and 17.1% (6/35), respectively. Descriptively, posttraumatic higher pain intensity at rest (difference of 0.9 ± 1.8 NRS) and the need for more frequent analgesics (by 34.3%) were associated with CPSP a year after surgery compared to those without. As soon as week 6, these patients had developed descriptively a 15% more impaired QoL, with 25% more impairment after 1 year. The patients with CPSP presented with at least 1 neuropathic symptom 12 months later in 68.6% (24/35) of cases, mainly with an early posttraumatic occurrence (without fulfilling the definition of neuropathic CPSP). CONCLUSIONS: After early fracture-related surgery, high incidences of CPSP (43%) were prospectively observed 1 year postsurgery, up to approximately 1 in 5 patients who had neuropathic CPSP. At the same time, CPSP was accompanied with an impacted QoL and analgesic dependence, both indicating clinical relevance. Moreover, the high incidence and the early posttraumatic occurrence of more intense pain suggest that the initial fracture-related trauma, rather than the surgical trauma, may predominantly trigger CPSP at Y1 (1 year). Therefore, these exploratory results set the direction of required future research. A future clinical hypothesis might be: treat first what hurts first.

Incidence, Time Course and Influence on Quality of Life of Intensive Care Unit-Acquired Weakness Symptoms in Long-Term Intensive Care Survivors.

PURPOSE: Intensive care unit-acquired weakness (ICUAW) can manifest as muscle weakness or neuropathy-like symptoms, with diagnosis remaining a challenge. Uncertainties surround the long-term cause and sequelae. Therefore, the purpose was to assess incidence, time course and long-term influence on quality of life (QoL) of symptoms in ICU survivors. METHODS: After ethical approval and registration (www.drks.de: DRKS00011593), in a single-center cohort study all patients admitted to the ICU in 2007-2017 in a German university hospital were screened. Out of 1,860 patients (≥7d ICU care including ventilation support for ≥72 h, at least 6mo-10y after ICU) 636 were deceased, 912 survivors were contacted. RESULTS: 149 former patients (age: 63.5 ± 13.1y; males: 73%; duration in ICU: 20.8 ± 15.7d; duration of ventilation: 16.5 ± 13.7 h; time post-ICU: 4.4 ± 2.7y, 5-10y: 43%) consented to be interviewed concerning occurrence, duration, recovery and consequences of ICUAW-associated muscle weakness or neuropathy-like symptoms after ICU. In 75% at least 1 persistent or previous symmetrical symptom was reported (myopathy-like muscle weakness: 43%; neuropathy-like symptoms: 13%; both: 44%) and rated as incidence of ICUAW. However, only 18% of participants had received an ICUAW diagnosis by their physicians, although 62% had persistent symptoms up to 10y after ICU (5-10y: 46%). Only 37% of participants reported a complete recovery of symptoms, significantly associated with an initially low number of symptoms after ICU (p < 0.0001), myopathy-like symptoms (p = 0.024), and younger age at the time of ICU admission (55.7 ± 13.1 vs. 62.6 ± 10.6y, p < 0.001). ICUAW still impaired the QoL at the time of the interview in 74% of affected survivors, with 30% reporting severe impairment. CONCLUSION: ICUAW symptoms were disturbingly common in the majority of long-term survivors, indicating that symptoms persist up to 10y and frequently impair QoL. However, only a small number of patients had been diagnosed with ICUAW. Trial registry: Deutsches Register Klinischer Studien (DRKS), https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011593, registration number: DRKS00011593.

Measuring the immune system: a comprehensive approach for the analysis of immune functions in humans.

The immune system is essential to provide protection from infections and cancer. Disturbances in immune function can therefore directly affect the health of the affected individual. Many extrinsic and intrinsic factors such as exposure to chemicals, stress, nutrition and age have been reported to influence the immune system. These influences can affect various components of the immune system, and we are just beginning to understand the causalities of these changes. To investigate such disturbances, it is therefore essential to analyze the different components of the immune system in a comprehensive fashion. Here, we demonstrate such an approach which provides information about total number of leukocytes, detailed quantitative and qualitative changes in the composition of lymphocyte subsets, cytokine levels in serum and functional properties of T cells, NK cells and monocytes. Using samples from a cohort of 24 healthy volunteers, we demonstrate the feasibility of our approach to detect changes in immune functions.

Pupillometric Monitoring of Nociception in Cardiac Anesthesia.

BACKGROUND: High-dose opioids are conventionally used for cardiac anesthesia, but without monitoring of nociception. In non-cardiac surgical procedures the intra - operative dose of opioids can be individualized and reduced with pupillometric monitoring of the pupillary pain index (PPI; scale 1-9). A randomized controlled trial was carried out to explore whether pupillometry can be used for nociception monitoring in cardiac anesthesia and whether it leads to opioid reduction. METHODS: A sample of 57 cardiac surgery patients receiving continuously administered sufentanil (initial dosage 0.7 µg*kg-¹*h-¹) was divided into a PPI group (sufentanil reduction if PPI<3 up to a minimum of 0.15 µg*kg-¹*h-¹, n=32) and a control group (standard anesthesia; n = 25). The primary outcome was the time from the end of anesthesia to extubation. The secondary outcomes were total intraoperative dose of sufentanil/noradrenaline, postoperative pain intensity (numeric rating scale [NRS] 0-10) and intraoperative awareness. German Clinical Trials Registry no. DRKS 00012329. RESULTS: The primary outcome, extubation time, did not differ between the two groups (1.14 h, 95% confidence interval [-0.99; 3.27], p = 0.592). Compared with the control patients (68% male, age 70 ± 10.4 years, PPI 1.1 ± 0.2), the mean sufentanil infusion rate in the PPI patients (81% male, age 68 ± 10.3 years, PPI 1.1 ± 0.2) decreased by 81.8% (-0.68 µg*kg-¹*h-¹ [-0,7; -0.67], p<0.001) to the predetermined minimum level, without intraoperative awareness. Moreover, the noradrenaline dose was reduced by 56% (1235.51 µg [321.91; 2149.12], p = 0.005) and the postoperative pain intensity by 45% (2.11 NRS [0.93; 3.3] after 24 h, p = 0.003). CONCLUSION: Pupillometry is appropriate for nociception monitoring in cardiac anesthesia. Thereby a considerable reduction of intraoperative opioids as well as increased intraoperative hemodynamic stability was achieved and postoperative opioid-induced hyperalgesia was prevented. The consistently low PPI scores, indicating adequate analgesia, suggest that further reduction of opioid doses is feasible.

Correction: Hybrid Adeno-Associated Viral Vectors Utilizing Transposase-Mediated Somatic Integration for Stable Transgene Expression in Human Cells.

[This corrects the article DOI: 10.1371/journal.pone.0076771.].

Impact of chronic and acute academic stress on lymphocyte subsets and monocyte function.

This study investigated the effects of a temporally confined naturalistic stressor (academic stress) on immune functions. Furthermore, moderating influences of a number of psychological variables were assessed. Five blood samples were obtained from 20 students during an observation period of 8 weeks, starting 4.5 weeks before an exam period up to 1 week following the last exam. The analysis of 45 immune parameters revealed several time-dependent changes attributable to examination stress. We observed a reduction in the absolute numbers of natural killer (NK) cells and monocytes in peripheral blood and a shift towards more immature and naïve cells within NK and T cell populations. In addition, IL-6 and TNF-α production by LPS-stimulated monocytes was increased. Psychological variables were grouped by means of factor analyses into two factors. One factor, which was interpreted as an indication of chronic stress, moderated the relationships between academic stress and percentages of mature CD57+ NK cells. This chronic stress factor was also associated with an increase in memory and a decrease in naïve CD8 T cells and increased serum levels of IL-17. The present study identifies important potential psychological mediators of stress-induced changes in specific immunological parameters.

Hybrid adeno-associated viral vectors utilizing transposase-mediated somatic integration for stable transgene expression in human cells.

Recombinant adeno-associated viral (AAV) vectors have been shown to be one of the most promising vectors for therapeutic gene delivery because they can induce efficient and long-term transduction in non-dividing cells with negligible side-effects. However, as AAV vectors mostly remain episomal, vector genomes and transgene expression are lost in dividing cells. Therefore, to stably transduce cells, we developed a novel AAV/transposase hybrid-vector. To facilitate SB-mediated transposition from the rAAV genome, we established a system in which one AAV vector contains the transposon with the gene of interest and the second vector delivers the hyperactive Sleeping Beauty (SB) transposase SB100X. Human cells were infected with the AAV-transposon vector and the transposase was provided in trans either by transient and stable plasmid transfection or by AAV vector transduction. We found that groups which received the hyperactive transposase SB100X showed significantly increased colony forming numbers indicating enhanced integration efficiencies. Furthermore, we found that transgene copy numbers in transduced cells were dose-dependent and that predominantly SB transposase-mediated transposition contributed to stabilization of the transgene. Based on a plasmid rescue strategy and a linear-amplification mediated PCR (LAM-PCR) protocol we analysed the SB100X-mediated integration profile after transposition from the AAV vector. A total of 1840 integration events were identified which revealed a close to random integration profile. In summary, we show for the first time that AAV vectors can serve as template for SB transposase mediated somatic integration. We developed the first prototype of this hybrid-vector system which with further improvements may be explored for treatment of diseases which originate from rapidly dividing cells.