胫骨交锁髓内钉术后感染分析

目的：探讨胫腌骨骨折交锁髓内钉术后感染的预防与治疗方法。方法;对12例术后感染的病例进行回顾性分析。3例经过抗菌素治疗,9例经过闭式滴不引流加抗菌素治疗,结果;全部病例获随访,随访时间10个月－2年,感染控制,骨折愈合,结论：对胫骨交锁髓内钉术后感染的病人,不必急于取出内固定,采用闭式滴注引流加抗菌素治疗可获得满意效果。     

Efficacy and Safety of Apatinib in Patients with Recurrent or Refractory Melanoma

BackgroundThe prognosis of patients with metastatic malignant melanoma is very poor and partly due to resistance to conventional chemotherapies. The study’s objectives were to assess the activity and tolerability of apatinib, an oral small molecule anti-angiogenesis inhibitor, in patients with recurrent advanced melanoma.MethodsThis was a single-arm, single-center phase II trial. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Eligible patients had received at least one first-line therapy for advanced melanoma and experienced recurrence. Apatinib (500 mg) was orally administered daily.ResultsFifteen patients (V660E BRAF status: 2 mutation, 2 unknown, 11 wild type) were included in the analysis. The median PFS was 4.0 months. There were two major objective responses, for a 13.3% response rate. Eleven patients had stable disease, with a DCR of 86.7%. The median OS was 12.0 months. The most common treatment-related adverse events of any grade were hypertension (80.0%), mucositis oral (33.3%), hand-foot skin reaction (26.7%), and liver function abnormalities, hemorrhage, diarrhea (each 20%). The only grade ≥3 treatment-related adverse effects that occurred in 2 patients was hypertension (6.7%) and mucositis (6.7%). No treatment-related deaths occurred.ConclusionApatinib showed antitumor activity as a second- or above-line therapy in patients with malignant melanoma. The toxicity was manageable.ClinicalTrials.gov Identifier{"type":"clinical-trial","attrs":{"text":"NCT03383237","term_id":"NCT03383237"}}NCT03383237     

The Effect of Pore Structure on Impact Behavior of Concrete Hollow Brick,Autoclaved Aerated Concrete and Foamed Concrete

Porous concrete is an energy absorption material, which has been widely used in civil engineering, traffic engineering and disaster reduction engineering. However, the effect of pore structure on the impact behavior of the porous concrete is lacked. In this study, a series of drop-weight impact tests were carried out on three typical types of porous concrete, i.e., concrete hollow brick (CHB), autoclaved aerated concrete (AAC) and foamed concrete (FC), to investigate the effect of pore structures on their impact behavior. For comparison, static load tests were also conducted as references. According to the damage to the samples, the developments of impact force, strain, contact stress–strain relationship and absorbed energy during drop-weight during the impact test were measured and analyzed. The results show that the ratio between the peak impact stress and compressive strength of CHB was 0.44, while that of AAC and FC increased to about 0.6, indicating that the small and uniform pore structure in AAC and FC had a higher resistance against impact load than the hollow cavity of CHB. In addition, the elastic recovery strain in AAC increased by about 0.2% and its strain at peak contact stress increased by about 160% for a comparison of CHB, implying that a small open pore structure could enhance ductility. Besides, the peak contact stress of FC was close to that of AAC during impact loading, while the strain at peak contact stress of FC increased by about 36% compared with AAC, revealing that the closed-pore structure could further enhance the deformation potential. Correspondingly, the energy absorption rates of CHB, AAC and FC were 85.9 kJ/s, 54.4 kJ/s and 49.7 kJ/s, respectively, where AAC decreased by about 58% compared with CHB, and FC decreased by about 10% compared with AAC.     

Self-adaptive integration of photothermal and radiative cooling for continuous energy harvesting from the sun and outer space

The sun (∼6,000 K) and outer space (∼3 K) are two significant renewable thermodynamic resources for human beings on Earth. The solar thermal conversion by photothermal (PT) and harvesting the coldness of outer space by radiative cooling (RC) have already attracted tremendous interest. However, most of the PT and RC approaches are static and monofunctional, which can only provide heating or cooling respectively under sunlight or darkness. Herein, a spectrally self-adaptive absorber/emitter (SSA/E) with strong solar absorption and switchable emissivity within the atmospheric window (i.e., 8 to 13 μm) was developed for the dynamic combination of PT and RC, corresponding to continuously efficient energy harvesting from the sun and rejecting energy to the universe. The as-fabricated SSA/E not only can be heated to ∼170 °C above ambient temperature under sunshine but also be cooled to 20 °C below ambient temperature, and thermal modeling captures the high energy harvesting efficiency of the SSA/E, enabling new technological capabilities.

Heating and cooling are two kinds of significant end uses of thermal energy in society, which exist in various conditions (e.g., space/water heating, space cooling, and industrial processes) and account for 51% of the total final energy consumption (1). For example, the heating and cooling of buildings are responsible for nearly 48% of the building energy consumption, increasing to be the largest individual energy expense (2). Therefore, heat and cool harvesting relying on clean techniques from renewable energy resources has drawn remarkable attention from fields of engineering to material science because it has considerable potential for global energy conservation and greenhouse emission reduction. Thermodynamically, any heat transportation and work-generation process requires a temperature gradient. The hot sun (∼6,000 K) and cold outer space (∼3 K) are the ultimate heat source and heat sink for the Earth. Theoretical analysis reveals that maximal output work can be extracted from nonreciprocal systems based on the temperature difference between the sun and Earth (∼300 K) with an ultimate solar energy harvesting efficiency limit of 93.3%, while a maximal work of 153.1 W·m⁻² can also be obtained on the basis of temperature difference between the Earth and outer space (3, 4). Thus, the sun and outer space are two significant renewable thermodynamic resources for the Earth, which can be effectively utilized for clean heat and cool collection.Photothermal (PT) is a widely used solar thermal collection method that employs solar absorbers to capture solar photons and convert them to heat. Thermal analysis reveals that a good candidate for a solar absorber should have high solar absorptivity and low thermal emissivity simultaneously for efficient solar thermal collection. Various materials, including multilayer metal/ceramic films (5, 6), photonic crystals (7, 8), and metamaterials (9, 10), have been developed for spectrally selective solar absorbers and have been used for real-world applications. Meanwhile, radiative cooling (RC) has re-elicited considerable interest in recent years because it can passively provide clean cooling without any extra energy input (11–14). The waste heat of terrestrial objects can be continuously pumped into the cold outer space, relying on the transparent atmospheric window (i.e., 8 to 13 μm). So, high emissivity within the atmospheric window of materials is necessary for efficient RC, and excellent solar reflection is also important for RC under sunshine. Thus, different materials with the tailored spectrum, such as photonic structures (15–17), structure materials (18), energy-saving paints (19–21), and even metamaterials (22–24), have been reported for passive cooling. On the potential application level, RC implementations also span a range of fields, including passive cooling of buildings (25–27), thermal management of textiles and color surfaces (28–30), atmospheric water harvesting (31), and thermoelectric generation (32, 33). Although the reported PT and RC can generate heat and cold with high efficiency through different spectrally selective materials, most of the approaches are static and monofunctional, which can only provide heating or cooling under sunlight or darkness. Therefore, the dynamical integration of PT and RC for continuously efficient heat and cool harvesting is a new topic for the energy exploitation of the sun and outer space. The tunable combination of PT and RC hybrid utilization has been recently proposed, but mechanical methods such as switching (e.g., flip action) a PT absorber and an RC emitter manually (34) or changing the optical properties of the materials through extra force stimuli (35) are preferred.Herein, a smart strategy for the dynamic combination of daytime PT and nighttime RC is proposed, corresponding to continuously efficient energy harvesting from the sun and rejecting energy to the universe. A spectrally self-adaptive absorber/emitter (SSA/E) with solar absorption of over 0.8 and emissivity modulation capability of regulating from broadband emissivity of 0.25 within the mid-infrared (MIR) region to the selective high emissivity of 0.75 within the atmospheric window is designed and fabricated for the proof of the concept. Outdoor thermal experimental results demonstrate that the SSA/E can be heated to ∼170 °C above ambient temperature in the daytime PT mode and passively cooled to ∼20 °C below ambient temperature in the nighttime RC mode. Moreover, the heat and cool energy gains of the SSA/E system are respectively predicted to be 78% and 103% larger than those of the reference system that combines static and monofunctional PT absorber and RC emitter.     

The acquisition of cold sensitivity during TRPM8 ion channel evolution

To cope with temperature fluctuations, molecular thermosensors in animals play a pivotal role in accurately sensing ambient temperature. Transient receptor potential melastatin 8 (TRPM8) is the most established cold sensor. In order to understand how the evolutionary forces bestowed TRPM8 with cold sensitivity, insights into both emergence of cold sensing during evolution and the thermodynamic basis of cold activation are needed. Here, we show that the trpm8 gene evolved by forming and regulating two domains (MHR1-3 and pore domains), thus determining distinct cold-sensitive properties among vertebrate TRPM8 orthologs. The young trpm8 gene without function can be observed in the closest living relatives of tetrapods (lobe-finned fishes), while the mature MHR1-3 domain with independent cold sensitivity has formed in TRPM8s of amphibians and reptiles to enable channel activation by cold. Furthermore, positive selection in the TRPM8 pore domain that tuned the efficacy of cold activation appeared late among more advanced terrestrial tetrapods. Interestingly, the mature MHR1-3 domain is necessary for the regulatory mechanism of the pore domain in TRPM8 cold activation. Our results reveal the domain-based evolution for TRPM8 functions and suggest that the acquisition of cold sensitivity in TRPM8 facilitated terrestrial adaptation during the water-to-land transition.

Given that temperature influences all biological operations, the evolution of thermosensory adaptation is crucial in shaping the specialized temperature-dependent inhabitation of an organism. At the cellular level, thermosensory neurons in the dorsal root ganglia or trigeminal ganglia innervate the skin and transmit temperature information to the spinal cord and the brain. To bestow such neurons with thermal sensitivity, animals have a toolkit of temperature-sensitive ion channels located on the cell membrane at the molecular level. Accordingly, several members of the transient receptor potential (TRP) superfamily with steep thermosensitivity (referred to as thermoTRP) have attracted the general interest in the field of thermal biology, as they sufficiently cause steep changes in depolarizing currents upon either heating or cooling and thus are considered as the primary molecular sensors of temperature (1–4). Therefore, the evolutionary strategy for directly tuning the thermal activation in thermoTRPs can be employed by animals for their specialized thermosensory adaptation, as seen in vampire bats, pit-bearing snakes, platypus, penguins, squirrels, and camels (5–9).As heat sensation (warmth and extreme heat) provides the precondition of a fundamental and conserved biological survival process, the genes that encode heat sensors are considered ancient in many metazoan organisms. The annotation of trpv1 is consistently available in the genomes of fishes, insects, amphibians, reptiles, birds, and mammals. Despite the species-specific temperature-sensitive ranges, a growing number of studies have reported the functional convergence of these heat-sensitive thermoTRP orthologs at the protein level (10), suggesting the essential role of these channels in heat perception across species. Compared to heat sensors, the cold-sensitive thermoTRP likely evolved late. As the most established cold sensor responsive to low temperatures and cooling compounds, transient receptor potential melastatin 8 (TRPM8) was found in somatosensory neurons, and genetic ablation of trpm8 either in the neurons or mice led to a largely decreased cold sensitivity (4, 11–13). Interestingly, cold activation of amphibian TRPM8 has been tested (14), while sequencing efforts indicated the absence of the trpm8 gene in 12 fish species from 10 different orders (15). Several specific domains that may alter TRPM8 cold activation have been reported, including the pore domain, voltage sensing apparatus, and C terminus (8, 16–19). Notably, although the efficacy of cold activation is largely altered by residue substitutions in the pore domain, the channel mutants are still cold sensitive (8). Therefore, these findings based on domain/residue swapping among cold-sensitive TRPM8 orthologs may not draw an overall picture in functionally important domains responsible for cold sensitivity. How did the trpm8 gene originate? How did TRPM8 integrate and modulate cold sensitivity throughout evolution? The answers to such questions probably lead us to understand the evolution of temperature perception and identify the essential structural elements that shape TRPM8 cold activation.In this study, we show the presence of the young trpm8 gene in lobe-finned fishes, believed to be the ancestors that gave rise to all land vertebrates (20). Such a young type of trpm8 derived from the trpm2 exon shuffling was originated and formed during the expansion of lobe-finned fish genomes. By detecting the positive selection-rich domains, we described the formation of the thermosensitive MHR1-3 domain in amphibian and reptile species that enables TRPM8 to undergo conformational changes at low temperatures. Furthermore, we found that the TRPM8 pore domain of terrestrial vertebrates evolved to tune the efficacy of cold activation, in which a cold-sensitive MHR1-3 domain is indispensable to achieve such a modulatory mechanism. Together, our findings suggest that the trpm8 gene origination and formation of the TRPM8 MHR1-3 domain contributed to the transition of vertebrate life from water to land and that the efficacy of cold activation tuned by the TRPM8 pore domain diversified the setting of temperature-adaptive phenotypes in terrestrial vertebrates.     

Simultaneous quantification of apolipoproteins A-I,E, and J in human plasma by LC-MS/MS for clinical application to diabetes mellitus complicated with cardiovascular disease

Apolipoproteins (Apos) play an important role in regulating plasma lipid concentration. Complex disorders of Apos are highly related with diabetes mellitus, cardiovascular and other diseases. Direct measures of lipoprotein fractions for risk assessment suffer from inaccuracy in the dyslipidemia and pathological states. Therefore, a reliable precise assay will be of high clinical utility. LC-MS/MS methods with multiple reaction monitoring modes have proven suitable for multiplexed quantification. We aimed to develop a simple, cost-effective and amenable LC-MS/MS assay for quantification of ApoA-I, ApoE and ApoJ in human plasma. Standards were constructed from substitute matrix and proteotypic peptides for external calibration and corresponding stable isotope labeled peptides were added as internal standards to remove matrix effects. Analytical validation of the assay included the assessment of linearity, accuracy (RE: −3.02% to 5.32%), intra-assay precision (RSD: 2.50% to 6.56%), inter-assay precision (RSD: 0.78% to 6.68%), spiking recovery rate (accuracy: 87.17% to 112.71%), matrix effect (accuracy: 88.03% to 114.87%), and reproducibility and repeatability of sample preparation (RSD: 1.95% to 7.26%). The performance of proteotypic peptides ApoA-I, ApoE and ApoJ was sufficient for triplex quantitation within a linear range from 16.26 to 1626.41 pmol mL⁻¹, 1.03 to 103.35 pmol mL⁻¹ and 0.86 to 86.46 pmol mL⁻¹ respectively. For all quantified peptides, the determination coefficient (R²) was >0.997. Besides, the validated LC-MS/MS method has been successfully applied to the quantification of plasma samples in diabetes mellitus and cardiovascular diseases. We anticipate that this assay may provide an alternative method for future clinical applications.

Simultaneous quantification of apolipoproteins A-I, E, and J in human plasma by LC-MS/MS.     

Dromedary camel nanobodies broadly neutralize SARS-CoV-2 variants

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is a trimer of S1/S2 heterodimers with three receptor-binding domains (RBDs) at the S1 subunit for human angiotensin-converting enzyme 2 (hACE2). Due to their small size, nanobodies can recognize protein cavities that are not accessible to conventional antibodies. To isolate high-affinity nanobodies, large libraries with great diversity are highly desirable. Dromedary camels (Camelus dromedarius) are natural reservoirs of coronaviruses like Middle East respiratory syndrome CoV (MERS-CoV) that are transmitted to humans. Here, we built large dromedary camel V_HH phage libraries to isolate nanobodies that broadly neutralize SARS-CoV-2 variants. We isolated two V_HH nanobodies, NCI-CoV-7A3 (7A3) and NCI-CoV-8A2 (8A2), which have a high affinity for the RBD via targeting nonoverlapping epitopes and show broad neutralization activity against SARS-CoV-2 and its emerging variants of concern. Cryoelectron microscopy (cryo-EM) complex structures revealed that 8A2 binds the RBD in its up mode with a long CDR3 loop directly involved in the ACE2 binding residues and that 7A3 targets a deeply buried region that uniquely extends from the S1 subunit to the apex of the S2 subunit regardless of the conformational state of the RBD. At a dose of ≥5 mg/kg, 7A3 efficiently protected transgenic mice expressing hACE2 from the lethal challenge of variants B.1.351 or B.1.617.2, suggesting its therapeutic use against COVID-19 variants. The dromedary camel V_HH phage libraries could be helpful as a unique platform ready for quickly isolating potent nanobodies against future emerging viruses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of COVID-19 (1, 2) that enters human cells by binding its envelope anchored type I fusion protein (spike) to angiotensin-converting enzyme 2 (ACE2) (3, 4). The SARS-CoV-2 spike is a trimer of S1/S2 heterodimers with three ACE2 receptor-binding domains (RBDs) attached to the distal end of the spike via a hinge region that allows conformational flexibility (4). In the all-down conformation, the RBDs are packed with their long axes contained in a plane perpendicular to the axis of symmetry of the trimer. Transition to the roughly perpendicular up conformation exposes the receptor-binding motif (RBM), located at the distal end of the RBD, which is sterically occluded in the down state. Numerous neutralizing antibodies targeting the spike, particularly its RBD, have been developed to treat COVID-19 using common strategies such as single B cell cloning, animal immunization, and phage display (5–9). Most vaccines, including those that are messenger RNA based, are designed to induce immunity against the spike or RBD (10–12). However, emerging SARS-CoV-2 variants such as D614G, B.1.1.7 (Alpha, United Kingdom), B.1.351 (Beta, South Africa), and P.1 (Gamma, Brazil) have exhibited increased resistance to neutralization by monoclonal antibodies or postvaccination sera elicited by the COVID-19 vaccines (13, 14). Monoclonal antibodies with Emergency Use Authorization for COVID-19 treatment partially (Casirivimab) or completely (Bamlanivimab) failed to inhibit the B.1.351 and P.1 variants. Similarly, these variants were less effectively inhibited by convalescent plasma and sera from individuals vaccinated with a COVID-19 vaccine (BNT162b2) (13). The B.1.617.2 (Delta, India) variant became the prevailing strain in many countries (15). Highly effective and broadly neutralizing antibody therapy is urgently demanded for COVID-19 patients.Due to their small size and unique conformations, camelid V_HH single-domain antibodies (also known as nanobodies) can recognize protein cavities that are not accessible to conventional antibodies (16). To isolate high-affinity nanobodies without a need for further affinity maturation, it is highly desirable to construct large nanobody libraries with great diversity. Dromedary camels have been found as potential natural reservoirs of Middle East respiratory syndrome CoV (MERS-CoV) (17). We speculated that dromedary camels would be an ideal source of neutralizing nanobodies against coronaviruses. In the present study, we built large camel V_HH single-domain antibody phage libraries with a diversity of over 10¹¹ from six dromedary camels (Camelus dromedarius), three males and three females, with ages ranging from 3 mo to 20 y. We used both the SARS-CoV-2 RBD and the stabilized spike ectodomain trimer protein as baits to conduct phage panning for nanobody screening. Among all the binders, we found NCI-CoV-7A3 (7A3), NCI-CoV-1B5 (1B5), NCI-CoV-8A2 (8A2), and NCI-CoV-2F7 (2F7) to be potent ACE2 blockers. In addition, these dromedary camel nanobodies displayed potent neutralization activity against the B.1.351 and B.1.1.7 variants and the original strain (Wuhan-Hu-1). The cryoelectron microscopy (cryo-EM) structure of the spike trimer protein complex with these V_HH nanobodies revealed two distinct nonoverlapping epitopes for neutralizing SARS-CoV-2. In particular, 7A3 recognizes a unique and deeply buried region that extends to the apex of the S2 subunit of the spike. Combined treatment with 7A3 and 8A2 shows more potent protection against various variants in culture and mice infected with the B.1.351 variant. Interestingly, 7A3 alone retains its neutralization activity against the lethal challenge of the B.1.617.2 variant in mice.     

产妇宫缩痛的心理护理

我科2005年1月～2006年3月对62例产妇施行了预防宫缩痛的方法,其中20例20～25岁初产妇采用按摩法,30例26～30岁初产妇采用深吸气法,12例31～35岁经产妇采用转移注意力法.结果:减轻了产妇痛苦,保证其顺利分娩.心理护理十分重要,是目前减轻宫缩痛的一种较好方法,值得临床重视.